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Genes and Pathways Regulated by Androgens in Human Neural Cells, Potential Candidates for the Male Excess in Autism Spectrum Disorder

  • Angélique Quartier
    Affiliations
    Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France

    Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France

    Université de Strasbourg, Illkirch, France
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  • Laure Chatrousse
    Affiliations
    Center for the Study of Stem Cells, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, French Muscular Disease Association, Corbeil-Essonnes, Paris, France
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  • Claire Redin
    Affiliations
    Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France

    Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France

    Université de Strasbourg, Illkirch, France
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  • Céline Keime
    Affiliations
    Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France

    Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France

    Université de Strasbourg, Illkirch, France
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  • Nicolas Haumesser
    Affiliations
    Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France

    Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France

    Université de Strasbourg, Illkirch, France
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  • Anne Maglott-Roth
    Affiliations
    Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France

    Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France

    Université de Strasbourg, Illkirch, France
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  • Laurent Brino
    Affiliations
    Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France

    Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France

    Université de Strasbourg, Illkirch, France
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  • Stéphanie Le Gras
    Affiliations
    Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France

    Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France

    Université de Strasbourg, Illkirch, France
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  • Alexandra Benchoua
    Affiliations
    Center for the Study of Stem Cells, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, French Muscular Disease Association, Corbeil-Essonnes, Paris, France
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  • Author Footnotes
    1 J-LM and AP contributed equally to this work.
    Jean-Louis Mandel
    Footnotes
    1 J-LM and AP contributed equally to this work.
    Affiliations
    Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France

    Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France

    Université de Strasbourg, Illkirch, France

    Human Genetics, Collège de France, Paris, France

    Laboratory of Genetic Diagnostics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

    University of Strasbourg Institute of Advanced Studies, Strasbourg, France
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  • Author Footnotes
    1 J-LM and AP contributed equally to this work.
    Amélie Piton
    Correspondence
    Address correspondence to Amélie Piton, Ph.D., Laboratoire “Mécanismes génétiques des maladies neurodéveloppementales,” IGBMC, 1, rue Laurent Fries, 67400 Illkirch, France.
    Footnotes
    1 J-LM and AP contributed equally to this work.
    Affiliations
    Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France

    Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France

    Université de Strasbourg, Illkirch, France

    Laboratory of Genetic Diagnostics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
    Search for articles by this author
  • Author Footnotes
    1 J-LM and AP contributed equally to this work.

      Abstract

      Background

      Prenatal exposure to androgens during brain development in male individuals may participate to increase their susceptibility to develop neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability. However, little is known about the action of androgens in human neural cells.

      Methods

      We used human neural stem cells differentiated from embryonic stem cells to investigate targets of androgens.

      Results

      RNA sequencing revealed that treatment with dihydrotestosterone (DHT) leads to subtle but significant changes in the expression of about 200 genes, encoding proteins of extracellular matrix or involved in signal transduction of growth factors (e.g., insulin/insulin growth factor 1). We showed that the most differentially expressed genes (DEGs), RGCC, RNF144B, NRCAM, TRIM22, FAM107A, IGFBP5, and LAMA2, are reproducibly regulated by different androgens in different genetic backgrounds. We showed, by overexpressing the androgen receptor in neuroblastoma cells SH-SY5Y or knocking it down in human neural stem cells, that this regulation involves the androgen receptor. A chromatin immunoprecipitation combined with direct sequencing analysis identified androgen receptor–bound sequences in nearly half of the DHT-DEGs and in numerous other genes. DHT-DEGs appear enriched in genes involved in ASD (ASXL3, NLGN4X, etc.), associated with ASD (NRCAM), or differentially expressed in patients with ASD (FAM107A, IGFBP5). Androgens increase human neural stem cell proliferation and survival in nutrient-deprived culture conditions, with no detectable effect on regulation of neurite outgrowth.

      Conclusions

      We characterized androgen action in neural progenitor cells, identifying DHT-DEGs that appear to be enriched in genes related to ASD. We also showed that androgens increase proliferation of neuronal precursors and protect them from death during their differentiation in nutrient-deprived conditions.

      Keywords

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