Li Mengtao, Lu Guang, Hu Jia, Shen Xue, Ju Jiabao, Gao Yuanxu, Qu Liujing, Xia Yan, Chen Yingyu, Bai Yun
Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Peking University Center for Human Disease Genomics, Peking University, Beijing 100191, China.
Stem Cell Reports. 2016 Mar 8;6(3):396-410. doi: 10.1016/j.stemcr.2016.01.011. Epub 2016 Feb 18.
Self-renewal and differentiation of neural stem cells is essential for embryonic neurogenesis, which is associated with cell autophagy. However, the mechanism by which autophagy regulates neurogenesis remains undefined. Here, we show that Eva1a/Tmem166, an autophagy-related gene, regulates neural stem cell self-renewal and differentiation. Eva1a depletion impaired the generation of newborn neurons, both in vivo and in vitro. Conversely, overexpression of EVA1A enhanced newborn neuron generation and maturation. Moreover, Eva1a depletion activated the PIK3CA-AKT axis, leading to the activation of the mammalian target of rapamycin and the subsequent inhibition of autophagy. Furthermore, addition of methylpyruvate to the culture during neural stem cell differentiation rescued the defective embryonic neurogenesis induced by Eva1a depletion, suggesting that energy availability is a significant factor in embryonic neurogenesis. Collectively, these data demonstrated that EVA1A regulates embryonic neurogenesis by modulating autophagy. Our results have potential implications for understanding the pathogenesis of neurodevelopmental disorders caused by autophagy dysregulation.
神经干细胞的自我更新和分化对于胚胎神经发生至关重要，而胚胎神经发生与细胞自噬相关。然而，自噬调节神经发生的机制仍不明确。在此，我们表明Eva1a/Tmem166，一个自噬相关基因，调节神经干细胞的自我更新和分化。在体内和体外，Eva1a缺失均损害新生神经元的生成。相反，EVA1A的过表达增强了新生神经元的生成和成熟。此外，Eva1a缺失激活了PIK3CA-AKT轴，导致雷帕霉素哺乳动物靶标激活以及随后自噬的抑制。此外，在神经干细胞分化过程中向培养物中添加丙酮酸钠可挽救由Eva1a缺失诱导的有缺陷的胚胎神经发生，这表明能量可用性是胚胎神经发生中的一个重要因素。总体而言，这些数据表明EVA1A通过调节自噬来调节胚胎神经发生。我们的结果对于理解由自噬失调引起的神经发育障碍的发病机制具有潜在意义。
