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  • 1.
    Alenius, Mattias
    et al.
    Umeå University.
    Bohm, S
    Umeå University.
    Differential function of RNCAM isoforms in precise target selection of olfactory sensory neurons2003In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 130, no 5, p. 917-927Article in journal (Refereed)
    Abstract [en]

    Olfactory sensory neurons (OSNs) are individually specified to express one odorant receptor (OR) gene among similar to1000 different and project with precision to topographically defined convergence sites, the glomeruli, in the olfactory bulb. Although ORs partially determine the location of convergence sites, the mechanism ensuring that axons with different OR identities do not co-converge is unknown. RNCAM (OCAM, NCAM2) is assumed to regulate a broad zonal segregation of projections by virtue of being a homophilic cell adhesion molecule that is selectively expressed on axons terminating in a defined olfactory bulb region. We have identified NADPH diaphorase activity as being an independent marker for RNCAM-negative axons. Analyses of transgenic mice that ectopically express RNCAM in NADPH diaphorasepositive OSNs show that the postulated function of RNCAM in mediating zone-specific segregation of axons is unlikely. Instead, analyses of one OR-specific OSN subpopulation (P2) reveal that elevated RNCAM levels result in an increased number of P2 axons that incorrectly co-converge with axons of other OR identities. Both Gpianchored and transmembrane-bound RNCAM isoforms are localized on axons in the nerve layer, while the transmembrane-bound RNCAM is the predominant isoform on axon terminals within glomeruli. Overexpressing transmembrane-bound RNCAM results in co-convergence events close to the correct target glomeruli. By contrast, overexpression of Gpi-anchored RNCAM results in axons that can bypass the correct target before co-converging on glomeruli located at a distance. The phenotype specific for Gpi-anchored RNCAM is suppressed in mice overexpressing both isoforms, which suggests that two distinct RNCAM isoform-dependent activities influence segregation of OR-defined axon subclasses.

  • 2.
    Alenius, Mattias
    et al.
    Umeå University.
    Bohm, S
    Umeå University.
    Identification of a novel neural cell adhesion molecule-related gene with a potential role in selective axonal projection1997In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 272, no 42, p. 26083-26086Article in journal (Refereed)
    Abstract [en]

    We describe here the cloning of mouse complementary DNAs encoding a novel protein, Rb-8 neural cell adhesion molecule (RNCAM), with a predicted extracellular region of five immunoglobulin Ca-type domains followed by two fibronectin type III domains, Alternative splicing is likely to generate two RNCAM isoforms, which are differently attached to the cell membrane, These structural features and overall sequence identity identify this protein as a novel member of a cell adhesion molecule subgroup together with vertebrate neural cell adhesion molecule, Aplysia cell adhesion molecule, and Drosophila fasciclin II, In insects, fasciclin II is present on a restricted subset of embryonic central nervous system axons where it controls selective axon fasciculation. Intriguingly, RNCAM likewise is expressed in subsets of olfactory and vomeronasal neurons with topographically defined axonal projections, The spatial expression RNCAM corresponds precisely to that of certain odorant receptor expression zones of the olfactory epithelium. These expression patterns thus render RNCAM the first described cell adhesion molecule with a potential regulatory role in formation of selective axonal projections important for olfactory sensory information coding.

  • 3.
    Alkhori, Liza
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Sanchez, Gonzalo M.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Schultz, Sebastian W.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Kuzhandaivel, Anujaianthi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, The Institute of Technology.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hh signalling regulates odorant receptor cilia localization in Drosophila2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Hedgehog (Hh) signaling is a key regulatory pathway during development. Here, we show that in adult OSNs the Hh pathway regulate 􀁒dorant receptor transport to cilia and put forward a novel non-developmental function of the pathway as a neuromodulator. We demonstrate that the level of Hh signal modulate the OSNs response to odors. We show that knock down of Hh and Smoothened (Smo), a transmembrane protein that transduce the signal, are required for receptor transport. We further show that the coreceptor, Orco, has an Hh independent transport path and that knock down of Smo segregate OR and Orco to different vesicular compartments. Last, we show that the odor response to the second receptor type in Drosophila olfaction, the ionotropic receptors (IRs), also require Hh signalling. Thus, Hh signalling is a general regulator of the odorant response that fulfils the criteria of being a potential player in Drosophila odorant adaptation.

