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  • 1.
    Agnvall, Beatrix
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Effects of Divergent Selection for Fear of Humans on Behaviour in Red Junglefowl2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, p. 1-12Article in journal (Refereed)
    Abstract [en]

    Domestication has caused a range of similar phenotypic changes across taxa, relating to physiology, morphology and behaviour. It has been suggested that this recurring domesticated phenotype may be a result of correlated responses to a central trait, namely increased tameness. We selected Red Junglefowl, the ancestors of domesticated chickens, during five generations for reduced fear of humans. This caused a marked and significant response in tameness, and previous studies have found correlated effects on growth, metabolism, reproduction, and some behaviour not directly selected for. Here, we report the results from a series of behavioural tests carried out on the initial parental generation (P0) and the fifth selected generation (S5), focusing on behaviour not functionally related to tameness, in order to study any correlated effects. Birds were tested for fear of humans, social reinstatement tendency, open field behaviour at two different ages, foraging/exploration, response to a simulated aerial predator attack and tonic immobility. In S5, there were no effects of selection on foraging/exploration or tonic immobility, while in the social reinstatement and open field tests there were significant interactions between selection and sex. In the aerial predator test, there were significant main effects of selection, indicating that fear of humans may represent a general wariness towards predators. In conclusion, we found only small correlated effects on behaviours not related to the tameness trait selected for, in spite of them showing high genetic correlations to fear of humans in a previous study on the same population. This suggests that species-specific behaviour is generally resilient to changes during domestication.

  • 2.
    Alkaissi, Hammoudi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Identification of candidate genes involved in Mercury Toxicokinetics and Mercury Induced Autoimmunity2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    BACKGROUND: Autoimmune diseases require the involvement and activation of immune cells and occur when the body builds up an immune response against its own tissues. This process takes place due to the inability to distinguish self-antigen from foreign antigen. Systemic autoimmunity represents an important cause of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Genome wide association study (GWAS) is a powerful method, used to identify genetic risk factors in numerous diseases, such as systemic autoimmune diseases. The goal of GWAS is to identify these genetic risk factors in order to make predictions about who is at risk and investigate the biological process of disease susceptibility. There are several valuable mouse models to investigate the underlying mechanisms causing systemic autoimmune diseases in which mercury induced autoimmunity (HgIA) is a well- established and relevant model. HgIA in mice includes development of autoantibodies, immune complex glomerulonephritis, lymphocyte proliferation, hypergammaglobulinemia and polyclonal B cell activation. In humans, mercury exposure accumulates with considerable concentrations in kidney, liver, and brain. Toxicokinetics of Hg has been studied extensively but the key for inter-individual variation in humans are largely unclear. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic inter-strain variation regulating retention or/and excretion of Hg.

    OBJECTIVES: To find loci and candidate genes associated with phenotypes involved in the development of autoimmunity and find candidate genes involved in the regulation of renal Hg excretion.

    METHODS: MHC II (H-2s) mice were paired (A.SW x B10.S) to obtain F2 offspring exposed to 2.0 or 4.0 mg Hg in drinking water for 6 weeks. Mercury induced autoimmune phenotypes were studied with immunofluorescence (anti-nucleolar antibodies (ANoA)), ELISA anti-DNP/anti-ssDNA (polyclonal B cell activation), anti-chromatin antibodies (ACA) (4.0 mg Hg), and serum IgG1 concentrations. Mercury accumulation in kidney was performed previously and data was included as phenotype. F2 mice exposed to 2.0 mg Hg were genotyped with microsatellites for genome-wide scan with Ion Pair Reverse Phase High Performance Liquid Chromatography (IP RP HPLC). F2 mice exposed to 4.0 mg Hg were genotyped with single nucleotide polymorphisms for genomewide scan with SNP&SEQ technology platform. Quantitative trait loci (QTL) was established with R/QTL. Denaturing HPLC, next generation sequencing, conserved region analysis and genetic mouse strain comparison were used for haplotyping and fine mapping on QTLs associated with Hg concentration in kidney, development of ANoA and serum IgG1 hypergammaglobulinemia. Candidate genes (Pprc1, Bank1 and Nfkb1) verified by additional QTL were further investigated by real time polymerase chain reaction. Genes involved in the intracellular signaling together with candidate genes were included for gene expression analysis.

    RESULTS: F2 mice exposed to 2.0 mg Hg had low or no development of autoantibodies and showed no significant difference in polyclonal B cell activation in the B10.S and F2 strains. F2 mice exposed to 4.0 mg Hg developed autoantibodies and significantly increased IgG1 concentration and polyclonal B cell activation (anti-DNP). QTL analysis showed a logarithm of odds ratio (LOD) score between 2.9 – 4.36 on all serological phenotypes exposed to 4.0 mg Hg, and a LOD score of 5.78 on renal Hg concentration. Haplotyping and fine mapping associated the development of ANoA with Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkb1 (nuclear factor kappa B subunit 1). The serum IgG1 concentration was associated with a locus on chromosome 3, in which Rxfp4 (Relaxin Family Peptide/INSL5 Receptor 4) is a potential candidate gene. The renal Hg concentration was associated with Pprc1 (Peroxisome Proliferator-Activated Receptor Gamma, Co-activator-Related). Gene expression analysis revealed that the more susceptible A.SW strain expresses significantly higher levels of Nfkb1, Il6 and Tnf than the less susceptible B10.S strain. The A.SW strain expresses significantly lower levels of Pprc1 and cascade proteins than the B10.S strain. Development of ACA was associated with chromosomes 3, 6, 7 and 16 (LOD 3.1, 3.2, 3.4 and 6.8 respectively). Polyclonal B cell activation was associated with chromosome 2 with a LOD score of 2.9.

    CONCLUSIONS: By implementing a GWAS on HgIA in mice, several QTLs were discovered to be associated with the development of autoantibodies, polyclonal B cell activation and hypergammaglobulinemia. This thesis plausibly supports Bank1 and Nfkb1 as key regulators for ANoA development and HgIA seems to be initiated by B cells rather than T cells. GWAS on renal mercury excretion plausibly supports Pprc1 as key regulator and it seems that this gene has a protective role against Hg.

    List of papers
    1. Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice
    Open this publication in new window or tab >>Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice
    Show others...
    2016 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 124, no 7, p. 920-926Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Following human mercury (Hg) exposure, the metal accumulates in considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg have been studied extensively, factors responsible for interindividual variation in humans are largely unknown. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic interstrain variation regulating retention or/and excretion of Hg. A. SW, DBA/2 and BALB/C mouse strains accumulate higher amounts of Hg than B10.S.

    OBJECTIVES: We aimed to find candidate genes associated with regulation of renal Hg concentrations.

    METHODS: A. SW, B10.S and their F1 and F2 offspring were exposed for 6 weeks to 2.0 mg Hg/L drinking water. Genotyping with microsatellites was conducted on 84 F2 mice for genome-wide scanning with ion pair reverse-phase high-performance liquid chromatography (IP RP HPLC). Quantitative trait loci (QTL) were established. Denaturing HPLC was used to detect single nucleotide polymorphisms for haplotyping and fine mapping in 184 and 32 F2 mice, respectively. Candidate genes (Pprc1, Btrc and Nfkb2) verified by fine mapping and QTL were further investigated by real-time polymerase chain reaction. Genes enhanced by Pprc1 (Nrf1 and Nrf2) were included for gene expression analysis.

    RESULTS: Renal Hg concentrations differed significantly between A. SW and B10. S mice and between males and females within each strain. QTL analysis showed a peak logarithm of odds ratio score 5.78 on chromosome 19 (p = 0.002). Haplotype and fine mapping associated the Hg accumulation with Pprc1, which encodes PGC-1-related coactivator (PRC), a coactivator for proteins involved in detoxification. Pprc1 and two genes coactivated by Pprc1 (Nrf1 and Nrf2) had significantly lower gene expression in the A. SW strain than in the B10. S strain.

    CONCLUSIONS: This study supports Pprc1 as a key regulator for renal Hg excretion.

    Place, publisher, year, edition, pages
    U.S. Department of Health and Human Services * National Institute of Environmental Health Sciences, 2016
    National Category
    Other Biological Topics
    Identifiers
    urn:nbn:se:liu:diva-131584 (URN)10.1289/ehp.1409284 (DOI)000380749300012 ()26942574 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council Branch of Medicine; County Council of Ostergotland; Linkoping University

    Available from: 2016-09-27 Created: 2016-09-27 Last updated: 2018-10-24Bibliographically approved
    2. Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development
    Open this publication in new window or tab >>Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development
    Show others...
    2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 7, article id e0199979Article in journal (Refereed) Published
    Abstract [en]

    Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg-exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkbl (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9,II6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, II6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkbl (produced in most immune cells) as key regulators of ANoA development in HgIA.

    Place, publisher, year, edition, pages
    PUBLIC LIBRARY SCIENCE, 2018
    National Category
    Genetics
    Identifiers
    urn:nbn:se:liu:diva-150265 (URN)10.1371/journal.pone.0199979 (DOI)000438866600014 ()30016332 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council Branch of Medicine; County Council of Ostergotland; Linkoping University

    Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-10-24
  • 3.
    Allan, Douglas W
    et al.
    Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115 USA.
    St Pierre, Susan E
    Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115 USA.
    Miguel-Aliaga, Irene
    Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115 USA.
    Thor, Stefan
    Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115 USA.
    Specification of Neuropeptide Cell Identity by the Integration of Retrograde BMP Signaling and a Combinatorial Transcription Factor Code2003In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 113, no 1, p. 73-86Article in journal (Refereed)
    Abstract [en]

    Individual neurons express only one or a few of the many identified neurotransmitters and neuropeptides, but the molecular mechanisms controlling their selection are poorly understood. In the Drosophila ventral nerve cord, the six Tv neurons express the neuropeptide gene FMRFamide. Each Tv neuron resides within a neuronal cell group specified by the LIM-homeodomain gene apterous. We find that the zinc-finger gene squeeze acts in Tv cells to promote their unique axon pathfinding to a peripheral target. There, the BMP ligand Glass bottom boat activates the Wishful thinking receptor, initiating a retrograde BMP signal in the Tv neuron. This signal acts together with apterous and squeeze to activate FMRFamide expression. Reconstituting this "code," by combined BMP activation and apterous/squeeze misexpression, triggers ectopic FMRFamide expression in peptidergic neurons. Thus, an intrinsic transcription factor code integrates with an extrinsic retrograde signal to select a specific neuropeptide identity within peptidergic cells.

  • 4.
    Alvarez-Rodriguez, Manuel
    University of Leon, Facultad de Ciencias Biologicas y Ambientales, Spain.
    Mejora y evolución de los protocolos de congelación de eyaculados de oso pardo (Ursus arctos)2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [es]

    La situación crítica del oso pardo (Ursus arctos) en España plantea la necesidad de aplicar diferentes estrategias de conservación, dentro de las cuales tiene especial relevancia la creación de un banco de recursos genéticos. La eficacia de esta herramienta depende, entre otros factores, de la adaptación específica de los protocolos de congelación espermática ya existentes y que permitan el almacenamiento eficaz de los espermatozoides del oso pardo en un banco de germoplasma. Este trabajo nos permite concluir la utilidad de la selección entre ciclos con el fin de mejorar la calidad de los espermatozoides sometidos a recongelación

  • 5.
    Alvarez-Rodriguez, Manuel
    et al.
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Alvarez, Mercedes
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Gomes-Alves, S
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Borragan, Santiago
    Cabárceno Park, Cantabria, Spain.
    Martinez-Pastor, Felipe
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, León, Spain.
    de Paz, Paulino
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, León, Spain.
    Anel, Luis
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Quality of frozen-thawed semen in brown bear is not affected by timing of glycerol addition.2011In: Theriogenology, ISSN 0093-691X, E-ISSN 1879-3231, Vol. 75, no 8, p. 1561-1565Article in journal (Refereed)
    Abstract [en]

    We have tested several freezing protocols for brown bear semen, modifying the time when glycerol was added (before and after cooling to 5 °C). No differences were found among protocols, indicating a good tolerance of brown bear semen to glycerol. This finding indicates that freezing protocols for brown bear semen could be modified to fit practical solutions which would facilitate preparation of the seminal samples in the field with the addition of glycerol at ambient temperature.

  • 6.
    Alvarez-Rodríguez, Manuel
    et al.
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Alvarez, Mercedes
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Anel-López, Luis
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Martínez-Rodríguez, Carmen
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, Campus de Vegazana, León Spain.
    Martínez-Pastor, Felipe
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, Campus de Vegazana, León Spain.
    Borragan, Santiago
    Cabárceno Park, Cantabria, Spain.
    Anel, Luis
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    de Paz, Paulino
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, Campus de Vegazana, León Spain.
    The antioxidant effects of soybean lecithin- or low-density lipoprotein-based extenders for the cryopreservation of brown-bear (Ursus arctos) spermatozoa.2013In: Reproduction, Fertility and Development, ISSN 1031-3613, E-ISSN 1448-5990, Vol. 25, no 8, p. 1185-1193Article in journal (Refereed)
    Abstract [en]

    Egg yolk low-density lipoproteins (LDL) and soybean lecithin were evaluated as replacements for egg yolk in extenders used for the cryopreservation of brown-bear spermatozoa. The motility, viability and acrosomal status of post-thawed spermatozoa were analysed, and an egg-yolk extender was used as a control. The total antioxidant capacity of these extenders was tested. Soybean lecithin showed an effect that was dependent on the soybean concentration (2%, 3.5% and 5%) and source (Type A: 24% L-α-phosphatidylcholine, and Type B: 14-23% L-α-phosphatidylcholine). Only semen cryopreserved with 5% Type A soybean exhibited a sperm motility similar to that of semen cryopreserved in egg-yolk-based extender after thawing, although the sperm viability and acrosome status were not as high. Semen frozen in an extender containing LDL (10-15%) exhibited improved sperm viability in comparison with the control, but sperm motility was lower. The LDL-based extender exhibited a higher anti-oxidant activity than the egg-yolk extender and soy lecithin-based extenders. The extenders with higher anti-oxidant activity showed improvements in frozen sperm viability but lower semen motility. These results indicate that soybean lecithin did not have the same protective effect as egg yolk during the freezing of brown-bear spermatozoa but suggest that LDL (10-15%) could be a useful substitute for egg yolk in these extenders.

  • 7.
    Alvarez-Rodríguez, Manuel
    et al.
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain .
    Alvarez, Mercedes
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Borragan, Santiago
    Cabárceno Park, Cantabria, Spain.
    Martinez-Pastor, Felipe
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, León, Spain .
    Holt, W V
    The Academic Unit of Reproductive and Developmental Medicine, University of Sheffield, Sheffield, UK.
    Fazeli, Alireza
    The Academic Unit of Reproductive and Developmental Medicine, University of Sheffield, Sheffield, UK.
    de Paz, Paulino
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, León, Spain .
    Anel, Luis
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    The addition of heat shock protein HSPA8 to cryoprotective media improves the survival of brown bear (Ursus arctos) spermatozoa during chilling and after cryopreservation.2013In: Theriogenology, ISSN 0093-691X, E-ISSN 1879-3231, Vol. 79, no 3, p. 541-550Article in journal (Refereed)
    Abstract [en]

    The Cantabrian brown bear survives as a small remnant population in northern Spain and semen cryopreservation for future artificial insemination is one of the measures being implemented for conservation of this species. As part of this program we investigated the value of adding heat shock protein A8 (HSPA8) to media (N-[Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid-TRIS-fructose with 20% egg yolk) used for chilling and cryopreserving the spermatozoa. Semen samples from eight brown bears were obtained by electroejaculation during the breeding season. In experiment 1, we tested three concentrations of HSPA8 (0.5, 1, and 5 μg/mL) to determine whether sperm motility (computer assisted sperm analysis system) and sperm survival could be improved during refrigeration (5 °C) up to 48 hours. Results showed that sperm viability (test with propidium iodide) was improved by the addition of 0.5 and 5 μg/mL HSPA8. In experiment 2, HSPA8 was added to the cryopreservation media (6% final glycerol concentration) before the freezing process. Though there were no differences in sperm viability immediately after thawing (analyses to 0 hours), plasma membrane permeability (test with YO-PRO-1) was significantly lower by the presence of HSPA8 (1 μg/mL) and acrosomal damage (test with peanut agglutinin-fluorescein isothiocyanate conjugate) was reduced by higher concentrations of HSPA8 (1 and 5 μg/mL) (analyses after thermal stress test incubating over 2 hours to 37 °C). In experiment 3, results of a simple progression test carried out through artificial mucus (hyaluronic acid 4 mg/mL) showed a significant decrease in the total number of sperm able to swim a distance of 0.5 to 2 cm through a capillary tube for all HSPA8-based extenders. Nevertheless, the distance traveled by the vanguard spermatozoa, which represent a highly motile subpopulation, was restored by the inclusion of 1 and 5 μg/mL HSPA8 in the cryopreservation media. Thus, the HSPA8 addition to extender improves the quality of brown bear (Ursus arctos) sperm during chilling (viability) and after cryopreservation (number of sperm with damaged acrosomes and "apoptotic-like" changes).

