SOX2-LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors
SOX2-LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors
复制标题
DOI：
10.1073/pnas.1220176110
复制
发表时间：
2013-08-06
影响因子：
11.1
通讯作者：
Terskikh, Alexey V.
中科院分区：
文献类型：
--
作者：
Cimadamore, Flavio;Amador-Arjona, Alejandro;Terskikh, Alexey V.
转录因子SRY(性别决定区)盒2(SOX2)是神经前体细胞的重要功能标记物，在神经前体细胞的自我更新和神经元分化中起着关键作用，但其功能的分子机制尚不清楚。使用人类胚胎干细胞来源的NPC来模拟神经发生，我们发现SOX2是维持LIN28的最佳水平所必需的，LIN28是一种很好地描述了let-7 microRNA生物发生的抑制因子。外源性LIN28的表达挽救了鼻咽癌的增殖缺陷，以及与SOX2缺失相关的神经源性缺陷的早期但不是晚期。我们发现SOX2结合到LIN28启动子区域的近端，并调节LIN28启动子的乙酰化，可能是通过与组蛋白乙酰转移酶复合体的相互作用来实现的。NPC中let-7microRNAs的错误表达减少了细胞的增殖和抑制了神经元的分化，从而导致SOX2的丢失。特别是，我们确定let-7i是一种针对MASH1和Ngn1这两个特征良好的神经原基因的新的和有效的神经元分化抑制因子。综上所述，我们发现SOX2-LIN28/let-7通路是调控鼻咽癌增殖和神经发生潜能的独特分子机制。
The transcription factor SRY (sex-determining region)-box 2 (SOX2) is an important functional marker of neural precursor cells (NPCs) and plays a critical role in self-renewal and neuronal differentiation; however, the molecular mechanisms underlying its functions are poorly understood. Using human embryonic stem cell-derived NPCs to model neurogenesis, we found that SOX2 is required to maintain optimal levels of LIN28, a well-characterized suppressor of let-7 microRNA biogenesis. Exogenous LIN28 expression rescued the NPC proliferation deficit, as well as the early but not the late stages of the neurogenic deficit associated with the loss of SOX2. We found that SOX2 binds to a proximal site in the LIN28 promoter region and regulates LIN28 promoter acetylation, likely through interactions with the histone acetyltransferase complex. Misexpression of let-7 microRNAs in NPCs reduced proliferation and inhibited neuronal differentiation, phenocopying the loss of SOX2. In particular, we identified let-7i as a novel and potent inhibitor of neuronal differentiation that targets MASH1 and NGN1, two well-characterized proneural genes. In conclusion, we discovered the SOX2-LIN28/let-7 pathway as a unique molecular mechanism governing NPC proliferation and neurogenic potential.