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  • 1.
    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.
    Show others...
    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
  • 2.
    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.

  • 3.
    Baumgardt, Magnus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology-IKE . Linköping University, Faculty of Health Sciences.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology-IKE . Linköping University, Faculty of Health Sciences.
    Terriente, Javier
    University of Autonoma.
    J Diaz-Benjumea, Fernando
    University of Autonoma.
    Thor , Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology-IKE . Linköping University, Faculty of Health Sciences.
    From stem cell to unique neuron: Temporal transitions in an identified CNS progenitor cell by feedforward combinatorial coding2009In: The 12th European Drosophila Neurobiology Conference 6-10 September 2008 Wuerzburg, Germany: in: Journal of Neurogenetics, Volume 23 Supplement 1 2009, 2009, Vol. 23, p. S14-S15Conference paper (Refereed)
  • 4.
    Baumgardt, Magnus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Miguel-Aliaga, Irene
    Medical Research Council National Institute for Medical Research, London,.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Ekman, Helen
    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.
    Specification of neuronal identities by feedforward combinatorial coding.2007In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 5, no 2, p. 0295-0308Article in journal (Refereed)
    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.

  • 5.
    Benito-Sipos, Jonathan
    et al.
    University of Autonoma.
    Estacio, Alicia
    CSIC, Spain.
    Moris, Marta
    CSIC, 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.
    Diaz-Benjumea , Fernando J
    CSIC, Spain.
    Analysis of the specification of the Leucokininergic cell fate2009In: The 12th European Drosophila Neurobiology Conference 6-10 September 2008 Wuerzburg, Germany: in: Journal of Neurogenetics, Volume 23 Supplement 1 2009, 2009, Vol. 23, p. S16-S16Conference paper (Refereed)
  • 6.
    Benito-Sipos, Jonathan
    et al.
    University Autonoma of Madrid.
    Estacio-Gomez, Alicia
    University Autonoma of Madrid.
    Moris-Sanz, Marta
    University Autonoma of Madrid.
    Baumgardt, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE.
    Thor, Stefan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE.
    J Diaz-Benjumea, Fernando
    University Autonoma of Madrid.
    A genetic cascade involving klumpfuss, nab and castor specifies the abdominal leucokinergic neurons in the Drosophila CNS2010In: DEVELOPMENT, ISSN 0950-1991, Vol. 137, no 19, p. 3327-3336Article in journal (Refereed)
    Abstract [en]

    Identification of the genetic mechanisms underlying the specification of large numbers of different neuronal cell fates from limited numbers of progenitor cells is at the forefront of developmental neurobiology. In Drosophila, the identities of the different neuronal progenitor cells, the neuroblasts, are specified by a combination of spatial cues. These cues are integrated with temporal competence transitions within each neuroblast to give rise to a specific repertoire of cell types within each lineage. However, the nature of this integration is poorly understood. To begin addressing this issue, we analyze 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 signaling pathway on their specification. We also show that the products of the genes klumpfuss, nab and castor play important roles in their specification via a genetic cascade.

  • 7.
    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.

  • 8.
    Benito-Sipos, Jonathan
    et al.
    University Autonoma Madrid.
    Ulvklo, Carina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    Gabilondo, Hugo
    University Autonoma Madrid.
    Angel, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    Torroja, Laura
    University Autonoma Madrid.
    Thor, Stefan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    Seven-up is critical at two different stages of Neuroblast 5-6 development in JOURNAL OF NEUROGENETICS, vol 24, issue , pp 83-832010In: JOURNAL OF NEUROGENETICS, Informa Healthcare , 2010, Vol. 24, p. 83-83Conference paper (Refereed)
    Abstract [en]

    n/a

  • 9.
    Benito-Sipos, Jonathan
    et al.
    University of Autonoma Madrid, Spain.
    Ulvklo, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Gabilondo, Hugo
    University of Autonoma Madrid, Spain.
    Baumgardt, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Angel, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Torroja, Laura
    University of Autonoma Madrid, Spain.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Seven up acts as a temporal factor during two different stages of neuroblast 5-6 development2011In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 138, no 24, p. 5311-5320Article in journal (Refereed)
    Abstract [en]

    Drosophila embryonic neuroblasts generate different cell types at different time points. This is controlled by a temporal cascade of Hb -greater than Kr -greater than Pdm -greater than Cas -greater than Grh, which acts to dictate distinct competence windows sequentially. In addition, Seven up (Svp), a member of the nuclear hormone receptor family, acts early in the temporal cascade, to ensure the transition from Hb to Kr, and has been referred to as a switching factor. However, Svp is also expressed in a second wave within the developing CNS, but here, the possible role of Svp has not been previously addressed. In a genetic screen for mutants affecting the last-born cell in the embryonic NB5-6T lineage, the Ap4/FMRFamide neuron, we have isolated a novel allele of svp. Expression analysis shows that Svp is expressed in two distinct pulses in NB5-6T, and mutant analysis reveals that svp plays two distinct roles. In the first pulse, svp acts to ensure proper downregulation of Hb. In the second pulse, which occurs in a Cas/Grh double-positive window, svp acts to ensure proper sub-division of this window. These studies show that a temporal factor may play dual roles, acting at two different stages during the development of one neural lineage.

  • 10.
    Berg, Ina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Curcumin alleviates Aβ indcuced neurotoxicity and vice versa without removing amyloid deposits in transgenic DrosophilaManuscript (preprint) (Other academic)
    Abstract [en]

    Curcumin has been proposed to facilitate clearance of toxic amyloid formed by the Aβ peptide. To further address this notion, different concentrations of curcumin were tried for its effects in various Drosophila Alzheimer’s disease (AD) models. This study entailed five different Drosophila AD models (four Aβ expressing lines, and one tau expressing line), expressing the AD associated proteins using the Gal4/UAS system. These were assayed for several aspects of neurological impairment, including survival, climbing behavior, as well as locomotor activity. In addition, amyloid deposition was assessed by histological analysis. Curcumin treatment substantially prolonged the lifespan and improved climbing and locomotor activity for flies with severe disease geneotypes (Aβ1-42 E22G and double expressing Aβ1-42). In comparison, curcumin feeding of control flies resulted in a concentration-dependent shortened lifespan, whereas no such toxic side effects were found for AD genotypes with a mild phenotype (single expressors of Aβ1-40 and Aβ1-42). All flies expressing Aβ and tau displayed a higher total locomotor activity, and a continuation of the activity over a larger number of hours upon curcumin treatment. Unexpectedly, no change in tissue amyloid deposition upon curcumin treatment was observed. In vitro fibrillation of Aβ1-42, followed by Western blot and transmission electron microscopy in the presence and absence of curcumin, displayed enhanced fibrillation into large aggregates and decreased population of oligomers in curcumin samples. The decrease in oligomer formation by curcumin may explain why it increases the lifespan and activity without removing of the amyloid deposits seen in tissues. We also suggest that Aβ, at least in the context of Drosophila, functions as a chemical detoxifier sequestering curcumin and thereby mitigating its toxicity.

  • 11.
    Berg, Ina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Efficient imaging of amyloid deposits in Drosophila models of human amyloidoses2010In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 5, p. 935-944Article in journal (Refereed)
    Abstract [en]

    Drosophila melanogaster is emerging as an important model system for neurodegenerative disease research. In this protocol, we describe an efficient method for imaging amyloid deposits in the Drosophila brain, by the use of a luminescent-conjugated oligothiophene (lco), p-Ftaa polymer probe. We also demonstrate the feasibility of co-staining with antibodies and compare the lco staining with standard amyloid-specific probes. the lco protocol enables high-resolution imaging of several different protein aggregates, such as aβ1-42, aβ1-42e22G, transthyretin V30M and human tau, in the Drosophila brain. aβ and tau aggregates could also be distinguished from each other because of distinct lco emission spectra. Furthermore, this protocol enables threedimensional brain mapping of amyloid distribution in whole-mount Drosophila brains. the use of p-Ftaa combined with other probes, antibodies and/or dyes will aid the rapid characterization of various amyloid deposits in the rapidly growing number of Drosophila models of neurodegenerative diseases.

