β-Catenin Enhances Oct-4 Activity and Reinforces Pluripotency through a TCF-Independent Mechanism
β-Catenin Enhances Oct-4 Activity and Reinforces Pluripotency through a TCF-Independent Mechanism
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DOI：
10.1016/j.stem.2010.12.010
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发表时间：
2011-02-04
期刊：
影响因子：
23.9
通讯作者：
Doble, Bradley W.
中科院分区：
文献类型：
--
作者：
Kelly, Kevin F.;Ng, Deborah Y.;Doble, Bradley W.
了解胚胎和诱导多能干细胞的多能性调节机制是确保其在临床应用中安全使用的必要条件。糖原合成酶激酶3 （GSK-3）已成为多能性的重要调节因子，主要基于对小分子GSK-3抑制剂的研究。在这里，我们使用缺乏GSK-3的小鼠胚胎干细胞（ESCs）来证明单个GSK-3底物，β -连环蛋白，控制ESCs退出多能状态并分化为神经外胚层的能力。出乎意料的是，基于利用β -catenin c端截断突变体或高效显性阴性TCF策略的实验，β -catenin对多能性的影响似乎并不依赖于TCF介导的信号传导。另外，我们发现稳定的β -连环蛋白与Oct-4形成复合物并增强其活性，Oct-4是调节多能性的转录网络的核心组成部分。总的来说，我们的数据表明，β -连环蛋白在ESCs中的作用以前被低估了，它依赖于tcf和不依赖于tcf。
Understanding the mechanisms regulating pluripotency in embryonic and induced pluripotent stem cells is required to ensure their safe use in clinical applications. Glycogen synthase kinase-3 (GSK-3) has emerged as an important regulator of pluripotency, based primarily on studies with small-molecule GSK-3 inhibitors. Here, we use mouse embryonic stem cells (ESCs) lacking GSK-3 to demonstrate that a single GSK-3 substrate, beta-catenin, controls the ability of ESCs to exit the pluripotent state and to differentiate into neurectoderm. Unexpectedly, the effects of beta-catenin on pluripotency do not appear to be dependent on TCF-mediated signaling, based on experiments utilizing a beta-catenin C-terminal truncation mutant or highly efficient dominant-negative TCF strategies. Alternatively, we find that stabilized beta-catenin forms a complex with and enhances the activity of Oct-4, a core component of the transcriptional network regulating pluripotency. Collectively, our data suggest previously underappreciated, divergent TCF-dependent and TCF-independent roles for beta-catenin in ESCs.