近日來(lái)自上海交通大學(xué)醫(yī)學(xué)院、中科院上海生命科學(xué)研究院的研究人員在新研究中證實(shí)Calcineurin-NFAT信號(hào)通路在胚胎干細(xì)胞及胚胎的早期譜系分化中發(fā)揮精密調(diào)控作用,，相關(guān)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(lǐng)導(dǎo)這一研究的是上海交大醫(yī)學(xué)院和中科院上海生命科學(xué)研究院健康科學(xué)研究所干細(xì)胞生物重點(diǎn)實(shí)驗(yàn)室的金穎博士。
胚胎干細(xì)胞(ES cells)來(lái)源于植入前胚胎囊胚期的內(nèi)細(xì)胞團(tuán),，具有自我更新和全能性的特點(diǎn)。盡管已有大量研究證實(shí)ES細(xì)胞的自我更新和全能性特性受到細(xì)胞外信號(hào)分子和細(xì)胞內(nèi)的關(guān)鍵轉(zhuǎn)錄因子的共同調(diào)控，然而一直以來(lái)科學(xué)家們對(duì)于啟動(dòng)胚胎干細(xì)胞從自我更新向分化狀態(tài)轉(zhuǎn)變的信號(hào)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(hào)在啟動(dòng)小鼠ESCs細(xì)胞的譜系分化中發(fā)揮了關(guān)鍵性的作用，阻斷Calcineurin-NFAT信號(hào)可以在不依賴于白血病抑制因子的情況下使ESC長(zhǎng)期維持在自我更新?tīng)顟B(tài),。此外研究人員還證實(shí)Calcineurin-NFAT信號(hào)可與Erk1/2信號(hào)共同作用激活下游效應(yīng)因子Src促進(jìn)上皮間質(zhì)轉(zhuǎn)化（EMT）,，并且兩條信號(hào)途徑相互依賴，當(dāng)其中任何一條信號(hào)被阻斷均可顯著地抑制ESC分化,。在進(jìn)一步的研究中研究人員證實(shí)在小鼠胚胎首次分化事件發(fā)生過(guò)程中Calcineurin-NFAT信號(hào)即被激活,，Calcineurin-NFAT信號(hào)抑制可導(dǎo)致胚胎發(fā)育終止，表明Calcineurin-NFAT信號(hào)通路是早期胚胎發(fā)育所必需的,。
新研究不僅揭示了干細(xì)胞分化和早期胚胎發(fā)育中的關(guān)鍵調(diào)控信號(hào)通路,，并進(jìn)一步地將Calcineurin-NFAT信號(hào)與Erk1/2信號(hào)通路聯(lián)系起來(lái)，確定了決定干細(xì)胞命運(yùn)的關(guān)鍵調(diào)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(kāi)發(fā)出更有效的平臺(tái)進(jìn)行ESC細(xì)胞編程以及體細(xì)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.