  • 12.
    Berg, Ina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Modeling Familial Amyloidotic Polyneuropathy (Transthyretin V30M) in Drosophila melanogaster2009In: NEURODEGENERATIVE DISEASES, ISSN 1660-2854, Vol. 6, no 3, p. 127-138Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Transthyretin (TTR) is a prevalent plasma and cerebrospinal fluid protein associated with sporadic and heritable amyloidosis. TTR amyloidosis is linked to a vast number of mutations with varying phenotype, tissue distribution and age of onset. The most prevalent mutation associated with familial amyloidotic polyneuropathy (FAP) is the V30M mutation. Studies of transgenic mouse models of TTR V30M FAP have been hampered by variable phenotype, low disease penetrance, and slow onset. Methods/Results: To model TTR-associated amyloid disease in the Drosophila model system, transgenic Drosophila were generated, expressing wild-type (wt) TTR or TTR V30M, associated with sporadic senile systemic amyloidosis (SSA) and inherited FAP, respectively. We found that expression of FAP-associated TTR V30M mutant in the nervous system resulted in reduced lifespan and in reduced climbing ability indicating neurological impairment, whereas expression of TTR wt showed a milder phenotype. Congo red staining of the Drosophila brain shows positive amyloid binding in the aged TTR V30M flies. Extensive brain vacuole formation was evident for the aged TTR V30M flies, whereas a milder phenotype was shown by the TTR wt flies. In addition, expression of TTR V30M in the eye leads to tissue damage, including rough eye, morphological changes and fibrous deposition. Conclusion: Our results suggest that Drosophila is a promising complementary system for studies of TTR-associated amyloid diseases.

  • 13.
    Bivik, Caroline
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Ulvklo, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Lundin, Erika
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, Patrik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Angel, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    A genetic screen for genes controlling Apterous neuron identity and FMRFamide expression2010In: Journal of neurogenetics, ISSN 0167-7063, E-ISSN 1563-5260, Vol. 24, no Suppl. 1, p. 70-71Article in journal (Other academic)
    Abstract [en]

    n/a

  • 14.
    Ceasar (Berg), Ina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Jonsson, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2Article in journal (Refereed)
    Abstract [en]

    The pathology of Alzheimers disease (AD) is characterized by the presence of extracellular deposits of misfolded and aggregated amyloid-beta (A beta) peptide and intraneuronal accumulation of tangles comprised of hyperphosphorylated Tau protein. For several years, the natural compound curcumin has been proposed to be a candidate for enhanced clearance of toxic A beta amyloid. In this study we have studied the potency of feeding curcumin as a drug candidate to alleviate A beta toxicity in transgenic Drosophila. The longevity as well as the locomotor activity of five different AD model genotypes, measured relative to a control line, showed up to 75% improved lifespan and activity for curcumin fed flies. In contrast to the majority of studies of curcumin effects on amyloid we did not observe any decrease in the amount of A beta deposition following curcumin treatment. Conformation-dependent spectra from p-FTAA, a luminescent conjugated oligothiophene bound to A beta deposits in different Drosophila genotypes over time, indicated accelerated pre-fibrillar to fibril conversion of A beta(1-42) in curcumin treated flies. This finding was supported by in vitro fibrillation assays of recombinant A beta(1-42). Our study shows that curcumin promotes amyloid fibril conversion by reducing the pre-fibrillar/oligomeric species of A beta, resulting in a reduced neurotoxicity in Drosophila.

  • 15.
    Engström, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Rosén, Khadijah
    Angel, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology-IKE . Linköping University, Faculty of Health Sciences.
    Fyrberg, Anna
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Mackerlova, Ludmila
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Konsman, Jan Pieter
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland2008In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, no 4, p. 1436-1450Article in journal (Refereed)
    Abstract [en]

    There is evidence from in vitro studies that inflammatory messengers influence the release of stress hormone via direct effects on the adrenal gland; however, the mechanisms underlying these effects in the intact organism are unknown. Here we demonstrate that systemic inflammation in rats elicited by iv injection of lipopolysaccharide results in dynamic changes in the adrenal immune cell population, implying a rapid depletion of dendritic cells in the inner cortical layer and the recruitment of immature cells to the outer layers. These changes are accompanied by an induced production of IL-1β and IL-1 receptor type 1 as well as cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in these cells, implying local cytokine-mediated prostaglandin E2 production in the adrenals, which also displayed prostaglandin E2 receptors of subtypes 1 and 3 in the cortex and medulla. The IL-1β expression was also induced by systemically administrated IL-1β and was in both cases attenuated by IL-1 receptor antagonist, consistent with an autocrine signaling loop. IL-1β similarly induced expression of cyclooxygenase-2, but the cyclooxygenase-2 expression was, in contrast, further enhanced by IL-1 receptor antagonist. These data demonstrate a mechanism by which systemic inflammatory agents activate an intrinsically regulated local signaling circuit that may influence the adrenals’ response to immune stress and may help explain the dissociation between plasma levels of ACTH and corticosteroids during chronic immune perturbations.

  • 16.
    Fernius, Josefin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Starkenberg, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Pokrzywa, Malgorzata
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Airopt Sp Zoo, Poland.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Human TTBK1, TTBK2 and MARK1 kinase toxicity in Drosophila melanogaster is exacerbated by co-expression of human Tau2017In: BIOLOGY OPEN, ISSN 2046-6390, Vol. 6, no 7, p. 1013-1023Article in journal (Refereed)
    Abstract [en]

    Tau protein is involved in numerous human neurodegenerative diseases, and Tau hyper-phosphorylation has been linked to Tau aggregation and toxicity. Previous studies have addressed toxicity and phospho-biology of human Tau (hTau) in Drosophila melanogaster. However, hTau transgenes have most often been randomly inserted in the genome, thus making it difficult to compare between different hTau isoforms and phospho-mutants. In addition, many studies have expressed hTau also in mitotic cells, causing nonphysiological toxic effects. Here, we overcome these confounds by integrating UAS-hTau isoform transgenes into specific genomic loci, and express hTau post-mitotically in the Drosophila nervous system. Lifespan and locomotor analyses show that all six of the hTau isoforms elicit similar toxicity in flies, although hTau(2N3R) showed somewhat elevated toxicity. To determine if Tau phosphorylation is responsible for toxicity, we analyzed the effects of co-expressing hTau isoforms together with Tau-kinases, focusing on TTBK1, TTBK2 and MARK1. We observed toxicity when expressing each of the three kinases alone, or in combination. Kinase toxicity was enhanced by hTau co-expression, with strongest co-toxicity for TTBK1. Mutagenesis and phosphorylation analysis indicates that hTau-MARK1 combinatorial toxicity may be due to direct phosphorylation of hTau, while hTau-TTBK1/2 combinatorial toxicity may result from independent toxicity mechanisms.

  • 17.
    Garcia, Emanuell
    et al.
    Department of Animal Environment and Health, Swedish University of Agricultural Sciences, Skara, Sweden.
    Hultgren, Jan
    Department of Animal Environment and Health, Swedish University of Agricultural Sciences, Skara, Sweden.
    Fällman, Pontus
    Department of Animal Environment and Health, Swedish University of Agricultural Sciences, Skara, Sweden.
    Geust, Johanna
    Nötcenter Viken, Vikens Egendom, Falköping, Sweden.
    Algers, Bo
    Department of Animal Environment and Health, Swedish University of Agricultural Sciences, Skara, Sweden.
    Stilwell, George
    Centro de Investigação Interdisciplinar em Sanidade Animal, Universidade Técnica de Lisboa, Lisboa, Portugal.
    Gunnarsson, Stefan
    Department of Animal Environment and Health, Swedish University of Agricultural Sciences, Skara, Sweden.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences. Department of Animal Environment and Health, Swedish University of Agricultural Sciences, Skara, Sweden.
    Intensity of Oestrus Signalling Is the Most Relevant Indicator for Animal Well-Being in High-Producing Dairy Cows2011In: Veterinary Medicine International, ISSN 2090-8113, E-ISSN 2042-0048, Vol. 2011, article id 540830Article in journal (Refereed)
    Abstract [en]

    Full signalling of oestrous behaviour is vital for proper timing of AI and good reproductive performance, currently jeopardized by shorter observations of oestrus behaviour. Alternative indicators including progesterone (P4) recordings on-farm are tested. Oestrous intensity of 37 heifers (H) and 30 1st-parity dairy cows (C1) either Swedish Red (32) or Swedish Holstein (35) with high genetic potential for milk production, was studied in relation to AI. P4-levels in blood or milk were monitored on-farm at 0, 7, and 20 d post-AI with a portable ELISA reader (eProCheck800). Avoidance distance and body condition were scored at day 7, and pregnancy diagnosed by P4 (day 20) and trans-rectal palpation (day 50). More heifers (46%) than C1-cows (10%) showed standing oestrus (strongest intensity, 𝑃<0.05), leading to higher pregnancy rate at d50 (72% versus 37% for C1, 𝑃<0.01) and calving rate (H: 64%, C1: 33%, 𝑃<0.05). Avoidance distances were short (<1 m), reflecting good human-animal interaction. Visually-recorded standing oestrus yielded 4.8 fold higher odds of pregnancy, respectively 4.6-fold higher odds of calving. On-farm P4-recordings had complementary value yet less accuracy. Intensity of oestrus signalling relates to animal well-being, reflected in pregnancy-to-term being a good indicator for optimal welfare in high-producing dairy cattle.

