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FRS2α 通过调节 Erk 水平来控制自我更新靶标 Hes1 和 FGF 反应性神经干细胞/祖细胞的增殖。

FRS2α regulates Erk levels to control a self-renewal target Hes1 and proliferation of FGF-responsive neural stem/progenitor cells.

机构信息

Division of Systems Biomedical Technology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

出版信息

Stem Cells. 2010 Sep;28(9):1661-73. doi: 10.1002/stem.488.

Abstract

Fibroblast growth factor (FGF) is among the most common growth factors used in cultures to maintain self-renewal and proliferative capabilities of a variety of stem cells, including neural stem cells (NSCs). However, the molecular mechanisms underlying the control by FGF have remained elusive. Studies on mutant mice of FGF receptor substrate 2α (FRS2α), a central mediator for FGF signaling, combined with FRS2α knockdown or gain-of-function experiments, allowed us to dissect the role of FGF signaling for the self-renewal and proliferation of NSCs and to provide novel molecular mechanisms for them. We identified Hes1 as a novel self-renewal target of FGF-signaling. Quantitatively different levels of Erk activation mediated by FRS2α may regulate self-renewal of NSCs and proliferation of neural stem/progenitor cells (NSPCs); low levels of Erk activation are sufficient for the former, however, higher levels are required for maximum activity of the latter. Thus, FRS2α fine-tunes the FGF-signaling to control qualitatively different biological activities, self-renewal at least partly through Hes1 versus proliferation of NSPCs.

摘要

成纤维细胞生长因子(FGF)是在培养物中用于维持各种干细胞(包括神经干细胞(NSC))自我更新和增殖能力的最常见生长因子之一。然而,FGF 控制的分子机制仍然难以捉摸。对 FGF 受体底物 2α(FRS2α)突变体小鼠的研究,FRS2α 是 FGF 信号的中心介质,结合 FRS2α 敲低或功能获得实验,使我们能够剖析 FGF 信号对 NSCs 的自我更新和增殖的作用,并为它们提供新的分子机制。我们确定 Hes1 是 FGF 信号的一个新的自我更新靶标。由 FRS2α 介导的不同定量水平的 Erk 激活可能调节 NSCs 的自我更新和神经干细胞/祖细胞(NSPC)的增殖;前者需要低水平的 Erk 激活,而后者则需要更高水平的 Erk 激活以达到最大活性。因此,FRS2α 微调 FGF 信号以控制定性不同的生物学活性,至少部分通过 Hes1 进行自我更新,而通过 NSPCs 进行增殖。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a799/2996081/ec491ad29d7d/stem0028-1661-f1.jpg

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