Cell Stem Cell:干细胞分化和早期胚胎发育中的关键调控信号通路
近日来自上海交通大学医学院、中科院上海生命科学研究院的研究人员在新研究中证实Calcineurin-NFAT信号通路在胚胎干细胞及胚胎的早期谱系分化中发挥精密调控作用,相关论文于2011年1月7日在线发表在Cell出版社旗下的Cell Stem Cell杂志上。领导这一研究的是上海交大医学院和中科院上海生命科学研究院健康科学研究所干细胞生物重点实验室的金颖博士。
胚胎干细胞(ES cells)来源于植入前胚胎囊胚期的内细胞团,具有自我更新和全能性的特点。尽管已有大量研究证实ES细胞的自我更新和全能性特性受到细胞外信号分子和细胞内的关键转录因子的共同调控,然而一直以来科学家们对于启动胚胎干细胞从自我更新向分化状态转变的信号途径却了解甚少。
在这篇文章中研究人员发现Calcineurin-NFAT信号在启动小鼠ESCs细胞的谱系分化中发挥了关键性的作用,阻断Calcineurin-NFAT信号可以在不依赖于白血病抑制因子的情况下使ESC长期维持在自我更新状态。此外研究人员还证实Calcineurin-NFAT信号可与Erk1/2信号共同作用激活下游效应因子Src促进上皮间质转化(EMT),并且两条信号途径相互依赖,当其中任何一条信号被阻断均可显著地抑制ESC分化。在进一步的研究中研究人员证实在小鼠胚胎首次分化事件发生过程中Calcineurin-NFAT信号即被激活,Calcineurin-NFAT信号抑制可导致胚胎发育终止,表明Calcineurin-NFAT信号通路是早期胚胎发育所必需的。
新研究不仅揭示了干细胞分化和早期胚胎发育中的关键调控信号通路,并进一步地将Calcineurin-NFAT信号与Erk1/2信号通路联系起来,确定了决定干细胞命运的关键调控因子Src。此外还深入揭示了EMT在ESC分化中的重要作用,为研究人员开发出更有效的平台进行ESC细胞编程以及体细胞重编程提供了新思路。
原文出处:
Cell Stem Cell doi:10.1016/j.stem.2010.11.027
Calcineurin-NFAT Signaling Critically Regulates Early Lineage Specification in Mouse Embryonic Stem Cells and Embryos
Li X, Zhu L, Yang A, Lin J, Tang F, Jin S, Wei Z, Li J and Jin Y*.
Highlights
Calcineurin-NFAT signaling triggers lineage commitment in embryonic stem cells
Src is a key player downstream of the NFAT and Erk1/2 pathways
Src-mediated signaling promotes epithelial to mesenchymal transition
Calcineurin-NFAT signaling is required for early embryonic lineage development
Summary
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.
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