  • 18.
    Gizejewski, Z
    et al.
    Institute of Animal Breeding and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
    Söderquist, L
    Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Sciences, SLU, Uppsala, Sweden.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Genital and sperm characteristics of wild, free rangingred deer stags (Cervus elaphus L) hunted in different regions of Poland2010In: Wildlife Biology in Practice, ISSN 1646-1509, E-ISSN 1646-2742, Vol. 6, no 2, p. 81-94Article in journal (Refereed)
    Abstract [en]

    In an attempt to establish reference values for sperm morphology in wild red deer, genital tracts were collected from thirty-six 3-11 years old free-ranging, wild red deer stags (Cervus elaphus L) shot down during 3 consecutive mating seasons (1996-1998) at three different environmental regions of Poland, defining two major ecotypes: (i) highland (outer eastern Carpathian range, Bieszczady mountains) and, (ii) lowland (Mazuria and Pomerania) and studied within 4.5h-49h after death for testis (T), epididymides (E) and vesicular gland (VG) variables. Spermatozoa collected from the E-cauda were examined for motility and morphology (light and electron microscopy levels). Both T size and weight and VS-weight differed with age (P<0.05-0.01) while habitat influenced T size and weight (P<0.01) a well as sperm motility (P<0.05). Neither sperm numbers nor morphology showed significant differences, mostly owing to

    the large variation recorded among stags (range 1-72%). Domain-grouped sperm morphological deviations were <5%, the mean total proportion of abnormal spermatozoa ranging 7.2-17.5%. Although variation was present, the values ought to be used as reference for spermiogrammes.

  • 19.
    Jafari, Shadi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Alkhori, Liza
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Schleiffer, Alexander
    Research Institute Molecular Pathol IMP, Vienna.
    Brochtrup, Anna
    University of Vienna.
    Hummel, Thomas
    University of Vienna.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression2012In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 10, no 3, p. e1001280-Article in journal (Refereed)
    Abstract [en]

    The mechanism that specifies olfactory sensory neurons to express only one odorant receptor (OR) from a large repertoire is critical for odor discrimination but poorly understood. Here, we describe the first comprehensive analysis of OR expression regulation in Drosophila. A systematic, RNAi-mediated knock down of most of the predicted transcription factors identified an essential function of acj6, E93, Fer1, onecut, sim, xbp1, and zf30c in the regulation of more than 30 ORs. These regulatory factors are differentially expressed in antennal sensory neuron classes and specifically required for the adult expression of ORs. A systematic analysis reveals not only that combinations of these seven factors are necessary for receptor gene expression but also a prominent role for transcriptional repression in preventing ectopic receptor expression. Such regulation is supported by bioinformatics and OR promoter analyses, which uncovered a common promoter structure with distal repressive and proximal activating regions. Thus, our data provide insight into how combinatorial activation and repression can allow a small number of transcription factors to specify a large repertoire of neuron classes in the olfactory system.

  • 20.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Specification of unique neuronal sub-types by integration of positional and temporal cues2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The nervous system contains vast numbers of neuronal sub-types, generated at specific time points, in the proper location, and in proper numbers. One of the fundamental issues in neurobiology is to understand the molecular genetic mechanisms that underlie the generation of this daunting neuronal diversity.

    To help shed light upon these fundamental questions, my PhD project has addressed the generation and specification of a certain group of neurons, the Ap cluster. This group of four neurons is found only in thoracic segments within the Drosophila melanogaster central nervous system, and consists of three different cell types. Mapping of the neuroblast (stem cell) that generates the Ap cluster neurons, neuroblast 5-6, and the highly restricted appearance of this cluster allowed me to address the following questions: How does NB 5-6 change its temporal competence over time to generate the Ap cluster neurons late in the lineage, and how is temporal competence altered to ensure diversity among the Ap neurons? What are the mechanisms that allow these Ap cluster neurons to emerge only in the thoracic segments?

    My studies have helped identify a number of mechanisms acting to specify the Ap cluster neurons. One type of mechanism involves several of different feed-forward loops that play out during NB 5-6 lineage development. These are triggered within the stem cell, where the temporal gene castor activates a number of genes. These castor targets are subsequently involved in several regulatory feed-forward loops, that ultimately result in the unique combinatorial expression of cell fate determinants in the different Ap neurons, which in turn ultimately lead to the activation of unique terminal differentiation genes. In addition, I have identified three different mechanisms by which the NB 5-6 lineage is modulated along the neuroaxis. In the abdomen I find that an early cell cycle exit is initiated by the Bx-C gene members and Pbx/Meis cofactors, which result in the truncation of the NB 5-6 lineage, preventing the Ap cluster neurons from being generated. In thoracic segments Hox, Pbx/Meisand temporal genes act in concert to specify Ap cluster neurons, by integrating with the castor temporal gene. In anterior segments, improper Hox and temporal coding results in a failure to specify bona fide Ap cluster neurons, even though equivalents of Ap cluster neurons are generated.

    In summary, my thesis work has helped identify a number of mechanisms acting to specify this unique neuronal sub-type, including: feed-forward combinatorial coding, opposing feed-forward loops and integrated temporal/Hox mediated specification throughout different axial levels. I suggest that these mechanisms may be widely used within the animal kingdom, hence contributing to the great cellular diversity observed within the central nervous system of most animal species.

    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.
    Show others...
    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
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    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 structurally plastic extension of the homeodomain recognition helix orchestrates central Hox protein activity
    Open this publication in new window or tab >>A structurally plastic extension of the homeodomain recognition helix orchestrates central Hox protein activity
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Protein function is encoded within the amino acid coding sequence and the variation in this sequence, and subsequent structure, provide the bases for functional diversification at the molecular and organismal levels. However, how separate protein domainscooperate to build protein activity remains largely unknown. Focusing on three domains of central Hox transcription factors, we mutagenized combinations of their domains to investigate their intrinsic functional organization. Our results demonstrate a high degree of domain interactivity, with an orchestrating role of a structurally plastic C-terminal extension of the homeodomain (HD). This domain provides, in a folding dependant manner, a topologically constrained contact with the Hox cofactor Extradenticle, which impacts the positioning of the recognition helix in the major groove of DNA. These findings provide novel insights in HD/DNA target recognition and, given the phylogeny of this C-terminal extension, also shed light on the molecular bases underlying the functional diversification of paralogous Hox families.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-63627 (URN)
    Available from: 2010-12-28 Created: 2010-12-28 Last updated: 2016-11-30
  • 21.
    Karlsson, Daniel
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE.
    Aspevall, O
    Linkoping Univ, S-58183 Linkoping, Sweden Karolinska Inst, Dept Immunol Microbiol Pathol & Infect Dis, Stockholm, Sweden Linkoping Univ, Div Clin Microbiol, S-58183 Linkoping, Sweden.
    Forsum, Urban
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology .
    A decision-support system for urinary tract infections1999In: JAMIA Journal of the American Medical Informatics Association, ISSN 1067-5027, E-ISSN 1527-974X, p. 1094-1094Conference paper (Other academic)
  • 22.
    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.