  • 8.
    Alvarez-Rodríguez, Manuel
    et al.
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Alvarez, Mercedes
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    López-Urueña, Elena
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Martínez-Rodriguez, Carmen
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, León, Spain.
    Borragan, Santiago
    Cabárceno Park, Cabárceno, Cantabria, Spain.
    Anel-López, Luis
    SaBio IREC (CSIC-UCLM-JCCM), Albacete, Spain.
    de Paz, Paulino
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, León, Spain.
    Anel, Luis
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Brown bear sperm double freezing: Effect of elapsed time and use of PureSperm(®) gradient between freeze-thaw cycles.2013In: Cryobiology, ISSN 0011-2240, E-ISSN 1090-2392, Vol. 67, no 3, p. 339-346Article in journal (Refereed)
    Abstract [en]

    The use of sexed spermatozoa has great potential to captive population management in endangered wildlife. The problem is that the sex-sorting facility is a long distance from the semen collection place and to overcome this difficulty two freeze-thaw cycles may be necessary. In this study, effects of refreezing on brown bear electroejaculated spermatozoa were analyzed. We carried out two experiments: (1) to assess the effects of the two freezing-thawing cycles on sperm quality and to analyze three different elapsed times between freezing-thawing cycles (30, 90 and 180 min), and (2) to analyze the use of PureSperm between freezing-thawing cycles to select a more motile and viable sperm subpopulation which better survived first freezing. The motility, viability and undamaged acrosomes were significantly reduced after the second thawing respect to first thawing into each elapsed time group, but the elapsed times did not significantly affect the viability and acrosome status although motility was damaged. Our results with the PureSperm gradient showed higher values of viability in freezability of select sample (pellet) respect to the rest of the groups and it also showed a significant decrease in the number of acrosome damaged. In summary, the double freezing of bear semen selected by gradient centrifugation is qualitatively efficient, and thus could be useful to carry out a sex-sorting of frozen-thawed bear spermatozoa before to send the cryopreserved sample to a biobank. Given the low recovery of spermatozoa after applying a selection gradient, further studies will be needed to increase the recovery rate without damaging of the cell quality.

  • 9.
    Anel-López, Luis
    et al.
    Biology of Reproduction Group. National Wildlife Research Institute (IREC) (UCLM-CSIC-JCCM), Albacete, Spain.
    Alvarez-Rodríguez, Manuel
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    García-Álvarez, Olga
    Biology of Reproduction Group. National Wildlife Research Institute (IREC) (UCLM-CSIC-JCCM), Albacete, Spain.
    Alvarez, Mercedes
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Maroto-Morales, Alejandro
    Biology of Reproduction Group. National Wildlife Research Institute (IREC) (UCLM-CSIC-JCCM), Albacete, Spain.
    Anel, Luis
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    de Paz, Paulino
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, León, Spain.
    Garde, J Julián
    Biology of Reproduction Group. National Wildlife Research Institute (IREC) (UCLM-CSIC-JCCM), Albacete, Spain.
    Martínez-Pastor, Felipe
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, León, Spain.
    Reduced glutathione and Trolox (vitamin E) as extender supplements in cryopreservation of red deer epididymal spermatozoa2012In: Animal Reproduction Science, ISSN 0378-4320, E-ISSN 1873-2232, Vol. 135, no 1-4, p. 37-46Article in journal (Refereed)
    Abstract [en]

    The use of assisted reproductive techniques in cervids is increasing as the commercial use of these species increase. We have tested the suitability of the antioxidants Trolox and reduced glutathione (GSH) for freezing red deer epididymal spermatozoa, aiming at improving post-thawing quality. Samples from 19 stags were frozen in a TES-Tris-fructose extender (20% egg yolk, 8% glycerol), with 1 or 5 mM of antioxidant. Motility (CASA), lipoperoxidation (malondialdehyde -MDA- production), membrane status, mitochondrial activity, acrosomal status (flow cytometry) and chromatin status (SCSA: %DFI and %HDS; flow cytometry) were assessed after thawing and after 6 h at 39°C. There were few differences between treatments after thawing, with Trolox reducing MDA production in a dose-response manner. After the incubation, sperm quality decreased and %DFI increased moderately, with no change for MDA. GSH improved motility, kinematic parameters and mitochondrial status, with a slight increase in %HDS. GSH 5 mM also increased moderately MDA production and %DFI, possibly due to enhanced metabolic activity and reducing power. Trolox maintained MDA low, but was detrimental to sperm quality. Trolox might not be appropriate for the cryopreservation of red deer epididymal spermatozoa, at least at the millimolar range. GSH results are promising, especially regarding motility improvement after the post-thawing incubation, and should be selected for future fertility trials.

  • 10.
    Bahrampour, Shahrzad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Genetic mechanisms regulating proliferation and cell specification in the Drosophila embryonic CNS2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The central nervous system (CNS) consists of an enormous number of cells, and large cellular variance, integrated into an elaborate network. The CNS is the most complex animal organ, and therefore its establishment must be controlled by many different genetic programs. Considering the high level of complexity in the human CNS, addressing issues related to human neurodevelopment represents a major challenge. Since comparative studies have revealed that neurodevelopmental programs are well conserved through evolution, on both the genetic and functional levels, studies on invertebrate neurodevelopmental programs are often translatable to vertebrates. Indeed, the basis of our current knowledge about vertebrate CNS development has been greatly aided by studies on invertebrates, and in particular on the Drosophila melanogaster (fruit fly) model system.

    This thesis attempted to identify novel genes regulating neural cell specification and proliferation in the CNS, using the Drosophila model system. Moreover, I aimed to address how those genes govern neural progenitor cells (neuroblasts; NBs) to obtain/maintain their stemness identity and proliferation capacity, and how they drive NBs through temporal windows and series of programmed asymmetric division, which gradually reduces their stemness identity in favor of neural differentiation, resulting in appropriate lineage progression. In the first project, we conducted a forward genetic screen in Drosophila embryos, aimed at isolating genes involved in regulation of neural proliferation and specification, at the single cell resolution. By taking advantage of the restricted expression of the neuropeptide FMRFa in the last-born cell of the NB lineage 5-6T, the Ap4 neuron, we could monitor the entire lineage progression. This screen succeeded in identifying 43 novel genes controlling different aspects of CNS development. One of the genes isolated, Ctr9, displayed extra Ap4/FMRFa neurons. Ctr9 encodes a component of the RNA polymerase II complex Paf1, which is involved in a number of transcriptional processes. The Paf1C, including Ctr9, is highly conserved from yeast to human, and in the past couple of years, its importance for transcription has become increasingly appreciated. However, studies in the Drosophila system have been limited. In the screen, we isolated the first mutant of Drosophila Ctr9 and conducted the first detailed phenotypic study on its function in the Drosophila embryonic CNS. Loss of function of Ctr9 leads to extra NB numbers, higher proliferation ratio and lower expression of neuropeptides. Gene expression analysis identified several other genes regulated by Ctr9, which may explain the Ctr9 mutant phenotypes. In summary, we identified Ctr9 as an essential gene for proper CNS development in Drosophila, and this provides a platform for future study on the Drosophila Paf1C. Another interesting gene isolated in the screen was worniou (wor), a member of the Snail family of transcription factors. In contrast to Ctr9, whichdisplayed additional Ap4/FMRFa neurons, wor mutants displayed a loss of these neurons. Previous studies in our group have identified many genes acting to stop NB lineage progression, but how NBs are pushed to proliferate and generate their lineages was not well known. Since wor may constitute a “driver” of proliferation, we decided to study it further. Also, we identified five other transcription factors acting together with Wor as pro-proliferative in both NBs and their daughter cells. These “drivers” are gradually replaced by the previously identified late-acting “stoppers.” Early and late factors regulate each other and the cell cycle, and thereby orchestrate proper neural lineage progression.

    List of papers
    1. Novel Genes Involved in Controlling Specification of Drosophila FMRFamide Neuropeptide Cells
    Open this publication in new window or tab >>Novel Genes Involved in Controlling Specification of Drosophila FMRFamide Neuropeptide Cells
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    2015 (English)In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 200, no 4, p. 1229-1244Article in journal (Refereed) Published
    Abstract [en]

    The expression of neuropeptides is often extremely restricted in the nervous system, making them powerful markers for addressing cell specification . In the developing Drosophila ventral nerve cord, only six cells, the Ap4 neurons, of some 10,000 neurons, express the neuropeptide FMRFamide (FMRFa). Each Ap4/FMRFa neuron is the last-born cell generated by an identifiable and well-studied progenitor cell, neuroblast 5-6 (NB5-6T). The restricted expression of FMRFa and the wealth of information regarding its gene regulation and Ap4 neuron specification makes FMRFa a valuable readout for addressing many aspects of neural development, i.e., spatial and temporal patterning cues, cell cycle control, cell specification, axon transport, and retrograde signaling. To this end, we have conducted a forward genetic screen utilizing an Ap4-specific FMRFa-eGFP transgenic reporter as our readout. A total of 9781 EMS-mutated chromosomes were screened for perturbations in FMRFa-eGFP expression, and 611 mutants were identified. Seventy-nine of the strongest mutants were mapped down to the affected gene by deficiency mapping or whole-genome sequencing. We isolated novel alleles for previously known FMRFa regulators, confirming the validity of the screen. In addition, we identified novel essential genes, including several with previously undefined functions in neural development. Our identification of genes affecting most major steps required for successful terminal differentiation of Ap4 neurons provides a comprehensive view of the genetic flow controlling the generation of highly unique neuronal cell types in the developing nervous system.

    Place, publisher, year, edition, pages
    Genetics Society of America, 2015
    Keywords
    Drosophila; CNS development; neural cell fate specification; forward genetic screening; FMRFamide
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-121318 (URN)10.1534/genetics.115.178483 (DOI)000359917000020 ()26092715 (PubMedID)
    Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2017-12-04Bibliographically approved
    2. Ctr9, a Key Component of the Paf1 Complex, Affects Proliferation and Terminal Differentiation in the Developing Drosophila Nervous System
    Open this publication in new window or tab >>Ctr9, a Key Component of the Paf1 Complex, Affects Proliferation and Terminal Differentiation in the Developing Drosophila Nervous System
    2016 (English)In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 6, no 10, p. 3229-3239Article in journal (Refereed) Published
    Abstract [en]

    The Paf1 protein complex (Paf1C) is increasingly recognized as a highly conserved and broadly utilized regulator of a variety of transcriptional processes. These include the promotion of H3K4 and H3K36 trimethylation, H2BK123 ubiquitination, RNA Pol II transcriptional termination, and also RNA-mediated gene silencing. Paf1C contains five canonical protein components, including Paf1 and Ctr9, which are critical for overall complex integrity, as well as Rtf1, Leo1, and Cdc73/Parafibromin(Hrpt2)/Hyrax. In spite of a growing appreciation for the importance of Paf1C from yeast and mammalian studies, there has only been limited work in Drosophila. Here, we provide the first detailed phenotypic study of Ctr9 function in Drosophila. We found that Ctr9 mutants die at late embryogenesis or early larval life, but can be partly rescued by nervous system reexpression of Ctr9. We observed a number of phenotypes in Ctr9 mutants, including increased neuroblast numbers, increased nervous system proliferation, as well as downregulation of many neuropeptide genes. Analysis of cell cycle and regulatory gene expression revealed upregulation of the E2f1 cell cycle factor, as well as changes in Antennapedia and Grainy head expression. We also found reduction of H3K4me3 modification in the embryonic nervous system. Genome-wide transcriptome analysis points to additional downstream genes that may underlie these Ctr9 phenotypes, revealing gene expression changes in Notch pathway target genes, cell cycle genes, and neuropeptide genes. In addition, we find significant effects on the gene expression of metabolic genes. These findings reveal that Ctr9 is an essential gene that is necessary at multiple stages of nervous system development, and provides a starting point for future studies of the Paf1C in Drosophila.

    Place, publisher, year, edition, pages
    Genetics Society of America, 2016
    Keywords
    neuroblast, lineage tree, cell cycle, epigenetics, terminal differentiation, FlyBook
    National Category
    Genetics
    Identifiers
    urn:nbn:se:liu:diva-132856 (URN)10.1534/g3.116.034231 (DOI)000386581200018 ()27520958 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [621-2013-5258]; Knut and Alice Wallenberg Foundation [KAW2011.0165]; Swedish Cancer Foundation [120531]; Swedish Royal Academy of Sciences

    Available from: 2016-12-06 Created: 2016-11-30 Last updated: 2017-11-29
    3. Neural Lineage Progression Controlled by a Temporal Proliferation Program.
    Open this publication in new window or tab >>Neural Lineage Progression Controlled by a Temporal Proliferation Program.
    Show others...
    2017 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 43, no 3, p. 332-348Article in journal (Refereed) Published
    Abstract [en]

    Great progress has been made in identifying transcriptional programs that establish stem cell identity. In contrast, we have limited insight into how these programs are down-graded in a timely manner to halt proliferation and allow for cellular differentiation. Drosophila embryonic neuroblasts undergo such a temporal progression, initially dividing to bud off daughters that divide once (type I), then switching to generating non-dividing daughters (type 0), and finally exiting the cell cycle. We identify six early transcription factors that drive neuroblast and type I daughter proliferation. Early factors are gradually replaced by three late factors, acting to trigger the type I→0 daughter proliferation switch and eventually to stop neuroblasts. Early and late factors regulate each other and four key cell-cycle genes, providing a logical genetic pathway for these transitions. The identification of this extensive driver-stopper temporal program controlling neuroblast lineage progression may have implications for studies in many other systems.less thanbr /greater than (Copyright © 2017 Elsevier Inc. All rights reserved.)

    Place, publisher, year, edition, pages
    Cell Press, 2017
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:liu:diva-143117 (URN)10.1016/j.devcel.2017.10.004 (DOI)000414584300011 ()29112852 (PubMedID)
    Note

    Funding agencies: Swedish Research Council [621-2013-5258]; Knut and Alice Wallenberg Foundation [KAW2011.0165, KAW2012.0101]; Swedish Cancer Foundation [140780, 150633]

    Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2017-11-20Bibliographically approved
  • 11.
    Bahrampour, Shahrzad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Gunnar, Erika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jönsson, Carolin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ekman, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Neural Lineage Progression Controlled by a Temporal Proliferation Program.2017In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 43, no 3, p. 332-348Article in journal (Refereed)
    Abstract [en]

    Great progress has been made in identifying transcriptional programs that establish stem cell identity. In contrast, we have limited insight into how these programs are down-graded in a timely manner to halt proliferation and allow for cellular differentiation. Drosophila embryonic neuroblasts undergo such a temporal progression, initially dividing to bud off daughters that divide once (type I), then switching to generating non-dividing daughters (type 0), and finally exiting the cell cycle. We identify six early transcription factors that drive neuroblast and type I daughter proliferation. Early factors are gradually replaced by three late factors, acting to trigger the type I→0 daughter proliferation switch and eventually to stop neuroblasts. Early and late factors regulate each other and four key cell-cycle genes, providing a logical genetic pathway for these transitions. The identification of this extensive driver-stopper temporal program controlling neuroblast lineage progression may have implications for studies in many other systems.less thanbr /greater than (Copyright © 2017 Elsevier Inc. All rights reserved.)

  • 12.
    Baumgardt, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Genetic mechanisms behind cell specification in the Drosophila CNS2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The human central nervous system (CNS) contains a daunting number of cells and tremendous cellular diversity. A fundamental challenge of developmental neurobiology is to address the questions of how so many different types of neurons and glia can be generated at the precise time and place, making precisely the right connections. Resolving this issue involves dissecting the elaborate genetic networks that act within neurons and glia, as well as in the neural progenitor cells that generates them, to specify their identities.

    My PhD project has involved addressing a number of unresolved issues pertaining to how neural progenitor cells are specified to generate different types of neurons and glial cells in different temporal and spatial domains, and also how these early temporal and spatial cues are integrated to activate late cell fate determinants, which act in post-mitotic neural cells to activate distinct batteries of terminal differentiation genes.

    Analyzing the development of a specific Drosophila melanogaster (Drosophila) CNS stem cell – the neuroblast 5-6 (NB5-6) – we have identified several novel mechanisms of cell fate specification in the Drosophila CNS. We find that, within this lineage, the differential specification of a group of sequentially generated neurons – the Ap cluster neurons – is critically dependent upon the simultaneous triggering of two opposing feed-forward loops (FFLs) within the neuroblast. The first FFL involves cell fate determinants and progresses within the post-mitotic neurons to establish a highly specific combinatorial code of regulators, which activates a distinct battery of terminal differentiation genes. The second loop, which progresses in the neuroblast, involves temporal and sub-temporal genes that together oppose the progression of the first FFL. This leads to the establishment of an alternative code of regulators in late-born Ap cluster neurons, whereby alternative cell fates are specified. Furthermore, we find that the generation and specification of the Ap cluster neurons is modulated along the neuraxis by two different mechanisms. In abdominal segments, Hox genes of the Bithorax cluster integrates with Pbx/Meis factors to instruct NB5-6 to leave the cell cycle before the Ap cluster neurons are generated. In brain segments, Ap cluster neuron equivalents are generated, but improperly specified due to the absence of the proper Hox and temporal code. Additionally, in thoracic segments we find that the specification of the Ap cluster neurons is critically dependent upon the integration of the Hox, Pbx/Meis, and the temporal genes, in the activation of the critical cell fate determinant FFL.

    We speculate that the developmental principles of (i) feed-forward combinatorial coding; (ii) simultaneously triggered yet opposing feed-forward loops; and (iii) integration of different Hox, Pbx/Meis, and temporal factors, at different axial levels to control inter-segmental differences in lineage progression and specification; might be used widely throughout the animal kingdom to generate cell type diversity in the CNS.

