自噬相关基因Eva1a促进神经干细胞神经发生及其机制研究

Embryonic neurogenesis is important for the development and the function of the brain. Autophaygy is an evolutionarily conserved process and has been reported to involve in a wide variety of physiological as well as pathological situations and plays a critical role in development and differentiation such as neurodegeneration diseases. The precise cellular processes of autophagy function in the embryonic brain development remain largely unknown. Eva1a is a novel autophagy-related molecule. Our research will demonstrate for the first time that Eva1a is a novel regulator of brain development. Eva1a regulates neurogenesis through the mTOR pathway by control the TSC1/2 ‘switch’. Eva1a regulates neural stem cells self-renewal and neuronal differentiation through modulates the process of autophagy in an energy-dependent manner. In this study, we will generate mice deficient in Eva1a to investigate the role of Eva1a in the development of central nervous system by in vivo and in vitro assay. Our results provide a better understanding of the function of Eva1a as well as the role of basal autophagy in the process of neurogenesis. Moreover, our findings also contribute to the understanding and treatment of neurodevelopmental disorders caused by autophagy dysregulation.

胚胎神经发生在早期脑发育及其功能形成中具有重要作用。自噬是广泛存在于真核细胞中的基本生命现象，自噬功能异常与胚胎发育障碍以及某些神经退行性病变密切相关。目前迫切需要阐明自噬调控神经系统早期发育的分子机制。Eva1a是一个广泛作用于细胞自噬各阶段的重要分子。本课题将首次证明Eva1a是一个新的神经发生调控分子，通过特异性调控分子开关TSC1/2，抑制mTOR信号通路活化，激活能量应激诱导的自噬通路，上调神经干细胞自噬水平及能量代谢，进而促进其自我更新及向神经元分化，调控胚胎神经发生。我们将制备神经系统特异性Eva1a基因敲除小鼠，在体动态观察Eva1a基因对神经系统发育的影响；体外培养NSCs，检测Eva1a对NSCs自我更新及向神经元分化的调控作用及其机制。本研究有助于阐明自噬在神经干细胞神经发生中的作用及其分子机制，为人类神经系统发育异常的诊断、治疗提供理论依据和新的思路。

神经干细胞的自我更新和分化是胚胎神经发生所必需的，而胚胎神经发生与细胞自噬密切相关。然而，自噬调控神经发生的具体机制仍不清楚。在本项目中我们首次证明：Eva1a/Tmem166，一个自噬相关基因，调控神经干细胞的自我更新和分化。体内和体外敲除Eva1a基因均可影响新生神经元的产生。相反，过表达EVA1A促进了新生神经元的产生和成熟。此外，敲除EVA1A可激活PIK3CA-AKT信号轴，导致mTOR通路的激活和自噬的抑制。此外，在培养的神经干细胞体外诱导分化过程中加入甲基丙酮酸可以挽救Eva1a敲除引起的胚胎神经发生异常，提示能量代谢是影响胚胎神经发生的重要因素。综上所述，我们的研究结果表明EVA1A通过调节自噬调控胚胎神经发生。本项目对于阐明自噬异常导致神经发育障碍的分子机制具有重要意义，为人类神经系统发育异常的诊断、治疗提供理论依据和新的思路。