  • 23.
    Landgraf, M.
    et al.
    Department of Zoology, University of Cambridge, Cambridge, CB2 3EJ, United Kingdom.
    Thor, Stefan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE.
    Development and Structure of Motoneurons2006In: International review of neurobiology, ISSN 0074-7742, E-ISSN 2162-5514, Vol. 75, p. 33-53Article, review/survey (Refereed)
    Abstract [en]

    [No abstract available]

  • 24.
    Losada-Perez, Maria
    et al.
    University Autonoma Madrid.
    Gabilondo, Hugo
    University Autonoma Madrid.
    del Saz, Delia
    University Autonoma Madrid.
    Baumgardt, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    Molina, Isabel
    University Autonoma Madrid.
    Leon, Yolanda
    University Autonoma Madrid.
    Monedero, Ignacio
    University Autonoma Madrid.
    Torroja, Laura
    University Autonoma Madrid.
    Benito-Sipos, Jonathan
    University Autonoma Madrid.
    Lineage-unrelated neurons generated in different temporal windows and expressing different combinatorial codes can converge in the activation of the same terminal differentiation gene in JOURNAL OF NEUROGENETICS, vol 24, issue , pp 80-802010In: JOURNAL OF NEUROGENETICS, Informa Healthcare , 2010, Vol. 24, p. 80-80Conference paper (Refereed)
    Abstract [en]

    n/a

  • 25.
    Losada-Perez, Maria
    et al.
    University of Autonoma Madrid, Spain.
    Gabilondo, Hugo
    University of Autonoma Madrid, Spain.
    Molina, Isabel
    University of Autonoma Madrid, Spain.
    Turiegano, Enrique
    University of Autonoma Madrid, Spain.
    Torroja, Laura
    University of Autonoma Madrid, Spain.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Benito-Sipos, Jonathan
    University of Autonoma Madrid, Spain.
    Klumpfuss controls FMRFamide expression by enabling BMP signaling within the NB5-6 lineage2013In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 140, no 10, p. 2181-2189Article in journal (Refereed)
    Abstract [en]

    A number of transcription factors that are expressed within most, if not all, embryonic neuroblast (NB) lineages participate in neural subtype specification. Some have been extensively studied in several NB lineages (e.g. components of the temporal gene cascade) whereas others only within specific NB lineages. To what extent they function in other lineages remains unknown. Klumpfuss (Klu), the Drosophila ortholog of the mammalian Wilms tumor 1 (WT1) protein, is one such transcription factor. Studies in the NB4-2 lineage have suggested that Klu functions to ensure that the two ganglion mother cells (GMCs) in this embryonic NB lineage acquire different fates. Owing to limited lineage marker availability, these observations were made only for the NB4-2 lineage. Recent findings reveal that Klu is necessary for larval neuroblast growth and self-renewal. We have extended the study of Klu to the well-known embryonic NB5-6T lineage and describe a novel role for Klu in the Drosophila embryonic CNS. Our results demonstrate that Klu is expressed specifically in the postmitotic Ap4/FMRFa neuron, promoting its differentiation through the initiation of BMP signaling. Our findings indicate a pleiotropic function of Klu in Ap cluster specification in general and particularly in Ap4 neuron differentiation, indicating that Klu is a multitasking transcription factor. Finally, our studies indicate that a transitory downregulation of klu is crucial for the specification of the Ap4/FMRFa neuron. Similar to WT1, klu seems to have either self-renewal or differentiation-promoting functions, depending on the developmental context.

  • 26.
    MacDonald, Ryan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ulvklo, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Bivik, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Baumgardt, Magnus
    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.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Notch Mediates a Genetic Switch in Neural Lineage Topology in DEVELOPMENTAL BIOLOGY, vol 356, issue 1, pp 227-2272011In: DEVELOPMENTAL BIOLOGY, Elsevier Science B.V., Amsterdam , 2011, Vol. 356, no 1, p. 227-227Conference paper (Refereed)
    Abstract [en]

    n/a

  • 27.
    Macias Garcia, B.
    et al.
    Veterinary Teaching Hospital, Laboratory of Spermatology, University of Extremadura, Cáceres, Spain.
    Gonzalez Fernandez, L.
    Department of Physiology, University of Extremadura, Avd de la Universidad s/n, Cáceres, Spain.
    Ortega Ferrusola, C.
    Veterinary Teaching Hospital, Laboratory of Spermatology, University of Extremadura, Cáceres, Spain.
    Salazar-Sandoval, C.
    Veterinary Teaching Hospital, Laboratory of Spermatology, University of Extremadura, Cáceres, Spain.
    Morillo Rodriguez, A.
    Veterinary Teaching Hospital, Laboratory of Spermatology, University of Extremadura, Cáceres, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Tapia, J.A.
    Department of Physiology, University of Extremadura, Avd de la Universidad s/n, Cáceres, Spain.
    Morcuende, D.
    Department of Animal Production and Food Science Faculty of Veterinary Medicine, University of Extremadura, Avd de la Universidad s/n, Cáceres, Spain.
    Pena, F.J.
    Veterinary Teaching Hospital, Laboratory of Spermatology, University of Extremadura, Cáceres, Spain.
    Membrane Lipids of the Stallion Spermatozoon in Relation to Sperm Quality and Susceptibility to Lipid Peroxidation2011In: Reproduction in domestic animals, ISSN 0936-6768, E-ISSN 1439-0531, Vol. 46, no 1, p. 141-148Article in journal (Refereed)
    Abstract [en]

    Contents: Lipids were extracted from ejaculated spermatozoa from seven individual stallions to distinguish neutral lipids (NL) and polar lipids (PL) and determine their variation among stallions and their relationship with sperm quality and sperm susceptibility to lipid peroxidation. The isolated fatty acids were correlated with sperm quality (membrane integrity, mitochondrial membrane potential (ΔΨm) and expression of active caspases) and the sensitivity of the sperm plasma membrane to LPO. The miristic (C14: 0), palmitic (C16: 0), stearic (C18: 0) and oleic (C18: 1n9) acids were predominant among the NLs. Within the phospholipid fraction, the docosapentanoic acid (C22: 5n6) was dominant, albeit varying among stallions. Surprisingly, the percentage of polyunsaturated fatty acids was positively correlated with sperm quality and a low propensity for LPO, probably because these particular fatty acids provide a higher fluidity of the plasma membrane. The stallion showing the poorest sperm membrane integrity plus a high level of LPO in his ejaculate had a lower percentage (p less than 0.05) of this fatty acid in his sperm plasma membranes. © 2010 Blackwell Verlag GmbH.

  • 28.
    Macías García, Beatriz
    et al.
    Faculty of Veterinary Medicine, Veterinary Teaching Hospital, Laboratory of Equine Reproduction, University of Extremadura, Cáceres, Spain.
    Miró Moran, Alvaro
    Department of Physiology, University of Extremadura, Cáceres, Spain.
    González Fernández, Lauro
    Department of Physiology, University of Extremadura, Cáceres, Spain.
    Ortega Ferrusola, Cristina
    Faculty of Veterinary Medicine, Veterinary Teaching Hospital, Laboratory of Equine Reproduction, University of Extremadura, Cáceres, Spain.
    Morillo Rodriguez, Antolin
    Faculty of Veterinary Medicine, Veterinary Teaching Hospital, Laboratory of Equine Reproduction, University of Extremadura, Cáceres, Spain.
    Gallardo Bolaños, Juan Maria
    Faculty of Veterinary Medicine, Veterinary Teaching Hospital, Laboratory of Equine Reproduction, University of Extremadura, Cáceres, Spain.
    Balao da Silva, Carolina Maria
    Faculty of Veterinary Medicine, Veterinary Teaching Hospital, Laboratory of Equine Reproduction, University of Extremadura, Cáceres, Spain.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Tapia, Jose A.
    Department of Physiology, University of Extremadura, Cáceres, Spain.
    Peña, Fernando J
    Faculty of Veterinary Medicine, Veterinary Teaching Hospital, Laboratory of Equine Reproduction, University of Extremadura, Cáceres, Spain.
    The mitochondria of stallion spermatozoa are more sensitive than the plasmalemma to osmotic induced stress: role of c-Jun N-terminal Kinase (JNKs) pathway2012In: Journal of Andrology, ISSN 0196-3635, E-ISSN 1939-4640, Vol. 33, no 1, p. 105-113Article in journal (Refereed)
    Abstract [en]

    Cryopreservation introduces extreme temperature and osmolality changes that impart lethal and sublethal effects on spermatozoa. Additionally, there is evidence that the osmotic stress induced by cryopreservation causes oxidative stress to spermatozoa. The main sources of reactive oxygen species in mammalian sperm are the mitochondria. In view of this, the aim of our study was to test whether or not osmotic stress was able to induce mitochondrial damage and to explore the osmotic tolerance of the mitochondria of stallion spermatozoa. Ejaculates from 7 stallions were subjected to osmolalities ranging from 75 to 1500 mOsm/kg, and the effect on sperm membrane integrity and mitochondrial membrane potential was studied. Additionally, the effects of changes in osmolality from hyposmotic to isosmotic and from hyperosmotic to isosmotic solutions were studied (osmotic excursions). The cellular volume of stallion spermatozoa under isosmotic conditions was 20.4 ± 0.33 μm3. When exposed to low osmolality, the stallion spermatozoa behaved like a linear osmometer, whereas exposure to high osmolalities up to 900 mOsm/kg resulted in decreased sperm volume. Although sperm membranes were relatively resistant to changes in osmolality, mitochondrial membrane potential decreased when osmolalities were low or very high (10.7 ± 1.74 and 16.5 ± 1.70 at 75 and 150 mOsm/kg, respectively, and 13.1 ± 1.83 at 1500 mOsm/kg), whereas in isosmolar controls the percentage of stallion sperm mitochondria with a high membrane potential was 41.1 ± 1.69 (P < .01). Osmotic excursions induced greater damage than exposure of spermatozoa to a given nonphysiologic osmolality, and again the mitochondria were more prone to damage induced by osmotic excursions than was the sperm plasma membrane. In search of intracellular components that could mediate these changes, we have detected for the first time the c-Jun N-terminal kinase 1/2 in stallion spermatozoa, which are apparently involved in the regulation of the viability of these cells.