    List of papers
    1. Specification of neuronal identities by feedforward combinatorial coding.
    Open this publication in new window or tab >>Specification of neuronal identities by feedforward combinatorial coding.
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    2007 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 5, no 2, p. 0295-0308Article in journal (Refereed) Published
    Abstract [en]

    Neuronal specification is often seen as a multistep process: earlier regulators confer broad neuronal identity and are followed by combinatorial codes specifying neuronal properties unique to specific subtypes. However, it is still unclear whether early regulators are re-deployed in subtype-specific combinatorial codes, and whether early patterning events act to restrict the developmental potential of postmitotic cells. Here, we use the differential peptidergic fate of two lineage-related peptidergic neurons in the Drosophila ventral nerve cord to show how, in a feedforward mechanism, earlier determinants become critical players in later combinatorial codes. Amongst the progeny of neuroblast 5-6 are two peptidergic neurons: one expresses FMRFamide and the other one expresses Nplp1 and the dopamine receptor DopR. We show the HLH gene collier functions at three different levels to progressively restrict neuronal identity in the 5-6 lineage. At the final step, collier is the critical combinatorial factor that differentiates two partially overlapping combinatorial codes that define FMRFamide versus Nplp1/DopR identity. Misexpression experiments reveal that both codes can activate neuropeptide gene expression in vast numbers of neurons. Despite their partially overlapping composition, we find that the codes are remarkably specific, with each code activating only the proper neuropeptide gene. These results indicate that a limited number of regulators may constitute a potent combinatorial code that dictates unique neuronal cell fate, and that such codes show a surprising disregard for many global instructive cues.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-50010 (URN)10.1371/journal.pbio.0050037 (DOI)
    Note
    Original Publication: Magnus Baumgardt, Irene Miguel-Aliaga, Daniel Karlsson, Helen Ekman and Stefan Thor, Specification of neuronal identities by feedforward combinatorial coding., 2007, PLoS biology, (5), 2, e37. http://dx.doi.org/10.1371/journal.pbio.0050037 Licensee: PLoS Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12Bibliographically approved
    2. Neuronal Subtype Specification within a Lineage by Opposing Temporal Feed-Forward Loops
    Open this publication in new window or tab >>Neuronal Subtype Specification within a Lineage by Opposing Temporal Feed-Forward Loops
    Show others...
    2009 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 139, no 5, p. 969-982Article in journal (Refereed) Published
    Abstract [en]

    Neural progenitors generate distinct cell types at different stages, but the mechanisms controlling these temporal transitions are poorly understood. In the Drosophila CNS, a cascade of transcription factors, the ‘temporal gene cascade’, has been identified, that acts to alter progenitor competence over time. However, many CNS lineages display broad temporal windows, and it is unclear how broad windows progress into sub-windows that generate unique cell types. We have addressed this issue in an identifiable Drosophila CNS lineage, and find that a broad castor temporal window is sub-divided by two different feed-forward loops, both of which are triggered by castor itself. The first loop acts to specify a unique cell fate, while the second loop suppresses the first loop, thereby allowing for the generation of alternate cell fates. This mechanism of temporal and ‘sub-temporal’ genes acting in opposing feed-forward loops may be used by many stem cell lineages to generate diversity.

    Place, publisher, year, edition, pages
    Cambridge,MA, USA: Cell Press, 2009
    Keywords
    neural progenitor, temporal transitions, feed-forward loops, combinatorial codes, cell fate specification
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:liu:diva-51638 (URN)10.1016/j.cell.2009.10.032 (DOI)000272169400020 ()
    Note

    Original Publication: Magnus Baumgardt, Daniel Karlsson, Javier Terriente, Fernando J. Díaz-Benjumea and Stefan Thor, Neuronal Subtype Specification within a Lineage by Opposing Temporal Feed-Forward Loops, 2009, Cell, (139), 5, 969-982. http://dx.doi.org/10.1016/j.cell.2009.10.032 Copyright: Elsevier Science B.V., Amsterdam. http://www.cell.com/cellpress

    Available from: 2009-11-11 Created: 2009-11-11 Last updated: 2017-12-12Bibliographically approved
    3. Segment-specific Neuronal Sub-type Specification by the Integration of Anteroposterior and Temporal Cues
    Open this publication in new window or tab >>Segment-specific Neuronal Sub-type Specification by the Integration of Anteroposterior and Temporal Cues
    2010 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 8, no 5Article in journal (Refereed) Published
    Abstract [en]

    The generation of distinct neuronal sub-types at different axial levels relies upon both anteroposterior and temporal cues. However, the integration between these cues is poorly understood. In the Drosophila CNS, the segmentally repeated neuroblast 5-6 generates a unique group of neurons, the Apterous cluster, only in thoracic segments. Recent studies have identified elaborate genetic pathways acting to control the generation of these neurons. These insights, combined with novel markers, provide a unique opportunity for addressing how anteroposterior and temporal cues are integrated to generate segment-specific neuronal sub-types. We find that Pbx/Meis, Hox and temporal genes act in three different ways. Posteriorly, Pbx/Meis and posterior Hox genes block lineage progression within an early temporal window, by triggering cell cycle exit. Because Ap neurons are generated late in the thoracic 5-6 lineage, this prevents generation of Ap cluster cells in the abdomen. Thoracically, Pbx/Meis and anterior Hox genes integrate with late temporal genes to specify Ap clusters, via activation of a specific feed-forward loop. In brain segments, ‘Ap cluster cells’ are present but lack both proper Hox and temporal coding. Only by simultaneously altering Hox and temporal gene activity in all segments can Ap clusters be generated throughout the neuroaxis. This study provides the first detailed analysis of an identified neuroblast lineage along the entire neuroaxis, and provides novel insight into how Hox/Pbx/Meis anteroposterior cues are integrated with temporal cues. It reveals a surprisingly restricted yet multifaceted function of the anteroposterior cues with respect to lineage control and cell fate specification.

    Keywords
    anteroposterior patterning, temporal transitions, Hox, Pbx/Meis, cell specification
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:liu:diva-51641 (URN)10.1371/journal.pbio.1000368 (DOI)000278759600005 ()
    Note
    Original Publication: Daniel Karlsson, Magnus Baumgardt and Stefan Thor, Segment-specific Neuronal Sub-type Specification by the Integration of Anteroposterior and Temporal Cues, 2010, PLoS biology, (8), 5. http://dx.doi.org/10.1371/journal.pbio.1000368 Licensee: Public Library of Science http://www.plos.org/ Available from: 2009-11-11 Created: 2009-11-11 Last updated: 2017-12-12Bibliographically approved
    4. A genetic cascade involving the genes klumfuss, nab and castor specifies the abdominal leucokinergic neurons in the Drosophila CNS
    Open this publication in new window or tab >>A genetic cascade involving the genes klumfuss, nab and castor specifies the abdominal leucokinergic neurons in the Drosophila CNS
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The genetic mechanisms underlying the specification of a large number of different cell fates starting from a limited group of progenitor cells are a major focus of investigations of central nervous system development. In Drosophila the identities of the different neuronal progenitor cells, the neuroblasts, are specified by a combination of spatial and temporal factors. But how each neuroblast gives rise to a specific repertoire of cell types via a precise programme is poorly understood. In this report we analyse the specification of a small set of peptidergic cells, the abdominal leucokinergic neurons. We identify the progenitors of these neurons, the temporal window in which they are specified, and the influence of the Notch signalling pathway on their specification. We also show that the products of the genes klumfuss, nab and castor play important roles in their specification via a genetic cascade.

    Keywords
    Drosophila, CNS development, neuronal fate specification, Leucokinin, ABLK
    National Category
    Developmental Biology
    Identifiers
    urn:nbn:se:liu:diva-51644 (URN)
    Available from: 2009-11-11 Created: 2009-11-11 Last updated: 2016-11-30Bibliographically approved
  • 13.
    Baumgardt, Magnus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Terriente, Javier
    Division of Developmental Neuroscience, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom.
    Díaz-Benjumea, Fernando J.
    Centro de Biología Molecular-Severo Ochoa/C.S.I.C., Universidad Autónoma-Cantoblanco, Madrid 28049, Spain.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Neuronal Subtype Specification within a Lineage by Opposing Temporal Feed-Forward Loops2009In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 139, no 5, p. 969-982Article in journal (Refereed)
    Abstract [en]

    Neural progenitors generate distinct cell types at different stages, but the mechanisms controlling these temporal transitions are poorly understood. In the Drosophila CNS, a cascade of transcription factors, the ‘temporal gene cascade’, has been identified, that acts to alter progenitor competence over time. However, many CNS lineages display broad temporal windows, and it is unclear how broad windows progress into sub-windows that generate unique cell types. We have addressed this issue in an identifiable Drosophila CNS lineage, and find that a broad castor temporal window is sub-divided by two different feed-forward loops, both of which are triggered by castor itself. The first loop acts to specify a unique cell fate, while the second loop suppresses the first loop, thereby allowing for the generation of alternate cell fates. This mechanism of temporal and ‘sub-temporal’ genes acting in opposing feed-forward loops may be used by many stem cell lineages to generate diversity.

  • 14.
    Benito-Sipos, Jonathan
    et al.
    Centro de Biología Molecular-Severo Ochoa, Universidad Autónoma de Madrid-C.S.I.C., Madrid, Spain.
    Estacio-Gómez, Alicia
    Centro de Biología Molecular-Severo Ochoa, Universidad Autónoma de Madrid-C.S.I.C., Madrid, Spain.
    Moris-Sanz, Marta
    Centro de Biología Molecular-Severo Ochoa, Universidad Autónoma de Madrid-C.S.I.C., Madrid, Spain.
    Baumgardt, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Díaz-Benjumea, Fernando J.
    Centro de Biología Molecular-Severo Ochoa, Universidad Autónoma de Madrid-C.S.I.C., Madrid, Spain.
    A genetic cascade involving the genes klumfuss, nab and castor specifies the abdominal leucokinergic neurons in the Drosophila CNSManuscript (preprint) (Other academic)
    Abstract [en]

    The genetic mechanisms underlying the specification of a large number of different cell fates starting from a limited group of progenitor cells are a major focus of investigations of central nervous system development. In Drosophila the identities of the different neuronal progenitor cells, the neuroblasts, are specified by a combination of spatial and temporal factors. But how each neuroblast gives rise to a specific repertoire of cell types via a precise programme is poorly understood. In this report we analyse the specification of a small set of peptidergic cells, the abdominal leucokinergic neurons. We identify the progenitors of these neurons, the temporal window in which they are specified, and the influence of the Notch signalling pathway on their specification. We also show that the products of the genes klumfuss, nab and castor play important roles in their specification via a genetic cascade.

  • 15.
    Bélteky, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Chicken domestication: Effects of tameness on brain gene expression and DNA methylation2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Domestication greatly increases phenotypic variation in a short time span, with selection for a single phenotype and a plethora of associated phenotypic changes as an outcome of the process. The domestication process influences the underlying genomic architecture of a species, and the success and speed of the process is likely influenced by it. The main aims of my thesis was to study how domestication affects the brain of chickens: specifically changes in morphology, gene expression, and DNA methylation. Differences in gene expression and DNA methylation between White Leghorn and Red Junglefowl chickens were mapped, and inheritance of these patterns were quantified, indicating a faithful transmission of breed-specific epigenetic markers. Selection on the behavioral trait fearfulness, generated high and low fearful lines of Red Junglefowl. Both the parental population and the fifth selected generation were used for the analyses in this thesis. One experiment studied morphological changes in the brain and other vital organs, and found that relative total brain size increased in high fearful birds, as a consequence of an increase in cerebral hemisphere size in high fearful birds and not in low fearful birds. Also, the relative heart, liver, spleen and testis size increased in high fearful birds, indicating correlated morphological changes with selection for fearfulness. Two additional experiments examined differential gene expression in the hypothalamus and the anterior cerebral hemisphere. The hypothalamus differed in expression of genes with reproductive and immunological functions, whilst the cerebral hemisphere differed in expression of genes related to social behaviors and neurological functions especially those upregulated in low fearful birds.  These results indicate the occurrence of tissue- and species-specific changes in gene expression as overlap with other domestication events were nearly nonexistent. A fourth experiment sought to associate the change in fear levels and gene expression differences with DNA methylation. Chromosomal regions with differential DNA methylation between high and low fearful birds were identified, and genes in these regions had annotated functions relevant to phenotypic differences between the selection lines. This thesis is the first to study the genetic alterations of domestication using the wild ancestor of an already domesticated species to repeat the domestication process selecting against fear of humans. The findings corroborate results from previous comparisons of wild and domestic animals, and further support the theory that rigorous selection for a behavioral trait can cause a cascade of genetic and epigenetic changes facilitating the domestication of a population.

    List of papers
    1. Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens
    Open this publication in new window or tab >>Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens
    Show others...
    2012 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, no 59Article in journal (Refereed) Published
    Abstract [en]

    Variations in gene expression, mediated by epigenetic mechanisms, may cause broad phenotypic effects in animals. However, it has been debated to what extent expression variation and epigenetic modifications, such as patterns of DNA methylation, are transferred across generations, and therefore it is uncertain what role epigenetic variation may play in adaptation. Here, we show that in Red Junglefowl, ancestor of domestic chickens, gene expression and methylation profiles in thalamus/hypothalamus differ substantially from that of a domesticated egg laying breed. Expression as well as methylation differences are largely maintained in the offspring, demonstrating reliable inheritance of epigenetic variation. Some of the inherited methylation differences are tissue-specific, and the differential methylation at specific loci are little changed after eight generations of intercrossing between Red Junglefowl and domesticated laying hens. There was an over-representation of differentially expressed and methylated genes in selective sweep regions associated with chicken domestication. Hence, our results show that epigenetic variation is inherited in chickens, and we suggest that selection of favourable epigenomes, either by selection of genotypes affecting epigenetic states, or by selection of methylation states which are inherited independently of sequence differences, may have been an important aspect of chicken domestication.

    Place, publisher, year, edition, pages
    BioMed Central, 2012
    Keywords
    Domestication, gene expression, tiling array, behaviour, methylation
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-70159 (URN)10.1186/1471-2164-13-59 (DOI)000301440800001 ()
    Note

    funding agencies|Swedish Research Council| 2008-14496-59340-36 |Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning| 221 2007 838 |

    Available from: 2011-08-22 Created: 2011-08-22 Last updated: 2017-12-08Bibliographically approved
    2. Domestication and tameness: brain geneexpression in red junglefowl selected for less fear of humans suggests effects on reproduction and immunology
    Open this publication in new window or tab >>Domestication and tameness: brain geneexpression in red junglefowl selected for less fear of humans suggests effects on reproduction and immunology
    Show others...
    2016 (English)In: Royal Society Open Science, E-ISSN 2054-5703, no 3, article id 160033Article in journal (Refereed) Published
    Abstract [en]

    The domestication of animals has generated a set of phenotypicmodifications, affecting behaviour, appearance, physiologyand reproduction, which are consistent across a range ofspecies. We hypothesized that some of these phenotypes couldhave evolved because of genetic correlation to tameness,an essential trait for successful domestication. Starting froman outbred population of red junglefowl, ancestor of alldomestic chickens, we selected birds for either high or lowfear of humans for five generations. Birds from the fifthselected generation (S5) showed a divergent pattern of growthand reproduction, where low fear chickens grew larger andproduced larger offspring. To examine underlying geneticmechanisms, we used microarrays to study gene expressionin thalamus/hypothalamus, a brain region involved in fearand stress, in both the parental generation and the S5. Whileparents of the selection lines did not show any differentiallyexpressed genes, there were a total of 33 genes with adjustedp-values below 0.1 in S5. These were mainly related to spermfunction,immunological functions, with only a few known tobe relevant to behaviour. Hence, five generations of divergentselection for fear of humans produced changes in hypothalamicgene expression profiles related to pathways associated withmale reproduction and to immunology. This may be linked to the effects seen on growth and size of offspring. These results support the hypothesis thatdomesticated phenotypes may evolve because of correlated effects related to reduced fear of humans.

    Place, publisher, year, edition, pages
    Royal Society Publishing, 2016
    Keywords
    artificial selection, gene expression, microarray, chicken, fearfulness
    National Category
    Ecology
    Identifiers
    urn:nbn:se:liu:diva-130501 (URN)10.1098/rsos.160033 (DOI)000384411000002 ()
    Note

    Funding agencies:  Research council Formas; Vetenskapsradet; ERC [322206]

    Available from: 2016-08-11 Created: 2016-08-11 Last updated: 2017-11-28
  • 16.
    Castells-Nobau, Anna
    et al.
    Radboud University of Nijmegen, Netherlands.
    Nijhof, Bonnie
    Radboud University of Nijmegen, Netherlands.
    Eidhof, Ilse
    Radboud University of Nijmegen, Netherlands.
    Wolf, Louis
    Radboud University of Nijmegen, Netherlands.
    Scheffer-de Gooyert, Jolanda M.
    Radboud University of Nijmegen, Netherlands.
    Monedero Cobeta, Ignacio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. University of Autonoma Madrid, Spain.
    Torroja, Laura
    University of Autonoma Madrid, Spain.
    van der Laak, Jeroen A. W. M.
    Radboud University of Nijmegen, Netherlands; Radboud University of Nijmegen, Netherlands.
    Schenck, Annette
    Radboud University of Nijmegen, Netherlands.
    Two Algorithms for High-throughput and Multi-parametric Quantification of Drosophila Neuromuscular Junction Morphology2017In: Journal of Visualized Experiments, ISSN 1940-087X, E-ISSN 1940-087X, no 123, article id e55395Article in journal (Refereed)
    Abstract [en]

    Synaptic morphology is tightly related to synaptic efficacy, and in many cases morphological synapse defects ultimately lead to synaptic malfunction. The Drosophila larval neuromuscular junction (NMJ), a well-established model for glutamatergic synapses, has been extensively studied for decades. Identification of mutations causing NMJ morphological defects revealed a repertoire of genes that regulate synapse development and function. Many of these were identified in large-scale studies that focused on qualitative approaches to detect morphological abnormalities of the Drosophila NMJ. A drawback of qualitative analyses is that many subtle players contributing to NMJ morphology likely remain unnoticed. Whereas quantitative analyses are required to detect the subtler morphological differences, such analyses are not yet commonly performed because they are laborious. This protocol describes in detail two image analysis algorithms Drosophila NMJ Morphometrics and Drosophila NMJ Bouton Morphometrics, available as Fiji-compatible macros, for quantitative, accurate and objective morphometric analysis of the Drosophila NMJ. This methodology is developed to analyze NMJ terminals immunolabeled with the commonly used markers Dlg-1 and Brp. Additionally, its wider application to other markers such as Hrp, Csp and Syt is presented in this protocol. The macros are able to assess nine morphological NMJ features: NMJ area, NMJ perimeter, number of boutons, NMJ length, NMJ longest branch length, number of islands, number of branches, number of branching points and number of active zones in the NMJ terminal.