  • 4.
    Alkhori, Liza
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Öst, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    The corepressor Atrophin specifies odorant receptor expression in Drosophila2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 3, p. 1355-1364Article in journal (Refereed)
    Abstract [en]

    In both insects and vertebrates, each olfactory sensory neuron (OSN) expresses one odorant receptor (OR) from a large genomic repertoire. How a receptor is specified is a tantalizing question addressing fundamental aspects of cell differentiation. Here, we demonstrate that the corepressor Atrophin (Atro) segregates OR gene expression between OSN classes in Drosophila. We show that the knockdown of Atro result in either loss or gain of a broad set of ORs. Each OR phenotypic group correlated with one of two opposing Notch fates, Notch responding, Nba (N(on)), and nonresponding, Nab (N(off)) OSNs. Our data show that Atro segregates ORs expressed in the Nba OSN classes and helps establish the Nab fate during OSN development. Consistent with a role in recruiting histone deacetylates, immunohistochemistry revealed that Atro regulates global histone 3 acetylation (H3ac) in OSNs and requires Hdac3 to segregate OR gene expression. We further found that Nba OSN classes exhibit variable but higher H3ac levels than the Nab OSNs. Together, these data suggest that Atro determines the level of H3ac, which ensures correct OR gene expression within the Nba OSNs. We propose a mechanism by which a single corepressor can specify a large number of neuron classes.-Alkhori, L., Öst, A., Alenius, M. The corepressor Atrophin specifies odorant receptor expression in Drosophila.

  • 5.
    Couto, A
    et al.
    Austrian Academy of Science.
    Alenius, Mattias
    Austrian Academy of Science.
    Dickson, BJ
    Austrian Academy of Science.
    Molecular, anatomical, and functional organization of the Drosophila olfactory system2005In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 15, no 17, p. 1535-1547Article in journal (Refereed)
    Abstract [en]

    Background: Olfactory receptor neurons (ORNs) convey chemical information into the brain, producing internal representations of odors detected in the periphery. A comprehensive understanding of the molecular and neural mechanisms of odor detection and processing requires complete maps of odorant receptor (Or) expression and ORN connectivity, preferably at singlecell resolution. Results: We have constructed near-complete maps of Or expression and ORN targeting in the Drosophila olfactory system. These maps confirm the general validity of the "one neuron-one receptor" and "one glomerulus-one receptor" principles and reveal several additional features of olfactory organization. ORNs in distinct sensilla types project to distinct regions of the antenna[ lobe, but neighbor relations are not preserved. ORNs grouped in the same sensilla do not express similar receptors, but similar receptors tend to map to closely appositioned glomeruli in the antennal lobe. This organization may serve to ensure that odor representations are dispersed in the periphery but clustered centrally. Integrated with electrophysiological data, these maps also predict glomerular representations of specific odorants. Representations of aliphatic and aromatic compounds are spatially segregated, with those of aliphatic compounds arranged topographically according to carbon chain length. Conclusions: These Or expression and ORN connectivity maps provide further insight into the molecular, anatomical, and functional organization of the Drosophila olfactory system. Our maps also provide an essential resource for investigating how internal odor representations are generated and how they are further processed and transmitted to higher brain centers.

  • 6.
    Hedman, H
    et al.
    University of Umeå.
    Alenius, Mattias
    University of Umeå.
    Lundgren, E
    University of Umeå.
    Defective expression of beta 1-integrins in cells with constitutively active alpha L beta 2-integrins1997In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 232, no 2, p. 270-276Article in journal (Refereed)
    Abstract [en]

    We have investigated a potential relationship between expression of beta 1-integrins and adhesiveness of the beta 2-integrin LFA-1 (alpha L beta 2, CD11a/CD18). By an approach of random mutagenesis and selection we established clones from the human acute lymphatic leukemia cell line HPB-ALL with (i) constitutively active LFA-1 and (ii) with no apparent integrin-beta 1 cell surface expression. Thirty seven of 42 clones selected for activated LFA-1 were found to have lost apparent integrin-beta 1 expression. Conversely, 7 of 21 clones selected for lack of beta 1 expression were found to have activated LFA-1. Since this pointed toward a possible coupling between beta 1 expression and LFA-1 activity, we further analyzed at which level beta 1 expression was blocked. We focused on one clone, HAP4, with activated LFA-I and no detectable beta 1 cell surface expression and found, surprisingly, that it expressed wild-type levels of beta 1 mRNA and, in Western blots of whole cell lysates, apparently normal levels of beta 1 protein. However, in addition to beta 1 of the expected molecular weight, HAP4 expressed a unique 48-kDa band recognized by the polyclonal anti-beta 1 antiserum. Immunoprecipitation experiments revealed that the epitope recognized by the anti-beta 1 antibody 4B4 was hidden or lost. The alpha 4-chain was found in its precursor form but it did not associate with any beta-chain, and it was not processed to its mature form. Instead alpha 4-chains were eventually degraded. Taken together this showed that beta 1-chains were produced but not properly processed in HAP4. From this we propose that HAP4 is deficient in a gene product required both for proper beta 1 folding and for repression of LFA-1 adhesiveness.