  • 29.
    Merabet, S.
    et al.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Litim, I.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Foos, N.
    AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
    Jesus Mate, M.
    AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
    Dixit, R.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Saadaoui, M.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Vincentelli, R.
    AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
    Monier, B.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Vijayraghavan, K.
    Perrin, L.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Pradel, J.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    Cambillau, C.
    AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
    Ortiz Lombardia, M.
    AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
    Graba, Y.
    Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
    A structurally plastic extension of the homeodomain recognition helix orchestrates central Hox protein activityManuscript (preprint) (Other academic)
    Abstract [en]

    Protein function is encoded within the amino acid coding sequence and the variation in this sequence, and subsequent structure, provide the bases for functional diversification at the molecular and organismal levels. However, how separate protein domainscooperate to build protein activity remains largely unknown. Focusing on three domains of central Hox transcription factors, we mutagenized combinations of their domains to investigate their intrinsic functional organization. Our results demonstrate a high degree of domain interactivity, with an orchestrating role of a structurally plastic C-terminal extension of the homeodomain (HD). This domain provides, in a folding dependant manner, a topologically constrained contact with the Hox cofactor Extradenticle, which impacts the positioning of the recognition helix in the major groove of DNA. These findings provide novel insights in HD/DNA target recognition and, given the phylogeny of this C-terminal extension, also shed light on the molecular bases underlying the functional diversification of paralogous Hox families.

  • 30.
    Merabet, Samir
    et al.
    Université de la Méditerranée, Marseille, France.
    Litim-Mecheri, Isma
    Université de la Méditerranée, Marseille, France.
    Karlsson, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Dixit, Richa
    Tata Institute of Fundamental Research, Bangalore, India.
    Saadaoui, Mehdi
    Université de la Méditerranée, Marseille, France.
    Monier, Bruno
    Université de la Méditerranée, Marseille, France.
    Brun, Christine
    Université de la Méditerranée, Marseille, France.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Vijayraghavan, K
    Tata Institute of Fundamental Research, Bangalore, India.
    Perrin, Laurent
    Université de la Méditerranée, Marseille, France.
    Pradel, Jacques
    Université de la Méditerranée, Marseille, France.
    Graba, Yacine
    Université de la Méditerranée, Marseille, France.
    Insights into Hox Protein Function from a Large Scale Combinatorial Analysis of Protein Domains2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 10Article in journal (Refereed)
    Abstract [en]

    Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences.

  • 31.
    Miguel-Aliaga, Irene
    et al.
    University of Cambridge.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Programmed cell death in the nervous system-a programmed cell fate?2009In: CURRENT OPINION IN NEUROBIOLOGY, ISSN 0959-4388, Vol. 19, no 2, p. 127-133Article, review/survey (Refereed)
    Abstract [en]

    Studies of developmental cell death in the nervous system have revealed two different modes of programmed cell death (PCD). One results from competition for target-derived trophic factors and leads to the stochastic removal of neurons and/or glia. A second, hard-wired form of PCD involves the lineage-specific, stereotypical death of identifiable neurons, glia or undifferentiated cells. Although traditionally associated with invertebrates, this programmed PCD can also occur in vertebrates. Recent studies have shed light on its genetic control and have revealed that activation of the apoptotic machinery can be under the same complex, combinatorial control as the expression of terminal differentiation genes. This review will highlight these findings and will suggest why such complex control evolved.

  • 32.
    Miguel-Aliaga, Irene
    et al.
    Division of Developmental Neurobiology Medical Research Council National Institute for Medical Research, London, United Kingdom.
    Thor, Stefan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE.
    Gould, Gould
    Division of Developmental Neurobiology Medical Research Council National Institute for Medical Research, London, United Kingdom.
    Postmitotic specification of Drosophila insulinergic neurons from pioneer neurons2008In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 6, no 3, p. 538-551Article in journal (Refereed)
    Abstract [en]

    Insulin and related peptides play important and conserved functions in growth and metabolism. Although Drosophila has proved useful for the genetic analysis of insulin functions, little is known about the transcription factors and cell lineages involved in insulin production. Within the embryonic central nervous system, the MP2 neuroblast divides once to generate a dMP2 neuron that initially functions as a pioneer, guiding the axons of other later-born embryonic neurons. Later during development, dMP2 neurons in anterior segments undergo apoptosis but their posterior counterparts persist. We show here that surviving posterior dMP2 neurons no longer function in axonal scaffolding but differentiate into neuroendocrine cells that express insulin-like peptide 7 (Ilp7) and innervate the hindgut. We find that the postmitotic transition from pioneer to insulin-producing neuron is a multistep process requiring retrograde bone morphogenetic protein (BMP) signalling and four transcription factors: Abdominal-B, Hb9, Fork Head, and Dimmed. These five inputs contribute in a partially overlapping manner to combinatorial codes for dMP2 apoptosis, survival, and insulinergic differentiation. Ectopic reconstitution of this code is sufficient to activate Ilp7 expression in other postmitotic neurons. These studies reveal striking similarities between the transcription factors regulating insulin expression in insect neurons and mammalian pancreatic β-cells. © 2008 Miguel-Aliaga et al.

  • 33.
    Morrell, J. M.
    et al.
    Division of Reproduction, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden .
    Johannisson, A.
    Division of Reproduction, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden .
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Effect of Osmolarity and Density of Colloid Formulations on the Outcome of SLC-Selection of Stallion Spermatozoa2011In: ISRN Veterinary Science, ISSN 2090-4452, E-ISSN 2090-4460, Vol. 2011, article id 128984Article in journal (Refereed)
    Abstract [en]

    The osmolarity and density of colloids used to prepare spermatozoa for assisted reproduction may affect sperm quality in the resultant preparation. In this study, two osmolarities of Androcoll-E for single-layer or density gradient centrifugation of stallion spermatozoa were compared: “normal” (320 mOsm) or “high” (345 mOsm). Mean yields for the two centrifugation techniques did not differ between treatments or osmolarities (single layer centrifugation:30.19±16.9×106 and 25.8±18.5×106 spermatozoa; density gradient centrifugation: 31.84±19.7×106 and 26.46±20.0×106 spermatozoa respectively for the two osmolarities). However, use of the high osmolarity colloid for single layer centrifugation increased the proportion of morphologically normal spermatozoa (𝑃<.05). Therefore, increasing the osmolarity of the colloid formulation may be beneficial for processing ejaculates containing a high proportion of abnormal spermatozoa by SLC. Reducing the density of the colloid used for the SLC substantially increased the yield of motile spermatozoa compared to the normal density colloid (mean ± SD: 72.6±28.9×106 versus 28.9±24.7×106), while also prolonging sperm survival by 24 hours compared to the uncentrifuged ejaculate. This increased yield may render Single Layer Centrifugation practical for use in the field.

