Calcineurin-NFAT Signaling Critically Regulates Early Lineage Specification in Mouse Embryonic Stem Cells and Embryos
Calcineurin-NFAT Signaling Critically Regulates Early Lineage Specification in Mouse Embryonic Stem Cells and Embryos
复制标题
DOI：
10.1016/j.stem.2010.11.027
复制
发表时间：
2011-01-07
期刊：
影响因子：
23.9
通讯作者：
Jin, Ying
中科院分区：
文献类型：
--
作者：
Li, Xiang;Zhu, Lili;Jin, Ying
自我更新和多能性是胚胎干细胞（ESC）的标志。然而，触发它们从自我更新到分化的信号通路仍然难以捉摸。在这里，我们报告说，钙调神经磷酸酶-NFAT信号是必要的和足够的开关ESC从未分化状态的谱系特异性细胞和抑制这一途径可以保持长期的ESC自我更新独立的白血病抑制因子。从机制上讲，该途径与Erk 1/2途径会聚以调节Src表达并促进上皮-间充质转化（EMT），这是响应分化刺激的谱系特化所需的过程。此外，当小鼠胚胎中发生最早的分化事件时，钙调神经磷酸酶-NFAT信号传导被激活，并且其抑制破坏胚外谱系发育。总的来说，我们的研究结果表明，NFAT和Erk 1/2级联形成了小鼠ESC早期谱系分离的信号开关，并为ESC自我更新和早期谱系特化之间的平衡调节提供了重要的见解，
Self-renewal and pluripotency are hallmarks of embryonic stem cells (ESCs). However, the signaling pathways that trigger their transition from self-renewal to differentiation remain elusive. Here, we report that calcineurin-NFAT signaling is both necessary and sufficient to switch ESCs from an undifferentiated state to lineage-specific cells and that the inhibition of this pathway can maintain long-term ESC self-renewal independent of leukemia inhibitory factor. Mechanistically, this pathway converges with the Erk1/2 pathway to regulate Src expression and promote the epithelial-mesenchymal transition (EMT), a process required for lineage specification in response to differentiation stimuli. Furthermore, calcineurin-NFAT signaling is activated when the earliest differentiation event occurs in mouse embryos, and its inhibition disrupts extraembryonic lineage development. Collectively, our results demonstrate that the NFAT and Erk1/2 cascades form a signaling switch for early lineage segregation in mouse ESCs and provide significant insights into the regulation of the balance between ESC self-renewal and early lineage specification,