  • 7.
    Jafari, Shadi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cis-Regulatory Mechanisms for Robust Olfactory Sensory Neuron Class-restricted Odorant Receptor Gene Expression in Drosophila2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 3, p. e1005051-Article in journal (Refereed)
    Abstract [en]

    Odor perception requires that each olfactory sensory neuron (OSN) class continuously express a single odorant receptor (OR) regardless of changes in the environment. However, little is known about the control of the robust, class-specific OR expression involved. Here, we investigate the cis-regulatory mechanisms and components that generate robust and OSN class-specific OR expression in Drosophila. Our results demonstrate that the spatial restriction of expression to a single OSN class is directed by clusters of transcription-factor DNA binding motifs. Our dissection of motif clusters of differing complexity demonstrates that structural components such as motif overlap and motif order integrate transcription factor combinations and chromatin status to form a spatially restricted pattern. We further demonstrate that changes in metabolism or temperature perturb the function of complex clusters. We show that the cooperative regulation between motifs around and within the cluster generates robust, class-specific OR expression.

  • 8.
    Jafari, Shadi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Drosophila olfactory sensory neurons have two phases of gene expression regulationManuscript (preprint) (Other academic)
    Abstract [en]

    Here, we investigate the gene regulatory mechanisms that buffer environmental challenges and are required for Drosophila OSNs to maintain their fate. Each OSN expresses one odorant receptor (OR) gene from a large OR gene repertoire and the expression is maintained throughout the life of the neuron. We demonstrate that OSNs transit from a permissive gene regulatory state at the end of development to a robust continuous regulatory state in mature OSNs that secure the expression of a single OR gene. We provide evidence that the switch is associated to a change in the H3K9 methylation state. We show that the H3K9 demetylase su(var)3-3 is required for the permissive phase and the robust phase require the H3K9 methylase, su(var) 3-9. We further show that H3K9 methylation status has a role in the regulation of gene expression during the environmental challenges. Thus, our data demonstrate that OSNs go through two separate phases that compensate the environmental fluctuations differently.

  • 9.
    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.

  • 10.
    Keleman, Krystyna
    et al.
    Research Institute of Molecular Pathology, Vienna.
    Kruettner, Sebastian
    Research Institute of Molecular Pathology, Vienna.
    Alenius, Mattias
    Research Institute of Molecular Pathology, Vienna.
    Dickson, Barry J.
    Research Institute of Molecular Pathology, Vienna.
    Function of the Drosophila CPEB protein Orb2 in long-term courtship memory2007In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 10, no 12, p. 1587-1593Article in journal (Refereed)
    Abstract [en]

    Both long-term behavioral memory and synaptic plasticity require protein synthesis, some of which may occur locally at specific synapses. Cytoplasmic polyadenylation element-binding (CPEB) proteins are thought to contribute to the local protein synthesis that underlies long-term changes in synaptic efficacy, but a role has not been established for them in the formation of long-term behavioral memory. We found that the Drosophila melanogaster CPEB protein Orb2 is acutely required for long-term conditioning of male courtship behavior. Deletion of the N-terminal glutamine-rich region of Orb2 resulted in flies that were impaired in their ability to form long-term, but not short-term, memory. Memory was restored by expressing Orb2 selectively in fruitless (fru)positive c neurons of the mushroom bodies and by providing Orb2 function in mushroom bodies only during and shortly after training. Our data thus demonstrate that a CPEB protein is important in long-term memory and map the molecular, spatial and temporal requirements for its function in memory formation.

  • 11.
    Kolterud, Åsa
    et al.
    Umeå University.
    Alenius, Mattias
    Umeå University.
    Carlsson, Leif
    Umeå University.
    Bohm, Staffan
    Umeå University.
    The Lim homeobox gene Lhx2 is required for olfactory sensory neuron identity2004In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 131, no 21, p. 5319-5326Article in journal (Refereed)
    Abstract [en]