  • 34.
    Neely, G Gregory
    et al.
    Austrian Academy of Science.
    Hess, Andreas
    University of Erlangen Nurnberg.
    Costigan, Michael
    Harvard University.
    Keene, Alex C
    NYU.
    Goulas, Spyros
    Austrian Academy of Science.
    Langeslag, Michiel
    Innsbruck Medical University.
    Griffin, Robert S
    Massachusetts General Hospital.
    Belfer, Inna
    University of Pittsburgh.
    Dai, Feng
    University of Pittsburgh.
    Smith, Shad B
    University N Carolina.
    Diatchenko, Luda
    University N Carolina.
    Gupta, Vaijayanti
    Strand Life Science Pvt Ltd.
    Xia, Cui-Ping
    Austrian Academy Science.
    Amann, Sabina
    Austrian Academy of Science.
    Kreitz, Silke
    University of Erlangen Nurnberg.
    Heindl-Erdmann, Cornelia
    University of Erlangen Nurnberg.
    Wolz, Susanne
    University of Erlangen Nurnberg.
    Ly, Cindy V
    Strand Life Science Pvt Ltd.
    Sarangi, Rinku
    Strand Life Science Pvt Ltd.
    Dan, Debasis
    Strand Life Science Pvt Ltd.
    Novatchkova, Maria
    Austrian Academy of Science.
    Rosenzweig, Mark
    Brandeis University.
    Gibson, Dustin G
    University N Carolina.
    Truong, Darwin
    Austrian Academy of Science.
    Schramek, Daniel
    Austrian Academy of Science.
    Zoranovic, Tamara
    Austrian Academy of Science.
    Cronin, Shane J F
    Austrian Academy of Science.
    Angjeli, Belinda
    Austrian Academy of Science.
    Brune, Kay
    University of Erlangen Nurnberg.
    Dietzl, Georg
    Stanford University.
    Maixner, William
    University N Carolina.
    Meixner, Arabella
    Austrian Academy of Science.
    Thomas, Winston
    Deltagen Inc.
    Pospisilik, J Andrew
    Max Planck Institute.
    Alenius, Mattias
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE.
    Kress, Michaela
    Innsbruck Medical University.
    Subramaniam, Sai
    Strand Life Science Pvt Ltd.
    Garrity, Paul A
    Brandeis University.
    Bellen, Hugo J
    Baylor College of Medicine.
    Woolf, Clifford J
    Harvard University.
    Penninger, Josef M
    Austrian Academy of Science.
    A Genome-wide Drosophila Screen for Heat Nociception Identifies alpha 2 delta 3 as an Evolutionarily Conserved Pain Gene2010In: CELL, ISSN 0092-8674, Vol. 143, no 4, p. 628-638Article in journal (Refereed)
    Abstract [en]

    Worldwide, acute, and chronic pain affects 20% of the adult population and represents an enormous financial and emotional burden. Using genome-wide neuronal-specific RNAi knockdown in Drosophila, we report a global screen for an innate behavior and identify hundreds of genes implicated in heat nociception, including the alpha 2 delta family calcium channel subunit straightjacket (stj). Mice mutant for the stj ortholog CACNA2D3 (alpha 2 delta 3) also exhibit impaired behavioral heat pain sensitivity. In addition, in humans, alpha 2 delta 3 SNP variants associate with reduced sensitivity to acute noxious heat and chronic back pain. Functional imaging in alpha 2 delta 3 mutant mice revealed impaired transmission of thermal pain-evoked signals from the thalamus to higher-order pain centers. Intriguingly, in alpha 2 delta 3 mutant mice, thermal pain and tactile stimulation triggered strong cross-activation, or synesthesia, of brain regions involved in vision, olfaction, and hearing.

  • 35.
    Pokrzywa, Malgorzata
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    Dacklin, Ingrid
    Umea University.
    Vestling, Monika
    Umea University.
    Hultmark, Dan
    Umea University.
    Lundgren, Erik
    Umea University.
    Cantera, Rafael
    Stockholm University.
    Uptake of Aggregating Transthyretin by Fat Body in a Drosophila Model for TTR-Associated Amyloidosis2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 12Article in journal (Refereed)
    Abstract [en]

    Background: A functional link has been established between the severe neurodegenerative disorder Familial amyloidotic polyneuropathy and the enhanced propensity of the plasma protein transthyretin (TTR) to form aggregates in patients with single point mutations in the TTR gene. Previous work has led to the establishment of an experimental model based on transgenic expression of normal or mutant forms of human TTR in Drosophila flies. Remarkably, the severity of the phenotype was greater in flies that expressed a single copy than with two copies of the mutated gene. Methodology/Principal Findings: In this study, we analyze the distribution of normal and mutant TTR in transgenic flies, and the ultrastructure of TTR-positive tissues to clarify if aggregates and/or amyloid filaments are formed. We report the formation of intracellular aggregates of 20 nm spherules and amyloid filaments in thoracic adipose tissue and in brain glia, two tissues that do not express the transgene. The formation of aggregates of nanospherules increased with age and was more considerable in flies with two copies of mutated TTR. Treatment of human neuronal cells with protein extracts prepared from TTR flies of different age showed that the extracts from older flies were less toxic than those from younger flies. Conclusions/Significance: These findings suggest that the uptake of TTR from the circulation and its subsequent segregation into cytoplasmic quasi-crystalline arrays of nanospherules is part of a mechanism that neutralizes the toxic effect of TTR.

  • 36.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Cryopreservation of Porcine Gametes, Embryos and Genital Tissues: State of the Art2012In: Current Frontiers in Cryobiology / [ed] Igor I. Katkov, Rijeka, Croatia: InTech, 2012, 1st, p. 231-258Chapter in book (Other academic)
  • 37.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Livestock semen biotechnology and management2012In: Encyclopedia of Life Support Systems (EOLSS): Animal Reproduction in Livestock / [ed] S Astiz Blanco & A Gonzalez Bulnes, Oxford, UK: Eolss Publishers, UNESCO , 2012, 1:a, p. 1-14Chapter in book (Other academic)
    Abstract [en]

    Modern livestock breeding is basically dependent on the proper use of semen for artificial insemination of females and of other reproductive biotechnologies such as the production of embryos in vitro for embryo transfer. Both these techniques have made possible not only the wide dissemination of genetic material onto breeding populations but also enhanced the selection of best sires, owing to the development of better diagnostic techniques for sperm function and of preservation of seminal material over time. Although use of liquid semen cooled to room temperature, to intermediate temperatures (+16-20°C) or chilled (+5°C) dominates in some livestock species (swine respectively small ruminants), cryopreservation is rule in bovine and it is advancing in other species by the design of new containers, freezing methods and the use of better insemination strategies. Reliable semen diagnostics is absolutely essential to disclose which semen is to be processed/cryopreserved but also to aim determination  of a potential fertilizing capacity in the laboratory, thus saving costs prior to artificial insemination. However, there is a yet no single laboratory method that accurately prognoses fertility in livestock, requiring use of a battery of diagnostic methods. Novel techniques for optimal use of ejaculates (low-dose) and intrauterine deposition of semen throughout species are those management techniques that shall increase our capabilities for better diagnostics/selection of semen/male potential fertility, of cryopreservation techniques and a more rational dissemination of genetics.

  • 38.
    Schultz, Sebastian
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Gu, Xiaohong
    Department of Medical Cell Biology, Uppsala University, SE-­‐75123, Uppsala, Sweden.
    Rusten, Tor Erik
    Centre for Cancer Biomedicine, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, N-­‐0317, Oslo, Norway.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    HIAPP and hproIAPP triggers elective autophagy and inhibit the neuro-­protective effect of autophagy2010Manuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: Amyloid formation is associated with cell death and islet amyloid is thought to participate in the 50-60% β-cell reduction detected in patients with type 2 diabetes. Islet amyloid polypeptide (IAPP) is the main amyloid protein in the islets of Langerhans. Initial IAPP-amyloid formation is intracellular and part of this amyloid constitutes of proIAPP.

    Material & methods: We have established a new model in Drosophila melanogaster where expression of hproIAPP and IAPP results in the formation of amyloid. With this model, we have investigated the effect of protein aggregation on pathways such as ER-stress, unfolded protein response (UPR), apoptosis and autophagy. Important steps in the different pathways were manipulated by RNAi-technique or over- expression of endogenous Drosophila proteins.

    Results: Expression of hproIAPP and hIAPP driven to the pdf-neurons led to cell death, but this was without activation of ER-stress, UPR or apoptosis. Aggregated hproIAPP and IAPP, labeled with antibodies against ubiquitin and p62 were accumulated intracellular, a finding that points to an involvement of autophagy. HproIAPP and hIAPP were shown to exert their toxic activity by an intracellular mechanism in contrary to Aβ42 and Aβ42 E22G that exhibit an extracellular toxic activity.

    Conclusion: Studies on toxicity suggest that hproIAPP and hIAPP aggregates can occupy the autophagy pathway and prevent maintenance of basal cellular homeostasis. Comparison of proIAPP/IAPP and Aβ42 toxicity shows that amyloid proteins of separate origin can exhibit different toxicity.

