近日來自上海交通大學醫(yī)學院、中科院上海生命科學研究院的研究人員在新研究中證實Calcineurin-NFAT信號通路在胚胎干細胞及胚胎的早期譜系分化中發(fā)揮精密調控作用,，相關論文于2011年1月7日在線發(fā)表在Cell出版社旗下的Cell Stem Cell雜志上,。領導這一研究的是上海交大醫(yī)學院和中科院上海生命科學研究院健康科學研究所干細胞生物重點實驗室的金穎博士。
胚胎干細胞(ES cells)來源于植入前胚胎囊胚期的內細胞團,，具有自我更新和全能性的特點,。盡管已有大量研究證實ES細胞的自我更新和全能性特性受到細胞外信號分子和細胞內的關鍵轉錄因子的共同調控，然而一直以來科學家們對于啟動胚胎干細胞從自我更新向分化狀態(tài)轉變的信號途徑卻了解甚少,。
在這篇文章中研究人員發(fā)現(xiàn)Calcineurin-NFAT信號在啟動小鼠ESCs細胞的譜系分化中發(fā)揮了關鍵性的作用,，阻斷Calcineurin-NFAT信號可以在不依賴于白血病抑制因子的情況下使ESC長期維持在自我更新狀態(tài)。此外研究人員還證實Calcineurin-NFAT信號可與Erk1/2信號共同作用激活下游效應因子Src促進上皮間質轉化（EMT）,，并且兩條信號途徑相互依賴,，當其中任何一條信號被阻斷均可顯著地抑制ESC分化。在進一步的研究中研究人員證實在小鼠胚胎首次分化事件發(fā)生過程中Calcineurin-NFAT信號即被激活,，Calcineurin-NFAT信號抑制可導致胚胎發(fā)育終止，表明Calcineurin-NFAT信號通路是早期胚胎發(fā)育所必需的,。
新研究不僅揭示了干細胞分化和早期胚胎發(fā)育中的關鍵調控信號通路,，并進一步地將Calcineurin-NFAT信號與Erk1/2信號通路聯(lián)系起來，確定了決定干細胞命運的關鍵調控因子Src,。此外還深入揭示了EMT在ESC分化中的重要作用,，為研究人員開發(fā)出更有效的平臺進行ESC細胞編程以及體細胞重編程提供了新思路。（生物谷 Bioon.com）
生物谷推薦原文出處：
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.