    Progenitor cells in the mouse olfactory epithelium generate over a thousand subpopulations of neurons, each expressing a unique odorant receptor (OR) gene. This event is under the control of spatial cues, since neurons in different epithelial regions are restricted to express region-specific subsets of OR genes. We show that progenitors and neurons express the LIM-homeobox gene Lhx2 and that neurons in Lhx2-null mutant embryos do not diversify into subpopullations expressing different OR genes and other region-restricted genes such as Nqo1 and Ncam2. Lhx2(-/-)embryos have, however, a normal distribution of Mashlpositive and neurogenin 1-positive neuronal progenitors that leave the cell cycle, acquire pan-neuronal traits and form axon bundles. Increased cell death in combination with increased expression of the early differentiation marker Neurod1, as well as reduced expression of late differentiation markers (Galphaolf and Omp), suggests that neuronal differentiation in the absence of Lhx2 is primarily inhibited at, or immediate prior to, onset of OR expression. Aberrant regional expression of early and late differentiation markers, taken together with unaltered region-restricted expression of the Msx1 homeobox gene in the progenitor cell layer of Lhx2-1- embryos, shows that Lhx2 function is not required for all aspects of regional specification of progenitors and neurons. Thus, these results indicate that a cell-autonomous function of Lhx2 is required for differentiation of progenitors into a heterogeneous population of individually and regionally specified mature olfactory sensory neurons.

  • 12.
    Kuzhandaivel, Anujaianthi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Schultz, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Alkhori, Liza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cilia-Mediated Hedgehog Signaling in Drosophila2014In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 7, no 3, p. 672-680Article in journal (Refereed)
    Abstract [en]

    Cilia mediate Hedgehog (Hh) signaling in vertebrates and Hh deregulation results in several clinical manifestations, such as obesity, cognitive disabilities, developmental malformations, and various cancers. Drosophila cells are nonciliated during development, which has led to the assumption that cilia-mediated Hh signaling is restricted to vertebrates. Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. We show that Cos2 and Fused are required for the ciliary transport of Smoothened and that cilia mediate the expression of the Hh pathway target genes. Taken together, our data demonstrate that Hh signaling in Drosophila can be mediated by two pathways and that the ciliary Hh pathway is conserved from Drosophila to vertebrates.

  • 13.
    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.

  • 14.
    Norlin, E Marianne
    et al.
    Umeå University.
    Alenius, Mattias
    Umeå University.
    Gussing, Fredrik
    Umeå University.
    Hägglund, Maria
    Umeå University.
    Vedin, Victoria
    Umeå University.
    Bohm, Staffan
    Umeå University.
    Evidence for gradients of gene expression correlating with zonal topography of the olfactory sensory map2001In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 18, no 3, p. 283-295Article in journal (Refereed)
    Abstract [en]

    Signals regulating diversification of olfactory sensory neurons to express odorant receptors and other genes necessary for correct assembly of the olfactory sensory map persist in the olfactory epithelium of adult mouse. We have screened for genes with an expression pattern correlating with the topography odorant receptor-expression zones. The Msx1 homeobox gene and a semaphorin receptor (Neuropilin-2) showed graded expression patterns in the olfactory epithelium. The gradients of Msx1 and Neuropilin-2 expression in basal cells and neurons, respectively, correlated with expression of a retinoic acid-synthesizing enzyme (RALDH2) in lamina propria. A BMP-type I receptor (Alk6) showed a reverse gradient of expression in the supporting cells of the epithelium. Considering known functions of identified genes in cell specification and axon guidance this suggests that zonal division of the olfactory sensory map is maintained, during continious neurogenesis, as a consequence of topographic counter gradients of positional information.

  • 15.
    Obernosterer, G
    et al.
    Austrian Academy of Science.
    Leuschner, PJF
    Austrian Academy of Science.
    Alenius, Matias
    Austrian Academy of Science.
    Martinez, J
    Austrian Academy of Science.
    Post-transcriptional regulation of microRNA expression2006In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 12, no 7, p. 1161-1167Article in journal (Refereed)
    Abstract [en]

    microRNAs ( miRNAs) are endogenous, noncoding similar to 22-nucleotide RNA molecules that have recently emerged as fundamental, post-transcriptional regulators of cognate target gene expression. Many mammalian miRNAs are expressed in a tissue-specific manner, a phenomenon that has so far been attributed to transcriptional regulation. We here show by Northern blots and in situ hybridization experiments that the expression of mammalian miRNAs can be regulated at the post-transcriptional level. In particular, miR-138 is spatially restricted to distinct cell types, while its precursor, pre-miR-138-2, is ubiquitously expressed throughout all tissues analyzed. Furthermore, pre-miR-138-2 is exported from the nucleus to the cytoplasm, suggesting that cleavage of this pre-miRNA by Dicer is restricted to certain tissues and cell types. Thus, differential processing of pre-miRNAs might be an alternative mechanism to control miRNA function.