  • 39.
    Schultz, Sebastian
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Fly model of type 2 diabetes: processing of proIAPP makes a difference2010In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 17, no S1, p. 44-45Article in journal (Other academic)
    Abstract [en]

    Patients  with type 2 diabetes  have a marked  reducedbeta cell mass and fail to produce  sufficient amounts of insulin required  for regulation  of glucose home- ostasis. Recent research supports that intracellular aggregation of islet amyloid polypeptide  (IAPP) leads to cell death and therefore makes IAPP aggregation a plausible cause for the beta cell reduction. Little is known about the mechanisms that precede amyloid formation  or which cellular pathways are involved in this process.  To  gain better  understanding we haveestablished  a Drosophila melanogaster model,  where GAL4 drives expression  of UAS-targeted transgenes in a cell or tissue specific pattern. The  fruit fly offers a unique  option  to manipulate any cellular  pathway with  different   genetic   tools.   The   knowledge   that*70%  of all Drosophila  melanogaster genes  have anorthologue in humans  stress  the  potential  for path- ways found in D. melanogaster to be of importance in humans  as well. Transgenic flies expressing  human proIAPP  (the precursor of IAPP)  and IAPP and the non-amyloidogenic mouse IAPP (mIAPP) have been generated.  Expression    of  proIAPP    in   the   brain reduced the lifespan of the fly whereas neither  IAPP nor mIAPP expression influenced survival. Immu- nolabelling  with  an  antibody  raised  against  human IAPP   and   that   cross-reacts    with   murine    IAPP labelled neurons  in all three strains, whereas a concomitant loss of cell nuclei only appeared  during proIAPP and IAPP expression. Furthermore, we detected  an early potentiated activation of the autophagy  pathway  in  proIAPP   flies. Interestingly, even  though  IAPP  expression  was not  related  to  a shorter  lifespan, both IAPP and proIAPP  expression in the  central  nervous  system  led  to  amyloid deposition  in the fat body of the head as shown with Congo  red  and  pFTAA,   a  newly  synthesised luminescent conjugated polymer. Our results de- monstrate that  D. melanogaster has a great  potential as a model  for studies  of proIAPP  and  IAPP expression with subsequent amyloid formation  and connected cellular  response  mechanisms. The  find- ing that proIAPP  aggregation  seems to exert a more toxic  impact  at  a  cellular  level is in  line  with  ourresults from mammalian cell lines.

  • 40.
    Sivik, Tove
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Hakkarainen, Janne
    Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
    Hilborn, Erik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Zhang, Fuping
    Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
    Poutanen, Matti
    Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
    Jansson, Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Characterisation of Hsd17b14 knockout miceManuscript (preprint) (Other academic)
    Abstract [en]

    17β hydroxysteroid dehydrogenase (17βHSD) enzymes catalyse the stereospecific oxidation/reduction at carbon 17β of androgens and oestrogens and thereby regulate the pool of bioactive sex hormones. 17βHSD type 14 (17βHSD14) catalyses the inactivation of 17β-hydroxysteroids into their less bioactive 17-keto formation in vitro, however, as the catalytic efficiency of this reaction is relatively low, the question is whether this reaction is the biological role of the enzyme in vivo, or if the enzyme additionally or altogether acts within alternative metabolic pathways. To investigate the role of 17βHSD14 in vivo, we studied the phenotype of a mouse model in which the Hsd17b14 gene had been targeted through homologous recombination. Tissues from male and female mice sacrificed at 3-4 months of age were collected and analysed with regards to gene expression of Hsd17b14 and Hsd17b2 and histological appearance of selected organs. Wild type animals expressed Hsd17b14 in a large number of tissues, peaking in reproductive tissues. Mice globally lacking Hsd17b14 were grossly morphologically identical to their WT counterparts. The histological examination however, revealed impaired mammary gland branching and increased hepatocellular vacuolisation in Hsd1714 knockout animals compared with their WT counterparts. In conclusion, while phenotypical aberrances were absent in most tissues, which may be the result of genetic redundancy or possibly an indication that the gene in question is only modulatory, the main differences, primarily a mammary gland phenotype in female KO mice, implicate disturbed hormonal homeostasis, and thus a role for Hsd17b14 in steroidogenesis in vivo.

  • 41.
    Suska, Anke
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Miguel-Aliaga, Irene
    University of Cambridge.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Segment-specific generation of Drosophila Capability neuropeptide neurons by multi-faceted Hox cues2011In: DEVELOPMENTAL BIOLOGY, ISSN 0012-1606, Vol. 353, no 1, p. 72-80Article in journal (Refereed)
    Abstract [en]

    In the Drosophila ventral nerve cord, the three pairs of Capability neuropeptide-expressing Va neurons are exclusively found in the second, third and fourth abdominal segments (A2-A4). To address the underlying mechanisms behind such segment-specific cell specification, we followed the developmental specification of these neurons. We find that Va neurons are initially generated in all ventral nerve cord segments and progress along a common differentiation path. However, their terminal differentiation only manifests itself in A2-A4, due to two distinct mechanisms: segment-specific programmed cell death (PCD) in posterior segments, and differentiation to an alternative identity in segments anterior to A2. Genetic analyses reveal that the Hox homeotic genes are involved in the segment-specific appearance of Va neurons. In posterior segments, the Hox gene Abdominal-B exerts a pro-apoptotic role on Va neurons, which involves the function of several RHG genes. Strikingly, this role of Abd-B is completely opposite to its role in the segment-specific apoptosis of other classes of neuropeptide neurons, the dMP2 and MP1 neurons, where Abd-B acts in an anti-apoptotic manner. In segments A2-A4 we find that abdominal A is important for the terminal differentiation of Va cell fate. In the A1 segment, Ultrabithorax acts to specify an alternate Va neuron fate. In contrast, in thoracic segments, Antennapedia suppresses the Va cell fate. Thus. Hox genes act in a multi-faceted manner to control the segment-specific appearance of the Va neuropeptide neurons in the ventral nerve cord.

  • 42.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Neuroscience: Light moulds plastic brains2008In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 456, no 7219, p. 177-178Article in journal (Other academic)
    Abstract [en]

    In tadpoles, the number of neurons expressing the neurotransmitter dopamine increases on exposure to light. Such plasticity might allow animals to physically match their brains’ activity to environmental stimuli.

  • 43.
    Thor, Stefan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    Baumgardt, Magnus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    Karlsson, Daniel
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology.
    From progenitor to unique neuron Neuronal sub-type specification by the integration of positional and temporal cues in INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE, vol 28, issue 8, pp 671-6712010In: INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE, Elsevier Science B.V., Amsterdam. , 2010, Vol. 28, no 8, p. 671-671Conference paper (Refereed)
    Abstract [en]

    n/a

  • 44.
    Ulvklo, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Genetic mechanisms controlling cell specification and cell numbers in the Drosophila CNS2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A central theme in developmental neurobiology pertains to how the  diversity of different cell types is generated. In addition, it is equally important to understand how the specific numbers of each cell type is regulated. The developing Drosophila central nervous system (CNS) is a widely used system in which to study the genetic mechanisms underlying these events. Earlier studies have shown that a small number of progenitors produce the daunting number of cells that builds the mature CNS. This is accomplished by a series of events that in an increasingly restricted manner results in different combinatorial transcription factor codes that act to specify the different cell types in the CNS. However the factors controlling the progressive restriction in developmental potential and the ultimate fate of cells have not been completely elucidated.

    My PhD project has been focused on a specific stem cell in the embryonic Drosophila CNS, the neuroblast 5-6 (NB 5-6), and the lineage of neural cells that is produced by that stem cell. Earlier work have provided both a lot of knowledge and a multitude of genetic tools regarding this specific stem cell, which allowed us to address these issues at single cell resolution in an identifiable lineage. In particular, a late-born group of neurons expressing the apterous gene, the Apterous neurons, had been extensively studied in the past. One particular Apterous neuron, Ap4, expresses the neuropeptide gene FMRFamide (FMRFa), and the selective expression of this gene makes it a powerful marker for addressing many aspects of NB 5-6 development.

    To identify novel genes acting to control neuronal development, a large scale forward genetic screen was performed utilizing an FMRFa-GFP transgenic reporter construct, thereby using a marker that reports perturbations of NB 5-6-lineage development. Flies were treated with EMS, a chemical that induces random point mutations and the progeny where screened for aberrant FMRFa-GFP expression. From a total of ~ 10,000 mutated chromosomes ~600 mutants where isolated and further characterized. One group of mutants displayed additional Apterous neurons when compared to wild type, and a number of them represented new alleles of three previously known genes: neuralized (neur), kuzbanian (kuz), and seven up (svp). Neur and Kuz are parts of the Notch signaling pathway and Svp is the Drosophila COUP-TF1/2 ortholog; an orphan member of the steroid/thyroid receptor superfamily. These findings initiated two separate studies regarding the roles of these genes in the NB 5-6 lineage.

    Mutants in the Notch pathway i.e., neur and kuz displayed an excess number of Apterous neurons, born from NB 5-6. We initiated detailed studies regarding the origin of these ectopic neurons and could show that Notch signaling is critical for controlling a switch in proliferation mode in the latter part of the NB 5-6 lineage. With this new mechanism we could independently and simultaneously manipulate cell proliferation and temporal progression, and thereby predictable control cell fate and cell numbers born from the NB 5-6.