  • 17.
    de Paz, Paulino
    et al.
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology, University of León, León, Spain.
    Alvarez-Rodriguez, Manuel
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León.
    Nicolas, Manuel Aguilar
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León.
    Alvarez, Mercedes
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León.
    Chamorro, Ca
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León.
    Borragán, Santiago
    Cabárceno Park, Cantabria, Spain.
    Martinez-Pastor, Felipe
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology, University of León, León, Spain.
    Anel, Luis
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León.
    Optimization of glycerol concentration and freezing rate in the cryopreservation of ejaculate from brown bear (Ursus arctos).2012In: Reproduction in domestic animals, ISSN 0936-6768, E-ISSN 1439-0531, Vol. 47, no 1, p. 105-112Article in journal (Refereed)
    Abstract [en]

    In order to establish a semen bank for the endangered Cantabrian brown bear, we tested five glycerol concentrations and three freezing rates for electroejaculated semen. Electroejaculation was performed on nine males. Semen was diluted in TES-Tris-Fructose (20% egg yolk, 2% EDTA, 1% Equex) with 2%, 4%, 6%, 8% or 10% glycerol and frozen at -10, -20 or -40°C/min. Before and after cryopreservation, samples were analysed for motility (CASA), viability and acrosomal status (flow cytometry). Pre-freezing results showed that glycerol concentration had no significant effect on total motility or progressive motility, but it significantly decreased VCL, ALH, viability and acrosomal status (p < 0.05). After thawing, sperm motility was higher at extender with 4%, 6% and 8% glycerol, but only at 4% and 6% glycerol for viability and acrosomal status. For 4% and 6% glycerol, freezing rates did not have significant effects. The curve fitting gave an estimate of the optimal glycerol concentration, with all the optimal values for every parameter between 6% and 7% glycerol falling. We propose using 6% glycerol and a freezing velocity of -20°C/min for freezing brown bear ejaculated spermatozoa.

  • 18.
    de Paz, Paulino
    et al.
    Department of Molecular Biology, University of León, León, Spain.
    Mata-Campuzano, María
    Department of Molecular Biology, University of León, León, Spain.
    Tizado, Emilio Jorge
    Department of Biodiversity and Environmental Management, University of León, León, Spain.
    Alvarez, Mercedes
    Department of Veterinary Medicine, Anatomy and Surgery, University of León, León, Spain.
    Alvarez-Rodríguez, Manuel
    Department of Veterinary Medicine, Anatomy and Surgery, University of León, León, Spain.
    Herraez, Paz
    Department of Molecular Biology, University of León, León, Spain.
    Anel, Luis
    Department of Veterinary Medicine, Anatomy and Surgery, University of León, León, Spain.
    The relationship between ram sperm head morphometry and fertility depends on the procedures of acquisition and analysis used.2011In: Theriogenology, ISSN 0093-691X, E-ISSN 1879-3231, Vol. 76, no 7, p. 1313-1325Article in journal (Refereed)
    Abstract [en]

    Sperm head morphometry is a parameter in the evaluation of semen that has been associated with fertility in two ways: comparing morphometric measures between predefined groups of fertility; or analyzing morphometric data by multivariate techniques to identify cell populations. We analyzed the morphometry of ram sperm head by three procedures and checked its relationship with male fertility. A Computer-Aided Sperm Morphometric Assessment procedure (CASMA), an image analysis software (NIS-Elements) in combination with an optical microscope (MO-NIS) and this image analysis software in combination with a scanning electron microscope (SEM-NIS) were used. Eight morphometric parameters were assessed: length, width, area, perimeter, ellipticity, form factor, elongation and regularity. We observed significant differences between the morphometric data of sperm head obtained with three study procedures. The CASMA procedure shows the highest values for all parameters and the SEM-NIS procedure the lowest. The analysis of a semen sample, when only the mean of morphometric parameters is used to describe the cell population, is too limited to interpret their fertilizing capacity. It is essential to analyze the complex structure of the samples by defining subpopulations by multivariate methods. With few exceptions, the means of each morphometric parameter differ between the three subpopulations analyzed in each procedure. Only the subpopulations obtained with the MO-NIS procedure showed a significant correlation with male fertility. In short, it is necessary to establish an instrumental standard for the analysis of sperm morphometry to obtain reliable results and we believe that the MO-NIS system presents these basic requirements.

  • 19.
    Ericsson, Maria
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Henriksen, Rie
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Bélteky, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Sundman, Ann-Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Shionoya, Kiseko
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Long-Term and Transgenerational Effects of Stress Experienced during Different Life Phases in Chickens (Gallus gallus)2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0153879Article in journal (Refereed)
    Abstract [en]

    Stress in animals causes not only immediate reactions, but may affect their biology for long periods, even across generations. Particular interest has been paid to perinatal stress, but also adolescence has been shown to be a sensitive period in mammals. So far, no systematic study has been performed of the relative importance of stress encountered during different life phases. In this study, groups of chickens were exposed to a six-day period of repeated stress during three different life phases: early (two weeks), early puberty (eight weeks) and late puberty (17 weeks), and the effects were compared to an unstressed control group. The short-term effects were assessed by behaviour, and the long-term and transgenerational effects were determined by effects on behavior and corticosterone secretion, as well as on hypothalamic gene expression. Short-term effects were strongest in the two week group and the eight week group, whereas long-term and transgenerational effects were detected in all three stress groups. However, stress at different ages affected different aspects of the biology of the chickens, and it was not possible to determine a particularly sensitive life phase. The results show that stress during puberty appears to be at least equally critical as the previously studied early life phase. These findings may have important implications for animal welfare in egg production, since laying hens are often exposed to stress during the three periods pinpointed here.

  • 20.
    Fallahshahroudi, Amir
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Domestication Effects on the Stress Response in Chickens: Genetics, Physiology, and Behaviour2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Animal domestication, the process where animals become adapted to living in proximity to humans, is associated with the alteration of multiple traits, including decreased fearfulness and stress response. With an estimated population of 50 billion, the domesticated chicken is the most populous avian species in the world. Hundreds of chicken breeds have been developed for meat and egg production, hobby or research purposes. Multidirectional selection and the relaxation of natural selection in captivity have created immense phenotypic diversity amongst domesticates in a relatively short evolutionary time. The extensive phenotypic diversity, existence of the wild ancestor, and feasibility of intercrossing various breeds makes the chicken a suitable model animal for deciphering genetic determinants of complex traits such as stress response. We used chicken domestication as a model to gain insights about the mechanisms that regulate stress response in an avian species. We studied behavioural and physiological stress response in the ancestral Red Junglefowl and one of its domesticated progenies, White Leghorn. An advanced intercross between the aforementioned breeds was later used to map genetic loci underlying modification of stress response. The general pattern of the stress response in chickens was comparable with that reported in mammals, however we identified distinctive differences in the stress modulatory pathways in chickens. We showed that changes in the expression levels of several stress modulatory genes in the brain, the pituitary and the adrenal glands underlie the observed modified stress response in domesticated chickens. Using quantitative trait loci (QTL) mapping, several QTL underlying stress induced corticosterone, aldosterone and baseline dehydroepiandrosterone (DHEA) levels were detected. As a next step, we combined QTL mapping with gene expression (eQTL) mapping and narrowed two QTL down to the putative causal genes, SERPINA10 and PDE1C. Both of these genes were differentially expressed in the adrenal glands of White Leghorn and the Red Junglefowl, had overlapping eQTL with hormonal QTL, and their expression levels in the adrenal glands were correlated with plasma levels of corticosterone and al-dosterone. These two genes thus serve as strong candidates for further functional investigation concerning modification of the stress response during domestication. This dissertation increase the knowledge about genetics and physiology of the stress response in an avian species and its modification during domestication. Our findings expand the basic knowledge about the stress response in chicken, which can potentially be used to improve welfare through appropriate genetic selection.

    List of papers
    1. Domestication effects on behavioural and hormonal responses to acute stress in chickens
    Open this publication in new window or tab >>Domestication effects on behavioural and hormonal responses to acute stress in chickens
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    2014 (English)In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 133, p. 161-169Article in journal (Refereed) Published
    Abstract [en]

    Comparative studies have shown that alterations in physiology, morphology and behaviour have arisen due tothe domestication. A driving factor behind many of the changes could be a shift in stress responses,withmodifiedendocrine and behavioural profiles. In the present study we compared two breeds of chicken (Gallus gallus), thedomesticWhite Leghorn (WL) egg laying breed and its ancestor, the Red Junglefowl (RJF). Birds were exposed toan acute stress event, invoked by 3 or 10 min of physical restraint. Theywere then continuouslymonitored for theeffects on a wide range of behaviours during a 60 min recovery phase. Blood samples were collected from thechicken at baseline, and after 10 and 60 min following a similar restraint stress, and the samples wereanalyzed for nine endogenous steroids of the HPA and HPG axes. Concentration of the steroids was determinedusing validated liquid chromatography tandem mass spectrometry methods. In RJF, an immediate behaviouralresponse was observed after release from restraint in several behaviours, with a relatively fast return to baselinewithin 1 h. In WL, somebehaviourswere affected for a longer period of time, and others not at all. Concentrationsof corticosterone increasedmore in RJF, but returned faster to baseline compared toWL. A range of baseline levelsfor HPG-related steroids differed between the breeds, and they were generally more affected by the stress in WLthan in RJF. In conclusion, RJF reacted stronger both behaviourally and physiologically to the restraint stress, butalso recovered faster. This would appear to be adaptive under natural conditions, whereas the stress recovery ofdomesticated birds has been altered by domestication and breeding for increased reproductive output.

    Place, publisher, year, edition, pages
    Elsevier, 2014
    Keywords
    Corticosterone Recovery Restraint White Leghorn Red Junglefowl
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-107167 (URN)10.1016/j.physbeh.2014.05.024 (DOI)000340315100022 ()
    Note

    Funders: Swedish Research Council (VR) [621-2011-4731]; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) [221-2011-1088]; ERC (project Genewell) [322206]; Swedish Centre of Excellence in Animal Welfare; ARUP Institute for Clinical and Experimental Pathology

    Available from: 2014-06-09 Created: 2014-06-09 Last updated: 2017-12-05
    2. Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens
    Open this publication in new window or tab >>Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens
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    2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 1-10, article id 15345Article in journal (Refereed) Published
    Abstract [en]

    Understanding the genetic basis of phenotypic diversity is a challenge in contemporary biology. Domestication provides a model for unravelling aspects of the genetic basis of stress sensitivity. The ancestral Red Junglefowl (RJF) exhibits greater fear-related behaviour and a more pronounced HPA-axis reactivity than its domesticated counterpart, the White Leghorn (WL). By comparing hormones (plasmatic) and adrenal global gene transcription profiles between WL and RJF in response to an acute stress event, we investigated the molecular basis for the altered physiological stress responsiveness in domesticated chickens. Basal levels of pregnenolone and dehydroepiandrosterone as well as corticosterone response were lower in WL. Microarray analysis of gene expression in adrenal glands showed a significant breed effect in a large number of transcripts with over-representation of genes in the channel activity pathway. The expression of the best-known steroidogenesis genes were similar across the breeds used. Transcription levels of acute stress response genes such as StAR, CH25 and POMC were upregulated in response to acute stress. Dampened HPA reactivity in domesticated chickens was associated with changes in the expression of several genes that presents potentially minor regulatory effects rather than by means of change in expression of critical steroidogenic genes in the adrenal.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2015
    National Category
    Bioinformatics and Systems Biology
    Identifiers
    urn:nbn:se:liu:diva-122305 (URN)10.1038/srep15345 (DOI)000362885300001 ()26471470 (PubMedID)
    Note

    Funding agencies: Swedish Research Council (VR) [621-2011-4731]; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) [221-2011-1088]; SRC [621-2011-5523]; ERC [322206]; Swedish Centre of Excellence in Animal Welfare

    Available from: 2015-10-28 Created: 2015-10-28 Last updated: 2017-12-01
    3. Genetic and Targeted eQTL Mapping Reveals Strong Candidate Genes Modulating the Stress Response During Chicken Domestication.
    Open this publication in new window or tab >>Genetic and Targeted eQTL Mapping Reveals Strong Candidate Genes Modulating the Stress Response During Chicken Domestication.
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    2017 (English)In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 7, no 2Article in journal (Refereed) Published
    Abstract [en]

    The stress response has been largely modified in all domesticated animals, offering a strong tool for genetic mapping. In chickens, ancestral Red Junglefowl react stronger both in terms of physiology and behavior to a brief restraint stress than domesticated White Leghorn, demonstrating modified functions of the hypothalamic-pituitary-adrenal (HPA) axis. We mapped quantitative trait loci (QTL) underlying variations in stress-induced hormone levels using 232 birds from the 12th generation of an advanced intercross between White Leghorn and Red Junglefowl, genotyped for 739 genetic markers. Plasma levels of corticosterone, dehydroepiandrosterone (DHEA), and pregnenolone (PREG) were measured using LC-MS/MS in all genotyped birds. Transcription levels of the candidate genes were measured in the adrenal glands or hypothalamus of 88 out of the 232 birds used for hormone assessment. Genes were targeted for expression analysis when they were located in a hormone QTL region and were differentially expressed in the pure breed birds. One genome-wide significant QTL on chromosome 5 and two suggestive QTL together explained 20% of the variance in corticosterone response. Two significant QTL for aldosterone on chromosome 2 and 5 (explaining 19% of the variance), and one QTL for DHEA on chromosome 4 (explaining 5% of the variance), were detected. Orthologous DNA regions to the significant corticosterone QTL have been previously associated with the physiological stress response in other species but, to our knowledge, the underlying gene(s) have not been identified. SERPINA10 had an expression QTL (eQTL) colocalized with the corticosterone QTL on chromosome 5 and PDE1C had an eQTL colocalized with the aldosterone QTL on chromosome 2. Furthermore, in both cases, the expression levels of the genes were correlated with the plasma levels of the hormones. Hence, both these genes are strong putative candidates for the domestication-induced modifications of the stress response in chickens. Improved understanding of the genes associated with HPA-axis reactivity can provide insights into the pathways and mechanisms causing stress-related pathologies.

    Place, publisher, year, edition, pages
    The Genetics Society, 2017
    Keywords
    animal, domestication, quantitative trait, genes, corticosterone, aldosterone
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-134649 (URN)10.1534/g3.116.037721 (DOI)000394357100015 ()27974436 (PubMedID)
    Note

    Funding agencies: Swedish Research Council (SRC) (Vetenskapsradet) [621-2011-4731]; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Forskningsradet for Miljo, Areella Naringar och Samhallsbyggande) [221-2011-1088]; European Research Co

    Available from: 2017-02-21 Created: 2017-02-21 Last updated: 2017-11-29
    4. QTL mapping of stress related gene expression in a cross between domesticated chickens and ancestral red junglefowl.
    Open this publication in new window or tab >>QTL mapping of stress related gene expression in a cross between domesticated chickens and ancestral red junglefowl.
    Show others...
    2017 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 446, p. 52-58, article id S0303-7207(17)30090-4Article in journal (Refereed) Published
    Abstract [en]

    Domestication of animals is associated with numerous alterations in physiology, morphology, and behavior. Lower reactivity of the hypothalamic-pituitary-adrenal (HPA) axis and reduced fearfulness is seen in most studied domesticates, including chickens. Previously we have shown that the physiological stress response as well as expression levels of hundreds of genes in the hypothalamus and adrenal glands are different between domesticated White Leghorn and the progenitor of modern chickens, the Red Junglefowl. To map genetic loci associated with the transcription levels of genes involved in the physiological stress response, we conducted an eQTL analysis in the F12 generation of an inter-cross between White Leghorn and Red Junglefowl. We selected genes for further studies based on their known function in the regulation of the HPA axis or sympathoadrenal (SA) system, and measured their expression levels in the hypothalamus and the adrenal glands after a brief stress exposure (physical restraint). The expression values were treated as quantitative traits for the eQTL mapping. The plasma levels of corticosterone were also assessed. We analyzed the correlation between gene expression and corticosterone levels and mapped eQTL and their potential effects on corticosterone levels. The effects on gene transcription of a previously found QTL for corticosterone response were also investigated. The expression levels of the glucocorticoid receptor (GR) in the hypothalamus and several genes in the adrenal glands were correlated with the post-stress levels of corticosterone in plasma. We found several cis- and trans-acting eQTL for stress-related genes in both hypothalamus and adrenal. In the hypothalamus, one eQTL for c-FOS and one QTL for expression of GR were found. In the adrenal tissue, we identified eQTL for the genes NR0B1, RGS4, DBH, MAOA, GRIN1, GABRB2, GABRB3, and HSF1. None of the found eQTL were significant predictors of corticosterone levels. The previously found QTL for corticosterone was associated with GR expression in hypothalamus. Our data suggests that domestication related modification in the stress response is driven by changes in the transcription levels of several modulators of the HPA and SA systems in hypothalamus and adrenal glands and not by changes in the expression of the steroidogenic genes. The presence of eQTL for GR in hypothalamus combined with the negative correlation between GR expression and corticosterone response suggests GR as a candidate for further functional studies regarding modification of stress response during chicken domestication.

