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.

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人类神经细胞中由雄激素调节的基因和通路，这是自闭症谱系障碍中男性过剩的潜在候选者

背景男性个体在大脑发育过程中产前暴露于雄激素可能会增加他们患神经发育障碍如自闭症谱系障碍（ASD）和智力障碍的易感性。然而，人们对雄激素在人类神经细胞中的作用知之甚少。方法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靶标。结果 RNA 测序显示，用二氢睾酮 (DHT) 治疗导致约 200 个基因表达发生微妙但显着的变化，这些基因编码细胞外基质的蛋白质或参与生长因子（例如胰岛素/胰岛素生长因子 1）的信号转导。我们展示了差异最大的基因 (DEG)、RGCC、RNF144B、NRCAM、TRIM22、FAM107A、IGFBP5 和 LAMA2，受不同遗传背景下不同雄激素的可重复调控。我们通过在神经母细胞瘤细胞 SH-SY5Y 中过度表达雄激素受体或在人类神经干细胞中将其敲低，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在近一半的 DHT-DEG 和许多其他基因中鉴定了雄激素受体结合序列。DHT-DEG 似乎富含与 ASD 相关的基因（ASXL3、NLGN4X 等）、与 ASD 相关（NRCAM）或在 ASD 患者中差异表达的基因（FAM107A、IGFBP5）。雄激素在缺乏营养的培养条件下增加人类神经干细胞的增殖和存活，对神经突生长的调节没有可检测的影响。结论 我们表征了神经祖细胞中的雄激素作用，鉴定似乎富含与 ASD 相关的基因的 DHT-DEG。我们还表明雄激素增加神经元前体的增殖并保护它们在营养缺乏条件下的分化过程中免于死亡。