Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells
Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells
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DOI：
10.1073/pnas.0506945103
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发表时间：
2006-07-05
影响因子：
11.1
通讯作者：
Belmonte, Juan Carlos Izpisua
中科院分区：
文献类型：
--
作者：
Suzuki, Atsushi;Raya, Angel;Belmonte, Juan Carlos Izpisua
胚胎干细胞是研究早期胚胎发育的一个有价值的模型，并为未来的再生医学策略带来了希望。多能小鼠ES细胞的自我更新已被证明需要通过骨形态发生蛋白（BMP）和白血病抑制因子信号传导途径以及转录因子Oct4和Nanog的表达的外源性刺激。然而，ES细胞多能性的外在和内在决定因素之间的相互作用网络目前知之甚少。在这里，我们表明，Nanog表达上调小鼠ES细胞的T（Brachyury）和STAT3的结合增强子元件在小鼠Nanog基因。我们进一步表明，Nanog块BMP诱导的ES细胞中胚层分化的物理相互作用与Smad1和干扰的招聘的辅激活剂的活性Smad转录复合物。总之，我们的研究结果说明了存在的ES细胞特异性的调控网络，支持维持ES细胞的多能性，并提供了机制的见解Nanog在这一过程中的作用。
ES cells represent a valuable model for investigating early embryo development and hold promise for future regenerative medicine strategies. The self-renewal of pluripotent mouse ES cells has been shown to require extrinsic stimulation by the bone morphogenetic protein (BMP) and leukemia inhibitory factor signaling pathways and the expression of the transcription factors Oct4 and Nanog. However, the network of interactions among extrinsic and intrinsic determinants of ES cell pluripotency is currently poorly understood. Here, we show that Nanog expression is up-regulated in mouse ES cells by the binding of T (Brachyury) and STAT3 to an enhancer element in the mouse Nanog gene. We further show that Nanog blocks BMP-induced mesoderm differentiation of ES cells by physically interacting with Smad1 and interfering with the recruitment of coactivators to the active Smad transcriptional complexes. Taken together, our findings illustrate the existence of ES cell-specific regulatory networks that underlie the maintenance of ES cell pluripotency and provide mechanistic insights into the role of Nanog in this process.