    Keywords
    Animal domestication, HPA axis, QTL, Stress response, eQTL
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-136027 (URN)10.1016/j.mce.2017.02.010 (DOI)000399509600006 ()28189567 (PubMedID)
    Note

    Funding agencies: Swedish Research Council (VR) [621-2011-4731]; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) [221-2011-1088]; ERC [Genewell 322206]; SRC grant [VR 621-2011-4423, 2015-4870]; Swedish Centre of Excellence in A

    Available from: 2017-03-27 Created: 2017-03-27 Last updated: 2018-09-27
  • 21.
    Franz, F
    et al.
    Clinic of Endocrinology and Nephrology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig, Leipzig, Germany.
    Weidinger, C
    Clinic of Endocrinology and Nephrology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig, Leipzig, Germany.
    Krause, K
    Clinic of Endocrinology and Nephrology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig, Leipzig, Germany.
    Gimm, Oliver
    Department of General, Visceral, and Vascular Surgery, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany.
    Dralle, H
    Department of General, Visceral, and Vascular Surgery, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany.
    Führer, D
    Department of Endocrinology & Metabolism and Division of Laboratory Research, University Hospital Essen, Essen, Germany.
    The Transcriptional Regulation of FOXO Genes in Thyrocytes.2016In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 48, no 9, p. 601-6Article in journal (Refereed)
    Abstract [en]

    FOXO transcription factors are key regulators of DNA damage repair, proliferation and apoptosis in thyrocytes. Thyroid malignancies show impaired FOXO function. In this study, we investigated the transcriptional regulation of FOXO isoforms in thyroid epithelial cells. mRNA expression of FOXO isoforms (FOXO1, 3 and 4) was determined in FRTL-5 cells stimulated with different growth factors and H2O2. Furthermore, the impact of PI3K/AKT signalling on FOXO transcription was investigated in PI3K p110α mutant FRTL-5 cells and regulatory dependence of FOXO transcription on FOXO was studied in FRTL-5 cells with hFOXO3 overexpression. Finally, mRNA expression levels of FOXO isoforms were determined in human epithelial thyroid tumours. Growth factor deprivation induced transcription of FOXO1, 3 and 4, whereas insulin stimulation decreased FOXO1 and FOXO4 transcription in FRTL-5 cells. Inhibition of the PI3K/AKT cascade amplified FOXO1 and FOXO4 expression. In contrast, H2O2 and TSH did not influence FOXO transcription in thyrocytes. Overexpression of PI3K p110α inhibited FOXO3 and induced FOXO4 transcription. In human thyroid tumours, FOXO1 and FOXO3 mRNA levels were significantly downregulated in papillary thyroid carcinoma when compared to normal tissues. In contrast, follicular thyroid carcinomas showed significant upregulation of FOXO4 mRNA.In this paper, we demonstrate an influence of PI3K signalling on FOXO transcription in thyrocytes. Moreover, we show that thyroid cancers exhibit alterations in FOXO transcription besides the previously reported alterations in posttranslational FOXO3 regulation. These findings may add to the concept of targeting the PI3K pathway in advanced thyroid cancers.

  • 22.
    Friberg, Urban
    et al.
    Animal Ecology, Department of Ecology and Evolution, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden / Department of Ecology and Environmental Science, Umeå University, Umeå , Sweden /Department of Ecology, Evolution and Marine Biology, University of California Santa Barbara, Santa Barbara, USA.
    Dowling, D.K.
    Animal Ecology, Department of Ecology and Evolution, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden.
    No evidence of mitochondrial genetic variation for sperm competition within a population of Drosophila melanogaster2008In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 21, no 6, p. 1798-1807Article in journal (Refereed)
    Abstract [en]

    Recent studies have advocated a role for mitochondrial DNA (mtDNA) in sperm competition. This is controversial because earlier theory and empirical work suggested that mitochondrial genetic variation for fitness is low. Yet, such studies dealt only with females and did not consider that variation that is neutral when expressed in females, might be non-neutral in males as, in most species, mtDNA is never selected in males. We measured male ability to compete for fertilizations, at young and late ages, across 25 cytoplasms expressed in three different nuclear genetic backgrounds, within a population of Drosophila melanogaster. We found no cytoplasmic (thus no mtDNA) genetic variation for either male offence or offensive sperm competitiveness. This contrasts with previous findings demonstrating cytoplasmic genetic variation for female fitness and female ageing across these same lines. Taken together, this suggests that mitochondrial genes do not contribute to variation in sperm competition at the within-population level.

  • 23.
    Gabilondo, Hugo
    et al.
    University of Autonoma Madrid, Spain.
    Stratmann, Johannes
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rubio-Ferrera, Irene
    University of Autonoma Madrid, Spain.
    Millan-Crespo, Irene
    University of Autonoma Madrid, Spain.
    Contero-Garcia, Patricia
    University of Autonoma Madrid, Spain.
    Bahrampour, Shahrzad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Benito-Sipos, Jonathan
    University of Autonoma Madrid, Spain.
    Neuronal Cell Fate Specification by the Convergence of Different Spatiotemporal Cues on a Common Terminal Selector Cascade2016In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 14, no 5, p. e1002450-Article in journal (Refereed)
    Abstract [en]

    Specification of the myriad of unique neuronal subtypes found in the nervous system depends upon spatiotemporal cues and terminal selector gene cascades, often acting in sequential combinatorial codes to determine final cell fate. However, a specific neuronal cell subtype can often be generated in different parts of the nervous system and at different stages, indicating that different spatiotemporal cues can converge on the same terminal selectors to thereby generate a similar cell fate. However, the regulatory mechanisms underlying such convergence are poorly understood. The Nplp1 neuropeptide neurons in the Drosophila ventral nerve cord can be subdivided into the thoracic-ventral Tv1 neurons and the dorsal-medial dAp neurons. The activation of Nplp1 in Tv1 and dAp neurons depends upon the same terminal selector cascade: colamp;gt;ap/eyaamp;gt;dimmamp;gt;Nplp1. However, Tv1 and dAp neurons are generated by different neural progenitors (neuroblasts) with different spatiotemporal appearance. Here, we find that the same terminal selector cascade is triggered by Kr/pdmamp;gt;grn in dAp neurons, but by Antp/hth/exd/lbe/cas in Tv1 neurons. Hence, two different spatiotemporal combinations can funnel into a common downstream terminal selector cascade to determine a highly related cell fate.

  • 24.
    Gunnar, Erika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Regulatory programs controlling profileration during Drosophila nervous system development2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The central nervous system (CNS) is the most complex organ in the body, responsible for complex functions, including thinking, reasoning and memory. The CNS contains cells of many different types, often generated in vast numbers. Hence, CNS development requires precise genetic control of both cell fate and of cell proliferation, to generate the right number of cells, with the proper identity, and in the proper location. The cells also need to make connections with each other for correct signaling and function. This complexity evokes the question of how this is regulated. How does the stem cells, responsible for building the CNS, know how many times to divide, and how does the daughters know which identity to acquire and in which location they shall end up? During Drosophila melanogaster development, the neuroblasts (NBs) are responsible for generating the CNS. In each hemisegment, every NB is unique in identity, and generates a predetermined number of daughters with specific identities. The lineages of different NBs vary in size, but are always the same for each specific NB, and the division modes of each NBs is hence stereotyped. Most NBs start dividing by renewing themselves while generating daughters that will in turn divide once to generate two neurons and/or glia (denoted type I mode). Many, maybe all, NBs later switch to generating daughters that will differentiate directly into a neuron or glia (denoted type 0 mode). This type I>0 switch occurs at different time-points during lineage progression, and influences the total numbers of cells generated from a single NB.

    The work presented in this thesis aimed at investigating the genetic regulation of proliferation, with particular focus on the type I>0 switch. In the first project, the implication of the Notch pathway on the type I>0 switch was studied. Mutants of the Notch pathway do not switch, and the results show that the Notch pathway regulates the switch by activation of several target genes, both regulators and cell cycle genes. One of the target genes, the E(spl)-C genes, have been difficult to study due to functional redundancy. This study reveals that even though they can functionally compensate for each other, they have individual functions in different lineages. Regarding cell cycle genes, both Notch and E(spl)-C regulate several key cell cycle genes, and molecular analysis indicated that this regulation is direct. In the second project we studied the seq gene, previously identified in a genetic screen. We found that seq controls the type I>0 switch by regulating the key cell cycle genes, but also through interplay with the Notch pathway. Notch and seq stop proliferation, and in the third project we wanted to identify genes that drive proliferation. We found that there is battery of early NB genes, socalled early factors, which activate the cell cycle, and drive NB and daughter proliferation. These are gradually replaced by late regulators, and the interplay between early and late factors acts to achieve precise control of lineage progression.

    The work presented here increases our understanding of how regulatory programs act to control the development of the CNS; to generate the right number of cells of different identities. These results demonstrate the importance of correct regulation of proliferation in both stem cells and daughters. Problems in this control can result in either an underdeveloped CNS or loss of control such as in cancer. Knowledge about these regulatory programs can contribute to the development of therapeutics against these diseases.

    List of papers
    1. Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling
    Open this publication in new window or tab >>Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling
    Show others...
    2016 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 4, article id e1005984Article in journal (Refereed) Published
    Abstract [en]

    The Notch pathway controls proliferation during development and in adulthood, and is frequently affected in many disorders. However, the genetic sensitivity and multi-layered transcriptional properties of the Notch pathway has made its molecular decoding challenging. Here, we address the complexity of Notch signaling with respect to proliferation, using the developing Drosophila CNS as model. We find that a Notch/Su(H)/E(spl)-HLH cascade specifically controls daughter, but not progenitor proliferation. Additionally, we find that different E(spl)-HLH genes are required in different neuroblast lineages. The Notch/Su(H)/E(spl)-HLH cascade alters daughter proliferation by regulating four key cell cycle factors: Cyclin E, String/Cdc25, E2f and Dacapo (mammalian p21(CIP1)/p27(KIP1)/p57(Kip2)). ChIP and DamID analysis of Su(H) and E(spl)-HLH indicates direct transcriptional regulation of the cell cycle genes, and of the Notch pathway itself. These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems.

    Place, publisher, year, edition, pages
    PUBLIC LIBRARY SCIENCE, 2016
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-128759 (URN)10.1371/journal.pgen.1005984 (DOI)000375231900032 ()27070787 (PubMedID)
    Note

    Funding Agencies|Knut and Alice Wallenberg Foundation [KAW2012.0101]; Swedish Research Council [621-2010-5214]; Swedish Cancer Foundation [120531]

    Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2017-11-30
    2. sequoia controls the type I>0 daughter proliferation switch in the developing Drosophila nervous system
    Open this publication in new window or tab >>sequoia controls the type I>0 daughter proliferation switch in the developing Drosophila nervous system
    2016 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 143, no 20, p. 3774-3784Article in journal (Refereed) Published
    Abstract [en]

    Neural progenitors typically divide asymmetrically to renew themselves, while producing daughters with more limited potential. In the Drosophila embryonic ventral nerve cord, neuroblasts initially produce daughters that divide once to generate two neurons/glia (type I proliferation mode). Subsequently, many neuroblasts switch to generating daughters that differentiate directly (type 0). This programmed type I&gt;0 switch is controlled by Notch signaling, triggered at a distinct point of lineage progression in each neuroblast. However, how Notch signaling onset is gated was unclear. We recently identified Sequoia (Seq), a C2H2 zinc-finger transcription factor with homology to Drosophila Tramtrack (Ttk) and the positive regulatory domain (PRDM) family, as important for lineage progression. Here, we find that seq mutants fail to execute the type I&gt;0 daughter proliferation switch and also display increased neuroblast proliferation. Genetic interaction studies reveal that seq interacts with the Notch pathway, and seq furthermore affects expression of a Notch pathway reporter. These findings suggest that seq may act as a context-dependent regulator of Notch signaling, and underscore the growing connection between Seq, Ttk, the PRDM family and Notch signaling.

    Place, publisher, year, edition, pages
    The Company of Biologists Ltd, 2016
    Keywords
    Lineage tree, Cell cycle, Asymmetric division, Combinatorial control, Notch
    National Category
    Cell and Molecular Biology Biochemistry and Molecular Biology Cell Biology Medical Biotechnology
    Identifiers
    urn:nbn:se:liu:diva-132739 (URN)10.1242/dev.139998 (DOI)000393452500013 ()27578794 (PubMedID)
    Note

    Funding agencies: Swedish Research Council (Vetenskapsradet); Knut and Alice Wallenberg Foundation (Knut och Alice Wallenbergs Stiftelse); Swedish Cancer Foundation (Cancerfonden)

    Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2018-01-13Bibliographically approved
  • 25.
    Helmfors, Linda
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bergkvist, Liza
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Serum Amyloid P Component Ameliorates Neurological Damage Caused by Expressing a Lysozyme Variant in the Central Nervous System of Drosophila melanogaster2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, p. e0159294-Article in journal (Refereed)
    Abstract [en]

    Lysozyme amyloidosis is a hereditary disease in which mutations in the gene coding for lysozyme leads to misfolding and consequently accumulation of amyloid material. To improve understanding of the processes involved we expressed human wild type (WT) lysozyme and the disease-associated variant F57I in the central nervous system (CNS) of a Drosophila melanogaster model of lysozyme amyloidosis, with and without co-expression of serum amyloid p component (SAP). SAP is known to be a universal constituent of amyloid deposits and to associate with lysozyme fibrils. There are clear indications that SAP may play an important role in lysozyme amyloidosis, which requires further elucidation. We found that flies expressing the amyloidogenic variant F57I in the CNS have a shorter lifespan than flies expressing WT lysozyme. We also identified apoptotic cells in the brains of F57I flies demonstrating that the flies neurological functions are impaired when F57I is expressed in the nerve cells. However, co-expression of SAP in the CNS prevented cell death and restored the F57I flies lifespan. Thus, SAP has the apparent ability to protect nerve cells from damage caused by F57I. Furthermore, it was found that co-expression of SAP prevented accumulation of insoluble forms of lysozyme in both WT- and F57I-expressing flies. Our findings suggest that the F57I mutation affects the aggregation process of lysozyme resulting in the formation of cytotoxic species and that SAP is able to prevent cell death in the F57I flies by preventing accumulation of toxic F57I structures.

  • 26.
    Hu, Yeguang
    et al.
    Harvard Medical Sch, MA 02129 USA.
    Zhang, Zhihong
    Harvard Medical Sch, MA 02129 USA.
    Kashiwagi, Mariko
    Harvard Medical Sch, MA 02129 USA.
    Yoshida, Toshimi
    Harvard Medical Sch, MA 02129 USA.
    Joshi, Ila
    Harvard Medical Sch, MA 02129 USA.
    Jena, Nilamani
    University of Calif Irvine, CA 92868 USA; University of Calif Irvine, CA 92868 USA.
    Somasundaram, Rajesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Olumide Emmanuel, Akinola
    University of Chicago, IL 60637 USA.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Fitamant, Julien
    Harvard Medical Sch, MA 02129 USA.
    El-Bardeesy, Nabeel
    Harvard Medical Sch, MA 02129 USA.
    Gounari, Fotini
    University of Chicago, IL 60637 USA.
    Van Etten, Richard A.
    University of Calif Irvine, CA 92868 USA; University of Calif Irvine, CA 92868 USA.
    Georgopoulos, Katia
    Harvard Medical Sch, MA 02129 USA.
    Superenhancer reprogramming drives a B-cell-epithelial transition and high-risk leukemia2016In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 30, no 17, p. 1971-1990Article in journal (Refereed)
    Abstract [en]

    IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors. IKAROS is also highly enriched at inactive enhancers of genes normally expressed in stem-epithelial cells. Upon IKAROS loss, expression of pre-B-cell differentiation genes is attenuated, while a group of extralineage transcription factors that are directly repressed by IKAROS and depend on EBF1 relocalization at their enhancers for expression is induced. LHX2, LMO2, and TEAD-YAP1, normally kept separate from native B-cell transcription regulators by IKAROS, now cooperate directly with them in a de novo superenhancer network with its own feed-forward transcriptional reinforcement. Induction of de novo superenhancers antagonizes Polycomb repression and superimposes aberrant stem epithelial cell properties in a B-cell precursor. This dual mechanism of IKAROS regulation promotes differentiation while safeguarding against a hybrid stem epithelial B-cell phenotype that underlies high-risk B-ALL.

  • 27.
    Karlsson, Anna-Carin
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Effects of domestication related genes on behaviour, physiology and gene expression in chickens2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Domestication, the process when animals adapt to captivity, tends to modify a whole array of traits towards what has been termed “the domesticated phenotype”, where the domesticated animal differs from its wild ancestor in morphology, physiology, development and behaviour. Physiological traits and behaviours are controlled by genes. One single gene can control several different traits (pleiotropy), be linked to a neighbouring gene on the chromosome, or interact with another gene that in turn controls another trait. This is the explanation why one can select for high egg production and at the same time get a change in the colour of the plumage. The aim of this thesis was to evaluate the effect of a mutation in two particular genes (PMEL17 and TSHR) related to domestication on behaviour, gene expression and other physiologial traits. The animals investigated were chickens from a cross between the ancestral Red Junglefowl (RJF) and the domesticated White Leghorn (WL) selected for high egg production traits. PMEL17 is a gene affecting plumage colour. A mutation in the gene causes a non-pigmented white plumage and has been shown to protect against feather pecking. Our studies showed that a mutation in the PMEL17 gene affects social, explorative and aggressive behaviour in chickens, but not visual ability. The thyroid stimulating hormone receptor (TSHR) plays an important role in the signal transduction of the hypothalamus-pituitary-thyroid axis that has general effects on development, behaviour and reproduction. A mutation in the TSHR gene affects incubation time, domestication related behaviours such as fear and aggression, gene expression, thyroid hormone levels and photoperiodic reproduction responses in chicken. The results from this thesis suggest that a mutation in the PMEL17 and TSHR genes have pleiotropic effects on behaviour and traits related to domestication, and it is therefore likely that both genes have been important for the domestication of the chicken.

