The ubiquitin ligase mLin41 temporally promotes neural progenitor cell maintenance through FGF signaling
The ubiquitin ligase mLin41 temporally promotes neural progenitor cell maintenance through FGF signaling
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DOI：
10.1101/gad.187641.112
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发表时间：
2012-04-15
影响因子：
10.5
通讯作者：
Niswander, Lee
中科院分区：
文献类型：
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作者：
Chen, Jianfu;Lai, Fan;Niswander, Lee
在早期发育过程中，神经前体细胞的自我更新和分化是如何在时间上受到控制的，目前仍不清楚。我们发现小鼠LIN41(MLin41)在神经前体细胞中高表达，在神经分化过程中其表达下降。小鼠mLin41功能的丧失会导致胚胎神经前体细胞增殖减少和过早分化。MLin41最近被认为是E3泛素连接酶，它介导了microRNA途径的关键效应因子ArgAerte 2(AGO2)的降解。然而，我们对神经前体细胞的机制研究表明，mLin41不是AGO2泛素化或稳定性所必需的。相反，mLin41缺失的神经前体细胞对成纤维细胞生长因子(FGF)信号表现出低敏感性。我们发现mLin41通过直接与Shc SH2结合蛋白1(SHCBP1)结合并增强其稳定性来促进成纤维细胞生长因子信号转导，SHCBP1是神经前体细胞中成纤维细胞生长因子信号的重要组成部分。因此，mLin41作为时间调节器促进神经前体细胞的维持，不是通过调节AGO2的稳定性，而是通过成纤维细胞生长因子信号。
How self-renewal versus differentiation of neural progenitor cells is temporally controlled during early development remains ill-defined. We show that mouse Lin41 (mLin41) is highly expressed in neural progenitor cells and its expression declines during neural differentiation. Loss of mLin41 function in mice causes reduced proliferation and premature differentiation of embryonic neural progenitor cells. mLin41 was recently implicated as the E3 ubiquitin ligase that mediates degradation of Argonaute 2 (AGO2), a key effector of the microRNA pathway. However, our mechanistic studies of neural progenitor cells indicate mLin41 is not required for AGO2 ubiquitination or stability. Instead, mLin41-deficient neural progenitors exhibit hyposensitivity for fibroblast growth factor (FGF) signaling. We show that mLin41 promotes FGF signaling by directly binding to and enhancing the stability of Shc SH2-binding protein 1 (SHCBP1) and that SHCBP1 is an important component of FGF signaling in neural progenitor cells. Thus, mLin41 acts as a temporal regulator to promote neural progenitor cell maintenance, not via the regulation of AGO2 stability, but through FGF signaling.