Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal.
Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal.
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DOI：
10.1038/ncb2283
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发表时间：
2011-06-19
影响因子：
21.3
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中科院分区：
文献类型：
--
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观察到Tcf 3（MGI名称：Tcf 7 l1）与核心干细胞转录因子Oct 4（MGI名称：Pou 5 f1）、Sox 2和Nanog结合相同的基因，揭示了Wnt刺激多能小鼠胚胎干（ES）细胞自我更新的机制的一个潜在重要方面。尽管传统观点认为Tcf蛋白是Wnt信号的β-catenin结合效应物，提示Tcf 3-β-catenin介导的靶基因激活会刺激ES细胞自我更新，但我们发现Wnt 3a和Tcf 3在基因表达上的拮抗关系对调节ES细胞自我更新很重要。Tcf 3的基因切除取代了ES细胞自我更新对外源性Wnt 3a或GSK 3抑制的需要，表明Tcf 3抑制剂的抑制是Wnt信号传导的必要下游效应。有趣的是，Wnt作用的分子机制需要Tcf 3-β-catenin和Tcf 1-β-catenin相互作用，因为它们各自有助于Wnt刺激自我更新和基因表达。最后，Tcf 3和Tcf 1的组合对于将Wnt稳定的β-catenin募集到ES细胞染色质中的Oct 4结合位点是必需的。这些结果阐明了Wnt效应与Oct 4/Sox 2/Nanog网络调控之间的分子联系。
The observation that Tcf3 (MGI name: Tcf7l1) bound the same genes as core stem cell transcription factors, Oct4 (MGI name:Pou5f1), Sox2 and Nanog, revealed a potentially important aspect of the poorly understood mechanism whereby Wnts stimulate self renewal of pluripotent mouse embryonic stem (ES) cells. Although the conventional view of Tcf proteins as the β-catenin-binding effectors of Wnt signaling suggested Tcf3-β-catenin mediated activation of target genes would stimulate ES cell self renewal, here we show that an antagonistic relationship between Wnt3a and Tcf3 on gene expression is important for regulating ES cell self renewal. Genetic ablation of Tcf3 replaced the requirement for exogenous Wnt3a or GSK3-inhibition for self renewal of ES cells, demonstrating that inhibition of Tcf3-repressor is the necessary downstream effect of Wnt signaling. Interestingly, the molecular mechanism underlying Wnt’s effects required both Tcf3-β-catenin and Tcf1-β-catenin interactions, as they each contributed to Wnt stimulation of self renewal and gene expression. Finally, the combination of Tcf3 and Tcf1 was necessary to recruit Wnt-stabilized β-catenin to Oct4 binding sites in ES cell chromatin. These results elucidate the molecular link between the effects of Wnt and the regulation of the Oct4/Sox2/Nanog network.
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