    List of papers
    1. Genotype at the PMEL17 locus affects social and explorative behaviour in chickens
    Open this publication in new window or tab >>Genotype at the PMEL17 locus affects social and explorative behaviour in chickens
    2010 (English)In: BRITISH POULTRY SCIENCE, ISSN 0007-1668, Vol. 51, no 2, p. 170-177Article in journal (Refereed) Published
    Abstract [en]

    1. We studied behaviour and brain gene expression in homozygous PMEL17 genotypes, using chickens originating from an advanced White Leghorn x red junglefowl intercross. The behavioural studies consisted of three social and one explorative behaviour test. There were significant differences between the genotypes in both social and explorative behaviour. 2. Gene expression studies showed no PMEL17 expression in brain, so the genotype differences must depend on extra-neural gene expression or expression during embryonic development. However, linkage or spurious family effects (genetic drift) can not be excluded. 3. The study strongly suggests a correlated effect between plumage colour and behaviour, and we conclude that PMEL17 may have a pleiotropic effect on social and explorative behaviour in chickens.

    Place, publisher, year, edition, pages
    Taylor and Francis, 2010
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-56690 (URN)10.1080/00071661003745802 (DOI)000277547700002 ()
    Available from: 2010-05-31 Created: 2010-05-31 Last updated: 2014-12-18
    2. Genotype on the Pigmentation Regulating PMEL17 Gene Affects Behavior in Chickens Raised Without Physical Contact with Conspecifics
    Open this publication in new window or tab >>Genotype on the Pigmentation Regulating PMEL17 Gene Affects Behavior in Chickens Raised Without Physical Contact with Conspecifics
    2011 (English)In: BEHAVIOR GENETICS, ISSN 0001-8244, Vol. 41, no 2, p. 312-322Article in journal (Refereed) Published
    Abstract [en]

    Chickens homozygous for the Dominant white or wild-type allele of PMEL17 were subjected to a broad phenotyping in order to detect consistent differences between genotypes. To exclude feather pecking, the chickens were individually housed without physical contact, from the day of hatching, and tested for social, aggressive, fear and exploratory behaviors, and corticosterone and testosterone levels were assessed. In a principal component analysis, 53.2% of the behavior variation was explained by two factors. Factor one was an activity and social factor, and there was a significant effect of genotype on the factor scores. On factor two, related to aggressive behavior, there were significant effects of genotype, sex and their interaction. There were no genotype effects on hormone levels or any other measured non-behavioral phenotypes. Hence, differences in behavior between PMEL17 genotypes remained when negative social experiences were excluded, indicating a direct pleiotropic effect of the gene on behavior.

    Place, publisher, year, edition, pages
    Springer Science Business Media, 2011
    Keywords
    Chicken, Behavior, PMEL17, Dominant white, Pigmentation
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-67038 (URN)10.1007/s10519-010-9379-4 (DOI)000287749700015 ()
    Note
    The original publication is available at www.springerlink.com: Anna-Carin Karlsson, Pierre Mormede, Susanne Kerje and Per Jensen, Genotype on the Pigmentation Regulating PMEL17 Gene Affects Behavior in Chickens Raised Without Physical Contact with Conspecifics, 2011, BEHAVIOR GENETICS, (41), 2, 312-322. http://dx.doi.org/10.1007/s10519-010-9379-4 Copyright: Springer Science Business Media http://www.springerlink.com/ Available from: 2011-03-25 Created: 2011-03-25 Last updated: 2014-12-18
    3. The Dominant white mutation in the PMEL17 gene does not cause visual impairment in chickens.
    Open this publication in new window or tab >>The Dominant white mutation in the PMEL17 gene does not cause visual impairment in chickens.
    2009 (English)In: Veterinary ophthalmology, ISSN 1463-5224, Vol. 12, no 5, p. 292-298Article in journal (Refereed) Published
    Abstract [en]

    Objective: To examine whether the Dominant white mutation (causing a hypopigmented phenotype in chicken) affects the visual ability and gives rise to ocular abnormalities in chickens (Gallus gallus). PROCEDURE: Chickens homozygous for either the Dominant white mutation or the wild-type alleles were tested in a visual contrast behavioral test and subjected to histological and ophthalmologic examination. RESULTS: There were no differences between the genotypes in the visual contrast behavioral test, and there were no abnormal structures among the Dominant white chickens in the ophthalmic examination. The histological sections from the Dominant white chickens did not differ from the wild-type chicken in structure, photoreceptor density, or RPE pigmentation. CONCLUSIONS: The results indicate that the Dominant white mutation in PMEL17 does not seem to affect the visual ability or eye structures in chickens.

    Keywords
    chickens • Dominant white • ocular abnormalities • pigmentation • PMEL17 • visual impairment
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-21337 (URN)10.1111/j.1463-5224.2009.00714.x (DOI)19751488 (PubMedID)
    Available from: 2009-10-01 Created: 2009-10-01 Last updated: 2014-12-18Bibliographically approved
    4. The effect of a mutation in the thyroid stimulating hormone receptor (TSHR) on development, behaviour and TH levels in domesticated chickens
    Open this publication in new window or tab >>The effect of a mutation in the thyroid stimulating hormone receptor (TSHR) on development, behaviour and TH levels in domesticated chickens
    Show others...
    2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0129040Article in journal (Refereed) Published
    Abstract [en]

    The thyroid stimulating hormone receptor (TSHR) has been suggested to be a “domestication locus” in the chicken, due to a strong selective sweep over the gene found in domesticated chickens, but not in their wild ancestor the Red Junglefowl (RJF). We investigated the effect of the mutation on development (incubation time), behaviour and thyroid hormone levels in intercross chickens homozygous for the mutation (d/d), wild type homozygotes (w/w) or heterozygotes (d/w). This allowed an assessment of the effect of genotype at this locus against a random mix of RJF and WL genotypes throughout the rest of the genome. The (d/d) genotype showed a longer incubation time, less fearful behaviours, lower number of aggressive behaviours and decreased levels of the thyroid hormone T4, in comparison to the (w/w) genotype. The difference between TSHR genotypes (d/d vs. w/w) in these respects mirrors the differences in development and behaviour between pure domesticated White Leghorns and pure RJF chickens. Our study indicates that the TSHR mutation affects typical domestication traits and may therefore have been important during the evolution of the domestic chicken.

    Place, publisher, year, edition, pages
    Public Library of Science, 2015
    National Category
    Developmental Biology Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-112866 (URN)10.1371/journal.pone.0129040 (DOI)000355955300078 ()26053744 (PubMedID)
    Note

    At the time for thesis presentation publication was in status: Manuscript

    Funding agencies|Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, FORMAS (Formel Excel) [221-2010-35]; Swedish Research Council, VR [621-2011-4731]; European Research Council (ERC grant GENEWELL) [322206]

    Available from: 2014-12-18 Created: 2014-12-18 Last updated: 2017-12-05Bibliographically approved
    5. The effect of a domestication related mutation in the thyroid stimulating hormone receptor (TSHR) on photoperiodic response and reproduction in chicken
    Open this publication in new window or tab >>The effect of a domestication related mutation in the thyroid stimulating hormone receptor (TSHR) on photoperiodic response and reproduction in chicken
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The thyroid stimulating hormone receptor (TSHR) has been suggested to be a “domestication locus” in the chicken. A strong selective sweep over the gene in domestic breeds of chicken, but not in the ancestral Red Junglefowl, and significant effects of a mutation in TSHR on domestication related traits in chicken, indicate that the gene has been important for the chicken domestication. The TSHR play a key role in the signal transduction of seasonal reproduction, which is characteristically less strict in domestic animals. We investigated the effect of the mutation on reproductive traits as well as TSHB, TSHR, DIO2 and DIO3 gene expression during altered day length (photoperiod) in females and males intercross chickens homozygous for the mutation (d/d) or wild type homozygotes (w/w). This allowed an assessment of the effect of genotype at this locus against a random mix of RJF and WL genotypes throughout the rest of the genome. The TSHR gene expression was significantly lower in both d/d females and males, in comparison to w/w individuals, indicating a strong effect of the “domestic” mutation on gene expression. The d/d females showed a faster increase in the onset of laying than w/w females, and d/d males showed a reduced response to altered day length in testicular size and significant lower levels of TSHB and DIO3 expression, in comparison to w/w males. Additionally, pure White Leghorn females kept under natural day length in Sweden during December showed active ovaries and significant lower levels of TSHR and DIO3 expression in comparison to Red Junglefowl females kept under similar conditions. Our study suggest that the TSHR mutation affects photoperiodic response in chicken in the direction of being less dependent on seasonal reproduction, a typical domestication feature, and may therefore have been important for the chicken domestication.

    National Category
    Developmental Biology Cell and Molecular Biology Other Biological Topics
    Identifiers
    urn:nbn:se:liu:diva-112867 (URN)
    Available from: 2014-12-18 Created: 2014-12-18 Last updated: 2018-01-11Bibliographically approved
  • 28.
    Karlsson, Anna-Carin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Fallahshahroudi, Amir
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Johnsen, Hanna
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Hagenblad, Jenny
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Wright, Dominic
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Andersson, Leif
    Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    The effect of a domestication related mutation in the thyroid stimulating hormone receptor (TSHR) on photoperiodic response and reproduction in chickenManuscript (preprint) (Other academic)
    Abstract [en]

    The thyroid stimulating hormone receptor (TSHR) has been suggested to be a “domestication locus” in the chicken. A strong selective sweep over the gene in domestic breeds of chicken, but not in the ancestral Red Junglefowl, and significant effects of a mutation in TSHR on domestication related traits in chicken, indicate that the gene has been important for the chicken domestication. The TSHR play a key role in the signal transduction of seasonal reproduction, which is characteristically less strict in domestic animals. We investigated the effect of the mutation on reproductive traits as well as TSHB, TSHR, DIO2 and DIO3 gene expression during altered day length (photoperiod) in females and males intercross chickens homozygous for the mutation (d/d) or wild type homozygotes (w/w). This allowed an assessment of the effect of genotype at this locus against a random mix of RJF and WL genotypes throughout the rest of the genome. The TSHR gene expression was significantly lower in both d/d females and males, in comparison to w/w individuals, indicating a strong effect of the “domestic” mutation on gene expression. The d/d females showed a faster increase in the onset of laying than w/w females, and d/d males showed a reduced response to altered day length in testicular size and significant lower levels of TSHB and DIO3 expression, in comparison to w/w males. Additionally, pure White Leghorn females kept under natural day length in Sweden during December showed active ovaries and significant lower levels of TSHR and DIO3 expression in comparison to Red Junglefowl females kept under similar conditions. Our study suggest that the TSHR mutation affects photoperiodic response in chicken in the direction of being less dependent on seasonal reproduction, a typical domestication feature, and may therefore have been important for the chicken domestication.

  • 29.
    Karlsson, Anna-Carin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Svemer, Frida
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Eriksson, Jonas
    Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Darras, Veerle M.
    Laboratory of Comparative Endocrinology, Department of Biology, Division of Animal Physiology and Neurobiology, Leuven, Belgium.
    Andersson, Leif
    Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    The effect of a mutation in the thyroid stimulating hormone receptor (TSHR) on development, behaviour and TH levels in domesticated chickens2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0129040Article in journal (Refereed)
    Abstract [en]

    The thyroid stimulating hormone receptor (TSHR) has been suggested to be a “domestication locus” in the chicken, due to a strong selective sweep over the gene found in domesticated chickens, but not in their wild ancestor the Red Junglefowl (RJF). We investigated the effect of the mutation on development (incubation time), behaviour and thyroid hormone levels in intercross chickens homozygous for the mutation (d/d), wild type homozygotes (w/w) or heterozygotes (d/w). This allowed an assessment of the effect of genotype at this locus against a random mix of RJF and WL genotypes throughout the rest of the genome. The (d/d) genotype showed a longer incubation time, less fearful behaviours, lower number of aggressive behaviours and decreased levels of the thyroid hormone T4, in comparison to the (w/w) genotype. The difference between TSHR genotypes (d/d vs. w/w) in these respects mirrors the differences in development and behaviour between pure domesticated White Leghorns and pure RJF chickens. Our study indicates that the TSHR mutation affects typical domestication traits and may therefore have been important during the evolution of the domestic chicken.

  • 30.
    Karlsson, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Baumgardt, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Segment-specific Neuronal Sub-type Specification by the Integration of Anteroposterior and Temporal Cues2010In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 8, no 5Article in journal (Refereed)
    Abstract [en]

    The generation of distinct neuronal sub-types at different axial levels relies upon both anteroposterior and temporal cues. However, the integration between these cues is poorly understood. In the Drosophila CNS, the segmentally repeated neuroblast 5-6 generates a unique group of neurons, the Apterous cluster, only in thoracic segments. Recent studies have identified elaborate genetic pathways acting to control the generation of these neurons. These insights, combined with novel markers, provide a unique opportunity for addressing how anteroposterior and temporal cues are integrated to generate segment-specific neuronal sub-types. We find that Pbx/Meis, Hox and temporal genes act in three different ways. Posteriorly, Pbx/Meis and posterior Hox genes block lineage progression within an early temporal window, by triggering cell cycle exit. Because Ap neurons are generated late in the thoracic 5-6 lineage, this prevents generation of Ap cluster cells in the abdomen. Thoracically, Pbx/Meis and anterior Hox genes integrate with late temporal genes to specify Ap clusters, via activation of a specific feed-forward loop. In brain segments, ‘Ap cluster cells’ are present but lack both proper Hox and temporal coding. Only by simultaneously altering Hox and temporal gene activity in all segments can Ap clusters be generated throughout the neuroaxis. This study provides the first detailed analysis of an identified neuroblast lineage along the entire neuroaxis, and provides novel insight into how Hox/Pbx/Meis anteroposterior cues are integrated with temporal cues. It reveals a surprisingly restricted yet multifaceted function of the anteroposterior cues with respect to lineage control and cell fate specification.

  • 31.
    Løvlie, Hanne
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Cryptic Female Choice2016In: Oxfords Bibliographies in Evolutionary BiologyArticle, review/survey (Refereed)
    Abstract [en]

    Sexual selection (see the Oxford Bibliographies article “Sexual Selection”) is a powerful evolutionary force, selecting fortraits that increase the reproductive success of individuals. Before copulation, sexual selection can occur throughintrasexual selection, typically observed as competition among individuals of the same sex for access to mating partnersof the other sex (see Oxford Bibliographies article on Evolutionary Biology “Male-Male Competition”), and intersexualselection, observed as (typically female) mate choice (see Oxford Bibliographies article on Evolutionary Biology “MateChoice”). When females are sexually promiscuous and mate with multiple males (which is more the rule than theexception in the animal kingdom), these two processes have the potential to continue also after copulation: intrasexualselection as sperm competition (Oxford Bibliographies article on Evolutionary Biology “Sperm Competition”), andintersexual selection as cryptic female choice. The term cryptic is applied because this form of female choice can be hardto observe (e.g., when it occurs inside the female reproductive tract) and hard to quantify with classical measures ofreproductive success (e.g., mating success). In addition, this form of female choice is hard to disentangle from otherepisodes of sexual selection (see below). The framework used to understand female choice occurring after (or sometimesduring) copulation is currently somewhat divergent, since some authors adopt a very broad definition of cryptic femalechoice, while others apply a more conservative definition (see discussion of this under Definition and History). Crypticfemale choice is a relatively young research topic (it first started properly after the publication of Eberhard’s seminal bookFemale Control: Sexual Selection by Cryptic Female Choice [Eberhard 1996, cited under General Overviews] in 1996). Itwas realized early on in the history of the field that a broad range of mechanisms across a variety of species exist throughwhich females can potentially bias the outcome of a copulation (e.g., ejaculate ejection, differential sperm storage, spermchoice—see section Mechanisms and Processes Used as Cryptic Female Choice). As a consequence, measures ofprecopulatory processes or sperm competition can be misleading in species with cryptic female choice, due to femalepostcopulatory influences on fertilization. Yet, although there is no doubt that females have great potential to bias paternityat the postcopulatory stage, cryptic female choice is the least studied of the processes through which sexual selection canoccur (e.g., compared to sperm competition, or male-male competition). This is probably because demonstration of crypticfemale choice is notoriously difficult. It can be challenging to separate pre- from postcopulatory processes, the interactionof male adaptations to sperm competition and female influences on fertilization, and variation in differential embryomortality from female-induced biases in paternity (see Potential Pitfalls in the Study of Cryptic Female Choice). Thestudies that have convincingly been able to separate these processes and demonstrate cryptic female choice are currentlyprimarily from insect, bird, and externally fertilizing species (see Mechanisms and Processes Used as Cryptic FemaleChoice). I here present when we may expect to observe cryptic female choice, how females may benefit from crypticfemale choice, some techniques that can

  • 32.
    Martínez-Pastor, Felipe
    et al.
    ITRA-ULE, INDEGSAL, Departments of Molecular Biology (Cell Biology), University of León, León, Spain.
    Mata-Campuzano, Maria
    ITRA-ULE, INDEGSAL, Departments of Molecular Biology (Cell Biology), University of León, León, Spain.
    Alvarez-Rodriguez, Manuel
    ITRA-ULE, INDEGSAL, Animal Reproduction and Obstetrics, University of León, León, Spain.
    Alvarez, Mercedes
    ITRA-ULE, INDEGSAL, Animal Reproduction and Obstetrics, University of León, León, Spain.
    Anel, Luis
    ITRA-ULE, INDEGSAL, Animal Reproduction and Obstetrics, University of León, León, Spain.
    de Paz, Paulino
    ITRA-ULE, INDEGSAL, Departments of Molecular Biology (Cell Biology), University of León, León, Spain.
    Probes and techniques for sperm evaluation by flow cytometry2010In: Reproduction in domestic animals, ISSN 0936-6768, E-ISSN 1439-0531, Vol. 45 Suppl 2, p. 67-78Article in journal (Refereed)
    Abstract [en]

    CONTENTS: Flow cytometry has become an important technique in sperm evaluation and is increasingly used both for routine assessment and for research in veterinary science. We have revised the literature, describing fluorescent probes that have been used for analysing spermatozoa by flow cytometry, regarding: viability, acrosomal status, capacitation, mitochondrial status, apoptotic markers, oxidative stress markers, DNA damage, sperm counting and sperm sizing. Details and problems of some techniques are reviewed, with special attention to the occurrence of non-sperm particles in the samples ('debris'). New and promising aspects of flow cytometry, such as sperm sorting using viability markers as selection criteria, are highlighted. The relationship between flow cytometry analyses and fertility and their future improvements are considered.