    The screen further identified additional mechanisms acting to specify the Ap cluster neurons. During NB 5-6 lineage development several temporal transitions acts to specify neurons born in different time windows. The temporal gene castor is expressed in a fairly large temporal window and the Ap neurons are sub-specified during that window by several combinatorial feed forward loops of transcription factors. In the screen, we identified a novel allele of the svp gene. We found that svp acts as a sub-temporal factor, fine-tuning the castor window into three different temporal parts. Previous studies have shown a role for svp earlier in the temporal cascade and we could confirm this in the NB 5-6 lineage. Together these data for the first time identify dual temporal roles of the same gene in a single NB lineage.

    In summary, my thesis has helped identify novel genetic mechanisms controlling neuron subtype specification and numbers.

    List of papers
    1. A genetic screen for genes controlling Ap neuron specification
    Open this publication in new window or tab >>A genetic screen for genes controlling Ap neuron specification
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    A central theme in developmental biology pertains to how the diversity of different cell types is generated. In addition, it is important to understand how the numbers of each cell type are regulated. In the developing Drosophila ventral nerve cord, only six neurons, the Ap4 neurons, express the neuropeptide gene FMRFamide (FMRFa). This is the result of proper lineage development and a cascade of regulatory information leading to final cell specification. In addition to these cascades, FMRFa expression is critically dependent upon a retrogarade TGFβ/BMP signal from the axonal target. Its restricted expression pattern and the wealth of information regarding its gene regulation, makes FMRFa a useful marker for understanding cell specification, as well as axon path finding and retrograde signaling. To identify novel genes acting at any level of neuronal development, including pattern formation, stem cell competence, cell cycle control, cell specification, axon transport and retrograde signaling, we have conducted a single cell resolution, forward genetic screen utilizing an FMRFa-EGFP reporter as our read-out. A total of 9,781 EMS-mutated chromosomes were screened for perturbations in FMRFa-EGFP expression, and 611 mutants were identified. Complementation tests showed that many of the previously known regulators had been isolated, which confirmed the validity of the screen. However, in addition to these known genes, the majority of mutants represent novel genes with previously undefined functions in neural development.

    Keywords
    Drosophila, CNS development, neural cell fate specification, forward genetic screening, FMRFamide
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-76155 (URN)
    Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2016-11-30Bibliographically approved
    2. Seven up acts as a temporal factor during two different stages of neuroblast 5-6 development
    Open this publication in new window or tab >>Seven up acts as a temporal factor during two different stages of neuroblast 5-6 development
    Show others...
    2011 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 138, no 24, p. 5311-5320Article in journal (Refereed) Published
    Abstract [en]

    Drosophila embryonic neuroblasts generate different cell types at different time points. This is controlled by a temporal cascade of Hb -greater than Kr -greater than Pdm -greater than Cas -greater than Grh, which acts to dictate distinct competence windows sequentially. In addition, Seven up (Svp), a member of the nuclear hormone receptor family, acts early in the temporal cascade, to ensure the transition from Hb to Kr, and has been referred to as a switching factor. However, Svp is also expressed in a second wave within the developing CNS, but here, the possible role of Svp has not been previously addressed. In a genetic screen for mutants affecting the last-born cell in the embryonic NB5-6T lineage, the Ap4/FMRFamide neuron, we have isolated a novel allele of svp. Expression analysis shows that Svp is expressed in two distinct pulses in NB5-6T, and mutant analysis reveals that svp plays two distinct roles. In the first pulse, svp acts to ensure proper downregulation of Hb. In the second pulse, which occurs in a Cas/Grh double-positive window, svp acts to ensure proper sub-division of this window. These studies show that a temporal factor may play dual roles, acting at two different stages during the development of one neural lineage.

    Place, publisher, year, edition, pages
    Company of Biologists, 2011
    Keywords
    Temporal genes; COUP-TFI/II; Cell specification; Lineage progression; Drosophila
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-73311 (URN)10.1242/dev.070946 (DOI)297329900004 ()
    Available from: 2012-01-03 Created: 2012-01-02 Last updated: 2017-12-08Bibliographically approved
    3. Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression
    Open this publication in new window or tab >>Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression
    Show others...
    2012 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, no 4, p. 678-689Article in journal (Refereed) Published
    Abstract [en]

    During neural lineage progression, differences in daughter cell proliferation can generate different lineage topologies. This is apparent in the Drosophila neuroblast 5-6 lineage (NB5-6T), which undergoes a daughter cell proliferation switch from generating daughter cells that divide once to generating neurons directly. Simultaneously, neural lineages, e.g. NB5-6T, undergo temporal changes in competence, as evidenced by the generation of different neural subtypes at distinct time points. When daughter proliferation is altered against a backdrop of temporal competence changes, it may create an integrative mechanism for simultaneously controlling cell fate and number. Here, we identify two independent pathways, Prospero and Notch, which act in concert to control the different daughter cell proliferation modes in NB5-6T. Altering daughter cell proliferation and temporal progression, individually and simultaneously, results in predictable changes in cell fate and number. This demonstrates that different daughter cell proliferation modes can be integrated with temporal competence changes, and suggests a novel mechanism for coordinately controlling neuronal subtype numbers.

    Place, publisher, year, edition, pages
    Company of Biologists, 2012
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-74790 (URN)10.1242/dev.074500 (DOI)000300259800005 ()
    Note

    funding agencies|Swedish Research Council||Knut and Alice Wallenberg foundation||Swedish Cancer Foundation||

    Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2017-12-07
  • 45.
    Ulvklo, Carina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Bivik, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Fransson, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    A genetic screen for genes controlling Ap neuron specificationManuscript (preprint) (Other academic)
    Abstract [en]

    A central theme in developmental biology pertains to how the diversity of different cell types is generated. In addition, it is important to understand how the numbers of each cell type are regulated. In the developing Drosophila ventral nerve cord, only six neurons, the Ap4 neurons, express the neuropeptide gene FMRFamide (FMRFa). This is the result of proper lineage development and a cascade of regulatory information leading to final cell specification. In addition to these cascades, FMRFa expression is critically dependent upon a retrogarade TGFβ/BMP signal from the axonal target. Its restricted expression pattern and the wealth of information regarding its gene regulation, makes FMRFa a useful marker for understanding cell specification, as well as axon path finding and retrograde signaling. To identify novel genes acting at any level of neuronal development, including pattern formation, stem cell competence, cell cycle control, cell specification, axon transport and retrograde signaling, we have conducted a single cell resolution, forward genetic screen utilizing an FMRFa-EGFP reporter as our read-out. A total of 9,781 EMS-mutated chromosomes were screened for perturbations in FMRFa-EGFP expression, and 611 mutants were identified. Complementation tests showed that many of the previously known regulators had been isolated, which confirmed the validity of the screen. However, in addition to these known genes, the majority of mutants represent novel genes with previously undefined functions in neural development.

  • 46.
    Ulvklo, Carina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    MacDonald, Ryan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Bivik, Caroline
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Baumgardt, Magnus
    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.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Control of neuronal cell fate and number by integration of distinct daughter cell proliferation modes with temporal progression2012In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, no 4, p. 678-689Article in journal (Refereed)
    Abstract [en]

    During neural lineage progression, differences in daughter cell proliferation can generate different lineage topologies. This is apparent in the Drosophila neuroblast 5-6 lineage (NB5-6T), which undergoes a daughter cell proliferation switch from generating daughter cells that divide once to generating neurons directly. Simultaneously, neural lineages, e.g. NB5-6T, undergo temporal changes in competence, as evidenced by the generation of different neural subtypes at distinct time points. When daughter proliferation is altered against a backdrop of temporal competence changes, it may create an integrative mechanism for simultaneously controlling cell fate and number. Here, we identify two independent pathways, Prospero and Notch, which act in concert to control the different daughter cell proliferation modes in NB5-6T. Altering daughter cell proliferation and temporal progression, individually and simultaneously, results in predictable changes in cell fate and number. This demonstrates that different daughter cell proliferation modes can be integrated with temporal competence changes, and suggests a novel mechanism for coordinately controlling neuronal subtype numbers.

  • 47.
    Ulvklo, Carina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology, IKE. Linköping University, Faculty of Health Sciences.
    Nilsson, Patrik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Angel, Anna
    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.
    A genetic screen for genes controlling Tv neuron identity and FMRFamide expression2009In: in MECHANISMS OF DEVELOPMENT, vol 126, 2009, Vol. 126, p. S165-S165Conference paper (Refereed)
    Abstract [en]

    n/a

1 - 47 of 47
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