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.
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.
Biol Psychiatry. 2018 Aug 15;84(4):239-252. doi: 10.1016/j.biopsych.2018.01.002. Epub 2018 Jan 9.
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.
We used human neural stem cells differentiated from embryonic stem cells to investigate targets of androgens.
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.
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.
男性个体在大脑发育过程中暴露于雄激素可能会增加他们患神经发育障碍的易感性，如自闭症谱系障碍（ASD）和智力障碍。然而，人们对雄激素在人类神经细胞中的作用知之甚少。
我们使用从胚胎干细胞分化而来的人类神经干细胞来研究雄激素的作用靶点。
RNA 测序显示，二氢睾酮（DHT）处理导致约 200 个基因的表达发生微妙但显著的变化，这些基因编码细胞外基质的蛋白质或参与生长因子的信号转导（例如胰岛素/胰岛素生长因子 1）。我们表明，最差异表达的基因（DEGs），RGCC、RNF144B、NRCAM、TRIM22、FAM107A、IGFBP5 和 LAMA2，在不同的遗传背景下，不同的雄激素可重复地调节。我们通过在神经母细胞瘤细胞 SH-SY5Y 中过表达雄激素受体或在人神经干细胞中敲低雄激素受体，表明这种调节涉及雄激素受体。染色质免疫沉淀结合直接测序分析鉴定了近一半 DHT-DEGs 和许多其他基因中的雄激素受体结合序列。DHT-DEGs 似乎富集在与 ASD 相关的基因（ASXL3、NLGN4X 等）、与 ASD 相关的基因（NRCAM）或在 ASD 患者中差异表达的基因（FAM107A、IGFBP5）中。雄激素在营养缺乏的培养条件下增加人神经干细胞的增殖和存活，对调节神经突生长没有明显影响。
我们描述了雄激素在神经祖细胞中的作用，鉴定了 DHT-DEGs，这些基因似乎在与 ASD 相关的基因中富集。我们还表明，雄激素在营养缺乏条件下增加神经元前体的增殖并保护它们免于死亡。