  • 33.
    Mata-Campuzano, Maria
    et al.
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, Spain.
    Alvarez-Rodríguez, Manuel
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, Spain.
    del Olmo, E
    Biology of Reproduction Group, National Wildlife Research Institute (IREC) (UCLM-CSIC-JCCM), Albacete, Spain.
    Fernández-Santos, M R
    Biology of Reproduction Group, National Wildlife Research Institute (IREC) (UCLM-CSIC-JCCM), Albacete, Spain.
    Garde, J J
    Biology of Reproduction Group, National Wildlife Research Institute (IREC) (UCLM-CSIC-JCCM), Albacete, Spain.
    Martínez-Pastor, Felipe
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, Spain.
    Quality, oxidative markers and DNA damage (DNA) fragmentation of red deer thawed spermatozoa after incubation at 37 °C in presence of several antioxidants.2012In: Theriogenology, ISSN 0093-691X, E-ISSN 1879-3231, Vol. 78, no 5, p. 1005-1019Article in journal (Refereed)
    Abstract [en]

    Antioxidants may be useful for supplementing sperm extenders. We have tested dehydroascorbic acid (DHA), TEMPOL, N-acetyl-cysteine (NAC) and rutin on epididymal spermatozoa from red deer, during incubation at 37 °C. Cryopreserved spermatozoa were thawed, washed and incubated with 1 mM or 0.1 mM of each antioxidant, including oxidative stress (Fe(2+)/ascorbate). Motility (CASA and clustering of subpopulations), viability, mitochondrial membrane potential, and acrosomal status were assessed at 2 and 4 h. Lipoperoxidation, intracellular reactive oxygen species (ROS) and DNA damage (DNA) status (TUNEL) were checked at 4 h. Oxidative stress increased ROS, lipoperoxidation and DNA damage. Overall, antioxidants negatively affected motility and physiological parameters. Only DHA 1 mm protected motility, increasing the fast and progressive subpopulation. However, it had a detrimental effect on acrosomal and DNA status, in absence of oxidative stress. Tempol and rutin efficiently reduced lipoperoxidation, ROS, and DNA damage in presence of oxidative stress. NAC was not as efficient as TEMPOL or rutin reducing lipoperoxidation or protecting DNA, and did not reduce ROS, but its negative effects were lower than the other antioxidants when used at 1 mm, increasing the subpopulation of hyperactivated-like spermatozoa at 2 h. Our results show that these antioxidants have mixed effects when spermatozoa are incubated at physiological temperatures. DHA may not be suitable because of prooxidant effects, but TEMPOL, NAC and rutin may be considered for cryopreservation trials. In general, exposure of red deer spermatozoa to these antioxidants should be limited to low temperatures, when only protective effects may develop.

  • 34.
    Mata-Campuzano, María
    et al.
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, Spain.
    Alvarez-Rodríguez, Manuel
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, Spain.
    Alvarez, Mercedes
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, Spain.
    Anel, Luis
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, Spain.
    de Paz, Paulino
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, Spain.
    Garde, Julian
    Biology of Reproduction Group, National Wildlife Research Institute (IREC) (UCLM-CSIC-JCCM), Albacete, Spain.
    Martínez-Pastor, Felipe
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology (Cell Biology), University of León, Spain.
    Effect of several antioxidants on thawed ram spermatozoa submitted to 37°C up to four hours.2012In: Reproduction in domestic animals, ISSN 0936-6768, E-ISSN 1439-0531, Vol. 47, no 6, p. 907-914Article in journal (Refereed)
    Abstract [en]

    Thawed ram spermatozoa were incubated at 37°C in the presence of dehydroascorbic acid (DHA), TEMPOL (TPL), N-acetyl-cysteine (NAC) and rutin (RUT), at 0.1 and 1 mm, in order to test their effects on sperm physiology. Cryopreserved spermatozoa from four rams were thawed, pooled, washed and incubated in TALP-Hepes with 1 mm or 0.1 mm of each antioxidant, performing a replicate with induced oxidative stress (Fe(2+) /ascorbate). Motility (CASA), viability and mitochondrial membrane potential (flow cytometry) were analysed at 2 and 4 h. Lipoperoxidation (MDA production), intracellular reactive oxygen species (ROS) and DNA status (TUNEL) were analysed at 4 h. Antioxidants, except DHA 0.1 mm, decreased motility and kinematic parameters, but had little effect on viability or mitochondrial activity. Except 1 mm DHA, the antioxidants reduced ROS at 4 h. Moreover, NAC 1 mm, rutin and TEMPOL reduced ROS and DNA damage in the presence of oxidative stress. N-acetyl-cysteine, rutin 1 mm and TEMPOL reduced lipoperoxidation in the presence of oxidative stress. However, DHA did not affect lipoperoxidation. At 1 mm, DHA increased DNA damage in the absence of oxidative stress. Dehydroascorbic acid effects could arise from spermatozoa having a low capacity for reducing it to ascorbic acid, and it may be tested in the presence of other antioxidants or reducing power. Future research should focus in testing whether the inhibition of motility observed for NAC, rutin and TEMPOL is reversible. These antioxidants might be useful at lower temperatures (refrigerated storage or cryopreservation) when their protective effects could be advantageous.

  • 35.
    Mata-Campuzano, María
    et al.
    INDEGSAL, University of León, León, Spain; Department of Molecular Biology, University of León, León, Spain.
    Álvarez-Rodríguez, Manuel
    INDEGSAL, University of León, León, Spain; Department of Molecular Biology, University of León, León, Spain; Department of Medicine, Surgery and Veterinary Anatomy, University of León, León, Spain; DEPI, Institute of Technology of Conkal, Conkal, Mexico.
    Tamayo-Canul, Julio
    INDEGSAL, University of León, León, Spain; Department of Molecular Biology, University of León, León, Spain.
    López-Urueña, Elena
    INDEGSAL, University of León, León, Spain; Department of Medicine, Surgery and Veterinary Anatomy, University of León, León, Spain.
    de Paz, Paulino
    INDEGSAL, University of León, León, Spain; Department of Molecular Biology, University of León, León, Spain.
    Anel, Luis
    INDEGSAL, University of León, León, Spain; Department of Medicine, Surgery and Veterinary Anatomy, University of León, León, Spain.
    Martínez-Pastor, Felipe
    INDEGSAL, University of León, León, Spain; Department of Molecular Biology, University of León, León, Spain.
    Álvarez, Mercedes
    INDEGSAL, University of León, León, Spain; Department of Medicine, Surgery and Veterinary Anatomy, University of León, León, Spain.
    Refrigerated storage of ram sperm in presence of Trolox and GSH antioxidants: effect of temperature, extender and storage time2014In: Animal Reproduction Science, ISSN 0378-4320, E-ISSN 1873-2232, Vol. 151, no 3-4, p. 137-147Article in journal (Refereed)
    Abstract [en]

    Antioxidants have a potential to improve the quality and fertility of refrigerated-stored ram semen. Reduced glutathione (GSH) and Trolox (0.2, 1 and 5mM) were evaluated in ram semen preserved at 15 and 5°C up to 48 and 96h, respectively. Extenders were also evaluated (15°C: Tris-citrate-fructose, TCF, without lipids, and TES-Tris-fructose 10% egg yolk, TTF-EY; 5°C: TTF-EY and 3.5% soybean lecithin, TTF-SL; INRA96 at both temperatures). Storage at 5°C resulted in poorer quality than 15°C up to 48h, while allowing acceptable quality at 96h. Antioxidants had few effects on sperm quality, with use of Trolox resulting in reduced motility and viability in TCF. Storage at 15°C in the TCF extender resulted in decreased motility, viability and mitochondrial activity compared with use of TTF-EY. Sperm quality when storage was at 5°C was similar, but storage in TTF-SL resulted in decreased motility and mitochondrial activity. Acrosomal status was only slightly affected by extender and antioxidant. Mitochondrial activity was improved by antioxidants in TTF-SL, and GSH at 5mM when semen was stored at 5°C in TTF-EY. A preliminary artificial insemination trial indicated that supplementation with GSH has the potential for improving lambing (P<0.1). In conclusion, use of antioxidants resulted in lesser effects than extender composition or storage time on quality of ram semen. Use of Trolox negatively impacted sperm quality and GSH had some positive impacts. The use of soybean lecithin requires further research to assess its impact on mitochondria.

  • 36.
    Mata-Campuzano, María
    et al.
    Institute for Animal Health and Cattle Development, University of León, León, Spain; Department of Molecular Biology, University of León, León, Spain.
    Álvarez-Rodríguez, Manuel
    Institute for Animal Health and Cattle Development, University of León, León, Spain.
    Álvarez, Mercedes
    Institute for Animal Health and Cattle Development, University of León, León, Spain; Department of Medicine, Surgery and Veterinary Anatomy, University of León, León, Spain.
    Tamayo-Canul, Julio
    Institute for Animal Health and Cattle Development, University of León, León, Spain; Division for Research and Post-graduate Studies, Technological Institute of Conkal, Yucatán, México.
    Anel, Luis
    Institute for Animal Health and Cattle Development, University of León, León, Spain; Department of Medicine, Surgery and Veterinary Anatomy, University of León, León, Spain.
    de Paz, Paulino
    Institute for Animal Health and Cattle Development, University of León, León, Spain; Department of Molecular Biology, University of León, León, Spain.
    Martínez-Pastor, Felipe
    Institute for Animal Health and Cattle Development, University of León, León, Spain; Department of Molecular Biology, University of León, León, Spain.
    Post-thawing quality and incubation resilience of cryopreserved ram spermatozoa are affected by antioxidant supplementation and choice of extender.2015In: Theriogenology, ISSN 0093-691X, E-ISSN 1879-3231, Vol. 83, no 4, p. 520-528Article in journal (Refereed)
    Abstract [en]

    The performance of cryopreserved semen in ovine artificial insemination still needs improvement. Some antioxidants have been tested, with variable success. We cryopreserved semen from Churra rams using TES-Tris-fructose with 4% glycerol and 10% egg yolk (EY) or 3.5% soybean lecithin (SL), with 1 mM of reduced glutathione (GSH), Trolox, crocin, or cysteamine. Samples were analyzed after thawing and incubation (6 hours, 38 °C) for motility (computer-assisted sperm analysis [CASA]), viability, acrosomal integrity, apoptosis, mitochondrial activity, chromatin status, and lipoperoxidation (malondialdehyde production). Interactions (antioxidant/extender/incubation) were significant for most variables. Extenders yielded similar results, although SL depressed mitochondrial activity and linearity (P < 0.001), it improved motility (P < 0.05), DNA fragmentation (P < 0.05), and acrosomal damage (P < 0.001). The control, GSH, and Trolox showed greater viability with SL (P < 0.01). Cysteamine depressed motility (0 hours: 51.6 ± 2.0% vs. 32.3 ± 4.3%; 6 hours: no motility vs. 32.5 ± 1.9%; P < 0.001), but improved viability when using EY (P = 0.004). Crocin increased acrosomal damage (P = 0.022) but improved linearity-related parameters after thawing (P = 0.014). Trolox considerably reduced malondialdehyde production in both extenders (8.6 ± 0.4 nmol per 10(8) cells vs. 14.2 ± 0.3 in EY and 20 ± 0.6 in SL; P < 0.001). Interestingly, thiol antioxidants (cysteamine and GSH) increased DNA fragmentation (percentage of DNA fragmentation index), whereas crocin reduced it (P < 0.05). Interactions between extender and antioxidant must be taken into account for improving sperm cryopreservation. Soybean lecithin seems to be a suitable replacement for EY, but its effect on mitochondria must be investigated. Trolox and crocin might be useful for ram semen freezing.

  • 37.
    Monedero Cobeta, Ignacio
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Yaghmaeian Salmani, Behzad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Anterior-Posterior Gradient in Neural Stem and Daughter Cell Proliferation Governed by Spatial and Temporal Hox Control2017In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 27, no 8, p. 1161-1172Article in journal (Refereed)
    Abstract [en]

    A readily evident feature of animal central nervous systems (CNSs), apparent in all vertebrates and many invertebrates alike, is its "wedge-like appearance, with more cells generated in anterior than posterior regions. This wedge could conceivably be established by an antero-posterior (A-P) gradient in the number of neural progenitor cells, their proliferation behaviors, and/or programmed cell death (PCD). However, the contribution of each of these mechanisms, and the underlying genetic programs, are not well understood. Building upon recent progress in the Drosophila melanogaster (Drosophila) ventral nerve cord (VNC), we address these issues in a comprehensive manner. We find that, although PCD plays a role in controlling cell numbers along the A-P axis, the main driver of the wedge is a gradient of daughter proliferation, with divisions directly generating neurons (type 0) being more prevalent posteriorly and dividing daughters (type I) more prevalent anteriorly. In addition, neural progenitor (NB) cell-cycle exit occurs earlier posteriorly. The gradient of type I amp;gt; 0 daughter proliferation switch and NB exit combine to generate radically different average lineage sizes along the A-P axis, differing by more than 3-fold in cell number. We find that the Hox homeotic genes, expressed in overlapping A-P gradients and with a late temporal onset in NBs, trigger the type I amp;gt; 0 daughter proliferation switch and NB exit. Given the highly evolutionarily conserved expression of overlapping Hox homeotic genes in the CNS, our results point to a common mechanism for generating the CNS wedge.

  • 38.
    Monedero, Ignacio
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Autonoma Madrid, Spain.
    Bivik, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Li, Jin
    Texas AandM Univ, TX USA; Texas AandM Univ, TX USA.
    Yu, Peng
    Texas AandM Univ, TX USA.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Benito-Sipos, Jonathan
    Univ Autonoma Madrid, Spain.
    Specification of Drosophila neuropeptidergic neurons by the splicing component brr22018In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 8, article id e1007496Article in journal (Refereed)
    Abstract [en]

    During embryonic development, a number of genetic cues act to generate neuronal diversity. While intrinsic transcriptional cascades are well-known to control neuronal sub-type cell fate, the target cells can also provide critical input to specific neuronal cell fates. Such signals, denoted retrograde signals, are known to provide critical survival cues for neurons, but have also been found to trigger terminal differentiation of neurons. One salient example of such target-derived instructive signals pertains to the specification of the Drosophila FMRFamide neuropeptide neurons, the Tv4 neurons of the ventral nerve cord. Tv4 neurons receive a BMP signal from their target cells, which acts as the final trigger to activate the FMRFa gene. A recent FMRFa-eGFP genetic screen identified several genes involved in Tv4 specification, two of which encode components of the U5 subunit of the spliceosome: brr2 (l(3) 72Ab) and Prp8. In this study, we focus on the role of RNA processing during target- derived signaling. We found that brr2 and Prp8 play crucial roles in controlling the expression of the FMRFa neuropeptide specifically in six neurons of the VNC (Tv4 neurons). Detailed analysis of brr2 revealed that this control is executed by two independent mechanisms, both of which are required for the activation of the BMP retrograde signaling pathway in Tv4 neurons: (1) Proper axonal pathfinding to the target tissue in order to receive the BMP ligand. (2) Proper RNA splicing of two genes in the BMP pathway: the thickveins (tkv) gene, encoding a BMP receptor subunit, and the Medea gene, encoding a co-Smad. These results reveal involvement of specific RNA processing in diversifying neuronal identity within the central nervous system.