  • 16.
    Obernosterer, Gregor
    et al.
    Austrian Academy of Science.
    Martinez, Javier
    Austrian Academy of Science.
    Alenius, Mattias
    IMP, Vienna.
    Locked nucleic acid-based in situ detection of microRNAs in mouse tissue sections2007In: NATURE PROTOCOLS, ISSN 1754-2189, Vol. 2, no 6, p. 1508-1514Article in journal (Refereed)
    Abstract [en]

    Here we describe a method for sensitive and specific histological detection of microRNAs (miRNAs) by in situ hybridization. The protocol focuses on the use of locked nucleic acids (LNAs), which are bi-cyclic RNA analogs that allow a significant increase in the hybridization temperature and thereby an enhanced stringency for short probes as required for miRNA detection. The protocol is optimized for cryosections in order to study the spatial and temporal expression of miRNAs with high sensitivity and resolution. We detail how to construct probes, set up and conduct an LNA in situ hybridization experiment. In addition, we discuss alternative colorimetric strategies that can be used to effectively detect and visualize miRNAs including double staining with other markers. Setting up and conducting the in situ experiment is estimated to take similar to 1 week, assuming that all the component parts are readily available.

  • 17.
    Sanchez, Gonzalo Manuel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Alkhori Franzén, Liza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Hatano, Eduardo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schultz, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Oslo University Hospital, Norway.
    Kuzhandaivel, Anujaianthi
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. University of Illinois, IL 60612 USA.
    Jafari, Shadi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Hedgehog Signaling Regulates the Ciliary Transport of Odorant Receptors in Drosophila2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 3, p. 464-470Article in journal (Refereed)
    Abstract [en]

    Hedgehog (Hh) signaling is a key regulatory pathway during development and also has a functional role in mature neurons. Here, we show that Hh signaling regulates the odor response in adult Drosophila olfactory sensory neurons (OSNs). We demonstrate that this is achieved by regulating odorant receptor (OR) transport to and within the primary cilium in OSN neurons. Regulation relies on ciliary localization of the Hh signal transducer Smoothened (Smo). We further demonstrate that the Hh- and Smo-dependent regulation of the kinesin-like protein Cos2 acts in parallel to the intraflagellar transport system (IFT) to localize ORs within the cilium compartment. These findings expand our knowledge of Hh signaling to encompass chemosensory modulation and receptor trafficking.

  • 18.
    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.

  • 19.
    Öst, Anita
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Max Planck Institute Immunobiol and Epigenet, Germany.
    Lempradl, Adelheid
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Casas, Eduard
    Institute Medical Predict and Personalitzada Canc, Spain; ICO Hospital GermansTrias and Pujol, Spain.
    Weigert, Melanie
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Tiko, Theodor
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Deniz, Merdin
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Pantano, Lorena
    Institute Medical Predict and Personalitzada Canc, Spain.
    Boenisch, Ulrike
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Itskov, Pavel M.
    Champalimaud Centre Unknown, Portugal.
    Stoeckius, Marlon
    Max Delbruck Centre Molecular Med, Germany.
    Ruf, Marius
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Rajewsky, Nikolaus
    Max Delbruck Centre Molecular Med, Germany.
    Reuter, Gunter
    University of Halle Wittenberg, Germany.
    Iovino, Nicola
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Ribeiro, Carlos
    Champalimaud Centre Unknown, Portugal.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Heyne, Steffen
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Vavouri, Tanya
    Institute Medical Predict and Personalitzada Canc, Spain; ICO Hospital GermansTrias and Pujol, Spain.
    Pospisilik, J. Andrew
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Paternal Diet Defines Offspring Chromatin State and Intergenerational Obesity2014In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 159, no 6, p. 1352-1364Article in journal (Refereed)
    Abstract [en]

    The global rise in obesity has revitalized a search for genetic and epigenetic factors underlying the disease. We present a Drosophila model of paternal-diet-induced intergenerational metabolic reprogramming (IGMR) and identify genes required for its encoding in offspring. Intriguingly, we find that as little as 2 days of dietary intervention in fathers elicits obesity in offspring. Paternal sugar acts as a physiological suppressor of variegation, desilencing chromatin-state-defined domains in both mature sperm and in offspring embryos. We identify requirements for H3K9/K27me3-dependent reprogramming of metabolic genes in two distinct germline and zygotic windows. Critically, we find evidence that a similar system may regulate obesity susceptibility and phenotype variation in mice and humans. The findings provide insight into the mechanisms underlying intergenerational metabolic reprogramming and carry profound implications for our understanding of phenotypic variation and evolution.

1 - 19 of 19
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