  • 39.
    Moriceau, Stephanie
    et al.
    Zoology Department, University of Oklahoma, Norman, USA.
    Shionoya, Kiseko
    Zoology Department, University of Oklahoma, Norman, USA.
    Sullivan, Regina M.
    Zoology Department, University of Oklahoma, Norman, USA.
    Concurrent Neonatal Activation Of The Amygdala-fear Circuit And The Attachment Circuit During Infancy2007Conference paper (Refereed)
    Abstract [en]

    Infant altricial species learn to prefer stimuli paired with pain, presumably due to the importance of learning to prefer the caregiver regardless of the qual ity of care. This attenuated avoidance/fear learning appears due to low corticosterone (CORT), which keeps the amygdala ‘‘dormant’’. Indeed, simply increasing CORT permits amygdala plasticity and fear conditioning. Here we assess whether CORT also activates the locus coeruleus (LC) and increases NE via amygdala CRF efferents to the LC. In all experiments, PN7–8 pups received 11 pairings of odor-0.5 mA shock and were tested the next day for an odor preference/aversion (Y-maze). 14C 2-DG was used for neural assessment during conditioning. In Experiment 1, we found that the CORT induced odor aversion was correlated with olfactory bulb activation. Since this neural change is usually dependent upon increased NE and limited to neonates, we next assessed the pathway from the amygdala to the LC. In Experiment 2, we directly infused CORT into the lateral amygdala that activates the CRF efferents to the LC and an odor aversion was again obtained. In Experiment 3, we infused CRF directly into the LC, which produced an odor aversion and an increase in olfactory bulb NE (microdialysis). Pups with control LC vehicle infusions continued to acquire the age characteristic shock-induced odor preference. These results suggested that early activation of the amygdala dependent fear system can be precociously induce in neonates, although this is done in concert with the neonatal NE olfactory bulb learning system. [RMS Funding NSF IBN0117234, NICHD HD33402, OCAST]

  • 40.
    Nicolas, Manuel
    et al.
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Alvarez, Mercedes
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Borragán, Santiago
    Cabárceno Park, Cantabria, Spain.
    Martinez-Pastor, Felipe
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Cell Biology, University of León, León, Spain.
    Chamorro, C A
    ITRA-ULE, INDEGSAL, University of León, León, Spain.
    Alvarez-Rodriguez, Manuel
    ITRA-ULE, INDEGSAL, University of León, León, Spain.
    de Paz, Paulino
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Cell Biology, University of León, León, Spain.
    Anel, Luis
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Evaluation of the qualitative and quantitative effectiveness of three media of centrifugation (Maxifreeze, Cushion Fluid Equine, and PureSperm 100) in preparation of fresh or frozen-thawed brown bear spermatozoa.2012In: Theriogenology, ISSN 0093-691X, E-ISSN 1879-3231, Vol. 77, no 6, p. 1119-1128Article in journal (Refereed)
    Abstract [en]

    Centrifugation is a crucial procedure in sperm cryopreservation protocols of brown bear (Ursus arctos), because the semen must be processed to increase sperm concentration and/or clean urine-contaminated samples. The efficacy of three media for centrifugation (Maxifreeze [IMV technologies, L'Aigle, France], Cushion Fluid Equine (Minitübe, Tiefenbach, Germany), and PureSperm [Nidacon, Gothenburg, Sweden]) on the quality of bear spermatozoa was evaluated. In experiment one, two cushioned media used for protecting against mechanical stress during centrifugation were analyzed. In experiment two, a density gradient based on PureSperm was assessed in relation to the maximum retrieval and the quality of fresh spermatozoa, and the freezability of the spermatozoa selected in this density gradient was studied in experiment three. Finally, the selection of frozen-thawed sperm using PureSperm was analyzed in experiment four. Our results indicate that the use of dense isotonic cushion solutions (Maxifreeze, Cushion Fluid Equine) in centrifugation did not improve the quality of recovered spermatozoa compared with standard centrifugation. However, a density gradient prepared with PureSperm improved the quality of spermatozoa in fresh semen and frozen-thawed semen, but the spermatozoa selected from the fresh sample with this density gradient did not show a better resistance to freezing with this density gradient in comparison with the control sample.

  • 41.
    Rice, William
    et al.
    Department of Ecology, Evolution, and Marine Biology, University of California, Santa Barbara.
    Linder, Jodell
    Department of Ecology, Evolution, and Marine Biology, University of California, Santa Barbara.
    Friberg, Urban
    Umeå universitet, Institutionen för ekologi, miljö och geovetenskap.
    Lew, Timothy
    Department of Ecology, Evolution, and Marine Biology, University of California, Santa Barbara.
    Morrow, Edward
    Department of Ecology, Evolution, and Marine Biology, University of California, Santa Barbara.
    Stewart, Andrew
    Department of Ecology, Evolution, and Marine Biology, University of California, Santa Barbara.
    Inter-locus antagonistic coevolution as an engine of speciation: assessment with hemiclonal analysis2005In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, no Suppl. 1, p. 6527-6534Article in journal (Refereed)
    Abstract [en]

    One of Ernst Mayr's legacies is the consensus that the allopatry model is the predominant mode of speciation in most sexually reproducing lineages. In this model, reproductive isolation develops as a pleiotropic byproduct of the genetic divergence that develops among physically isolated populations. Presently, there is no consensus concerning which, if any, evolutionary process is primarily responsible for driving the specific genetic divergence that leads to reproductive isolation. Here, we focus on the hypothesis that inter-locus antagonistic coevolution drives rapid genetic divergence among allopatric populations and thereby acts as an important “engine” of speciation. We assert that only data from studies of experimental evolution, rather than descriptive patterns of molecular evolution, can provide definitive evidence for this hypothesis. We describe and use an experimental approach, called hemiclonal analysis, that can be used in theDrosophila melanogaster laboratory model system to simultaneously screen nearly the entire genome for both standing genetic variation within a population and the net-selection gradient acting on the variation. Hemiclonal analysis has four stages: (i) creation of a laboratory “island population”; (ii) cytogenetic cloning of nearly genome-wide haplotypes to construct hemiclones; (iii) measurement of additive genetic variation among hemiclones; and (iv) measurement of the selection gradient acting on phenotypic variation among hemiclones. We apply hemiclonal analysis to test the hypothesis that there is ongoing antagonistic coevolution between the sexes in the D. melanogaster laboratory model system and then discuss the relevance of this analysis to natural systems.

  • 42.
    Rothenberg, Ellen V.
    et al.
    CALTECH, CA 91125 USA.
    Ungerbäck, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. CALTECH, CA 91125 USA.
    Champhekar, Ameya
    University of Calif Los Angeles, CA USA.
    Forging T-Lymphocyte Identity: Intersecting Networks of Transcriptional Control2016In: Advances in Immunology, ISSN 0065-2776, E-ISSN 1557-8445, Vol. 129, p. 109-174Article, review/survey (Refereed)
    Abstract [en]

    T-lymphocyte development branches off from other lymphoid developmental programs through its requirement for sustained environmental signals through the Notch pathway. In the thymus, Notch signaling induces a succession of T-lineage regulatory factors that collectively create the T-cell identity through distinct steps. This process involves both the staged activation of T-cell identity genes and the staged repression of progenitor-cell-inherited regulatory genes once their roles in self-renewal and population expansion are no longer needed. With the recent characterization of innate lymphoid cells (ILCs) that share transcriptional regulation programs extensively with T-cell subsets, T-cell identity can increasingly be seen as defined in modular terms, as the processes selecting and actuating effector function are potentially detachable from the processes generating and selecting clonally unique T-cell receptor structures. The developmental pathways of different classes of T cells and ILCs are distinguished by the numbers of prerequisites of gene rearrangement, selection, and antigen contact before the cells gain access to nearly common regulatory mechanisms for choosing effector function. Here, the major classes of transcription factors that interact with Notch signals during T-lineage specification are discussed in terms of their roles in these programs, the evidence for their spectra of target genes at different stages, and their cross-regulatory and cooperative actions with each other. Specific topics include Notch modulation of PU.1 and GATA-3, PU.1-Notch competition, the relationship between PU.1 and GATA-3, and the roles of E proteins, Bcl11b, and GATA-3 in guiding acquisition of T-cell identity while avoiding redirection to an ILC fate.

  • 43.
    Sandin, Linnea
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bergkvist, Liza
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kielkopf, Claudia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Helmfors, Linda
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Zetterberg, Henrik
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden / UCL Institute of Neurology, London, UK.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Li, Hongyun
    Illawarra Health and Medical Research Institute, University of Wollongong, Australia.
    Nilsberth, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Garner, Brett
    Illawarra Health and Medical Research Institute, University of Wollongong, Australia / School of Biological Sciences, University of Wollongong, Australia.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Beneficial effects of increased lysozyme levels in Alzheimer’s disease modelled in Drosophila melanogaster2016In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 283, no 19, p. 3508-3522Article in journal (Refereed)
    Abstract [en]

    Genetic polymorphisms of immune genes that associate with higher risk to develop Alzheimer’s disease (AD) have led to an increased research interest on the involvement of the immune system in AD pathogenesis. A link between amyloid pathology and immune gene expression was suggested in a genome-wide gene expression study of transgenic amyloid mouse models. In this study, the gene expression of lysozyme, a major player in the innate immune system, was found to be increased in a comparable pattern as the amyloid pathology developed in transgenic mouse models of AD. A similar pattern was seen at protein levels of lysozyme in human AD brain and CSF, but this lysozyme pattern was not seen in a tau transgenic mouse model. Lysozyme was demonstrated to be beneficial for different Drosophila melanogaster models of AD. In flies that expressed Aβ1-42 or AβPP together with BACE1 in the eyes, the rough eye phenotype indicative of toxicity was completely rescued by coexpression of lysozyme. In Drosophila flies bearing the Aβ1-42 variant with the Arctic gene mutation, lysozyme increased the fly survival and decreased locomotor dysfunction dose dependently. An interaction between lysozyme and Aβ1-42 in the Drosophila eye was discovered. We propose that the increased levels of lysozyme, seen in mouse models of AD and in human AD cases, were triggered by Aβ1-42 and caused a beneficial effect by binding of lysozyme to toxic species of Aβ1-42, which prevented these from exerting their toxic effects. These results emphasize the possibility of lysozyme as biomarker and therapeutic target for AD.

  • 44.
    Somasundaram, Rajesh
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Prasad, Mahadesh A. J.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ungerbäck, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 2, p. 144-152Article in journal (Refereed)
    Abstract [en]

    B-lymphocyte development in the bone marrow is controlled by the coordinated action of transcription factors creating regulatory networks ensuring activation of the B-lymphoid program and silencing of alternative cell fates. This process is tightly connected to malignant transformation because B-lineage acute lymphoblastic leukemia cellsdisplay a pronounced block in differentiation resulting in the expansion of immature progenitor cells. Over the last few years, high-resolution analysis of genetic changes in leukemia has revealed that several key regulators of normal B-cell development, including IKZF1, TCF3, EBF1, and PAX5, are genetically altered in a large portion of the human B-lineage acute leukemias. This opens the possibility of directly linking the disrupted development as well as aberrant gene expression patterns in leukemic cells to molecular functions of defined transcription factors in normal cell differentiation. This review article focuses on the roles of transcription factors in early B-cell development and their involvement in the formation of human leukemia.

  • 45.
    Stratmann, Johannes
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Neuronal cell fate specification by the molecular convergence of different spatio-temporal cues on a common initiator terminal selector gene2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, p. 26Article in journal (Refereed)
    Abstract [en]

    The extensive genetic regulatory flows underlying specification of different neuronal subtypes are not well understood at the molecular level. The Nplp1 neuropeptide neurons in the developing Drosophila nerve cord belong to two sub-classes; Tv1 and dAp neurons, generated by two distinct progenitors. Nplp1 neurons are specified by spatial cues; the Hox homeotic network and GATA factor grn, and temporal cues; the hb -greater than Kr -greater than Pdm -greater than cas -greater than grh temporal cascade. These spatio-temporal cues combine into two distinct codes; one for Tv1 and one for dAp neurons that activate a common terminal selector feedforward cascade of col -greater than ap/eya -greater than dimm -greater than Nplp1. Here, we molecularly decode the specification of Nplp1 neurons, and find that the cis-regulatory organization of col functions as an integratory node for the different spatio-temporal combinatorial codes. These findings may provide a logical framework for addressing spatio-temporal control of neuronal sub-type specification in other systems. [ABSTRACT FROM AUTHOR]

  • 46.
    Tamayo-Canul, Julio
    et al.
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Alvarez, Mercedes
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Mata-Campuzano, Maria
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology, University of León, León, Spain.
    Alvarez-Rodríguez, Manuel
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    de Paz, Paulino
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology, University of León, León, Spain.
    Anel, Luis
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Animal Reproduction and Obstetrics, University of León, León, Spain.
    Martínez-Pastor, Felipe
    ITRA-ULE, INDEGSAL, University of León, León, Spain; Molecular Biology, University of León, León, Spain.
    Effect of storage method and extender osmolality in the quality of cryopreserved epididymal ram spermatozoa.2011In: Animal Reproduction Science, ISSN 0378-4320, E-ISSN 1873-2232, Vol. 129, no 3-4, p. 188-199Article in journal (Refereed)
    Abstract [en]

    Post-mortem sperm recovery and cryopreservation could be a complement to germplasm banking in sheep, especially for endangered breeds. This study is an attempt to identify factors for improving the success of cryopreserving ram epididymal spermatozoa, considering the decrease of sperm quality with post-mortem time. Epididymal spermatozoa from 9 rams were kept at 5°C using three storage methods: within the epididymes, undiluted sperm mass, and diluted in extenders of different osmolality (TES-Tris-fructose at 320, 370 or 420 mOsm/kg, 20% egg yolk, 8% glycerol). At 0, 24, 48 and 72h, spermatozoa were cryopreserved using each extender. Samples were analyzed before and after cryopreservation by CASA (motility) and flow cytometry (viability and acrosomal status). Post-mortem time decreased pre-freezing and post-thawing sperm quality. Some storage x extender combinations improved the effect of post-mortem time on sperm quality. Both epididymis storage combined with the 420 extender, and storing the spermatozoa diluted in the 320 extender improved post-thawing quality, especially at long post-mortem times. Storing the spermatozoa diluted in the 370 extender was detrimental for the acrosomal status. These findings have practical applications. The simplest storage method (within the epididymes) seems to be adequate if hyperosmotic extenders were used for freezing. An alternative method could be storing the spermatozoa diluted in a hypoosmotic extender. These recommendations are limited to the osmolalities tested in this study (420 mOsm/kg and 320 mOsm/kg); other osmolalities should be tested.

  • 47.
    Vennerholm, Linn
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Ontogeny of personality in red junglefowl chicks, Gallus gallus2012Independent thesis Basic level (degree of Bachelor), 10,5 credits / 16 HE creditsStudent thesis
    Abstract [en]

    Many studies have been performed on animals to study their behavior, but not as many on the development of behavior, and not yet on chickens. Therefore, 42 red junglefowls were tested in three Novel Arena, Novel Object and Tonic Immobility tests to investigate the ontogeny of personality. Several behaviors were stable over time in the Novel Arena and Novel Object tests, and are a part of the bird’s personality, while other behaviors were plastic. The stability of the behaviors increased over time. The decrease in duration of the Tonic Immobility can be due to decreased stress during the length of the study. The study showed that personality can be detected early in a chicken’s life, even though a lot of the observed behaviors change. Further studies are needed to figure out duration of the stability and why certain behaviors are stable.

  • 48.
    Vicente Carrillo, Alejandro
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Alvarez-Rodriguez, Manuel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    The mu (µ) and delta (δ) opioid receptors modulate boar sperm motility2016In: Molecular Reproduction and Development, ISSN 1040-452X, E-ISSN 1098-2795, Vol. 83, no 8, p. 724-734Article in journal (Refereed)
    Abstract [en]

    Endogenous and exogenous opioids modulate reproductive functions in target cells via opioid receptors (µ, δ, and κ). Sperm motility is a metric of gamete functionality, and serves as a suitable parameter for in vitro drug-induced toxicity assays. This study identifies the presence and location of opioid receptors in pig spermatozoa as well as their functional response after in vitro challenge with known agonists (morphine [µ]; [D-Pen 2,5]-enkephanile [δ]; and U 50488 [κ]) and antagonists (naloxone [µ]; naltrindole [δ]; and nor-binaltrorphimine [κ]). Only the µ- and δ-opioid receptors were present in the sperm plasma membrane, overlying the acrosome, neck, and principal piece. Challenge experiments with agonists and antagonists identified both µ- and δ-opioid receptors as regulators of sperm kinematics, wherein µ maintains or increases sperm movement whereas δ decreases sperm motility over time. This article is protected by copyright. All rights reserved.

  • 49.
    Vicente-Carrillo, Alejandro
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Ekwall, H
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Álvarez-Rodríguez, Manuel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Membrane Stress During Thawing Elicits Redistribution of Aquaporin 7 But Not of Aquaporin 9 in Boar Spermatozoa2016In: Reproduction in domestic animals, ISSN 0936-6768, E-ISSN 1439-0531, Vol. 51, no 5, p. 665-679Article in journal (Refereed)
    Abstract [en]

    Freezing of boar spermatozoa includes the cryoprotectant glycerol, but renders low cryosurvival, owing to major changes in osmolarity during freezing/thawing. We hypothesize that aquaporins (AQPs) 7 and 9 adapt their membrane domain location to these osmotic challenges, thus maintaining sperm homeostasis. Western blotting (WB) and immunocytochemistry (ICC) at light and electron microscope levels with several commercial primary antibodies and protocols explored AQP location on cauda epididymal and ejaculated spermatozoa (from different fractions of the ejaculate), unprocessed, extended, chilled and frozen-thawed. Although differences in WB and ICC labelling were seen among antibodies, AQP-7 was conspicuously located in the entire tail and cytoplasmic droplet in caudal spermatozoa, being restricted to the mid-piece and principal piece domains in ejaculated spermatozoa. AQP-9 was mainly localized in the sperm head in both caudal and ejaculated spermatozoa. While unaffected by chilling (+5°C), freezing and thawing of ejaculated spermatozoa clearly relocated the head labelling of AQP-7, but not that of AQP-9. In vitro mimicking of cell membrane expansion during quick thawing maintained the localization of AQP-9 but relocated AQP-7 towards the acrosome. AQP-7, but not AQP-9, appears as a relevant marker for non-empirical studies of sperm handling.

  • 50.
    Wilhelms, Daniel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Zajdel, Joanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Singh, Anand Kumar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Cyclooxygenase Isoform Exchange Blocks Brain-Mediated Inflammatory Symptoms2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0166153Article in journal (Refereed)
    Abstract [en]

    Cyclooxygenase-2 (COX-2) is the main source of inducible prostaglandin E-2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. COX-1 is dispensable for fever, anorexia and hyperalgesia but is important for several other functions both under basal conditions and during inflammation. The differential functionality of the COX isoforms could be due to differences in the regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, resulting in distinct functional properties of the proteins. To study the molecular underpinnings of the functional differences between the two isoforms in the context of inflammatory symptoms, we used mice in which the coding sequence of COX-2 was replaced by the corresponding sequence of COX-1. In these mice, COX-1 mRNA was induced by inflammation but COX-1 protein expression did not fully mimic inflammation-induced COX-2 expression. Just like mice globally lacking COX-2, these mice showed a complete lack of fever and inflammation-induced anorexia as well as an impaired response to inflammatory pain. However, as previously reported, they displayed close to normal survival rates, which contrasts to the high fetal mortality in COX-2 knockout mice. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate the inflammatory symptoms studied, making the line an interesting alternative to COX-2 knockouts for the study of inflammation. Our results also show that the functional differences between COX-1 and COX-2 in the context of inflammatory symptoms are not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels.

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