胚胎干細(xì)胞（embryonic stem cells, ES細(xì)胞）來(lái)源于著床前囊胚的內(nèi)細(xì)胞團(tuán),，具有自我更新和分化多能性的特點(diǎn),，這使得其具有巨大的基礎(chǔ)研究和臨床應(yīng)用價(jià)值,。ES細(xì)胞的自我更新和分化受到細(xì)胞內(nèi)轉(zhuǎn)錄因子與細(xì)胞外分子介導(dǎo)的信號(hào)通路的共同調(diào)控,。
研究表明,，以O(shè)ct4為代表的關(guān)鍵轉(zhuǎn)錄因子對(duì)于ES細(xì)胞保持未分化狀態(tài)至關(guān)重要,；而Erk/MAPK通路對(duì)于ES細(xì)胞的分化是必不可少的。然而,，細(xì)胞內(nèi)轉(zhuǎn)錄因子與細(xì)胞外信號(hào)通路之間是如何調(diào)控的,，它們對(duì)于ES細(xì)胞分化命運(yùn)的決定有何意義，關(guān)于這方面的研究報(bào)道還較少,。
中科院上海生命科學(xué)研究院/上海交通大學(xué)醫(yī)學(xué)院健康科學(xué)研究所干細(xì)胞生物學(xué)重點(diǎn)實(shí)驗(yàn)室金穎課題組最新研究發(fā)現(xiàn)了Oct4的新的靶基因Stk40（serine/threonie kinase 40）,。他們的研究證明Stk40能夠激活Erk/MAPK通路，并能誘導(dǎo)小鼠ES細(xì)胞向胚外內(nèi)胚層（extraembryonic endoderm, ExEn）方向分化,。當(dāng)Stk40高表達(dá)的細(xì)胞注入小鼠囊胚時(shí),，這些細(xì)胞能整合并進(jìn)一步參與嵌合胚胎中胚外內(nèi)胚層的發(fā)育；而Stk40缺失則導(dǎo)致ES 細(xì)胞向胚外內(nèi)胚層方向分化的能力顯著降低,。進(jìn)一步的研究表明,，Stk40能夠與Rcn2相互作用。Rcn2表達(dá)于早期發(fā)育中的胚外內(nèi)胚層區(qū)域,，并作為重要的調(diào)控分子參與Erk/MAPK通路的激活以及胚外內(nèi)胚層分化,。抑制Rcn2的表達(dá)，能夠阻止Stk40對(duì)Erk1/2的激活和ES細(xì)胞的分化,。這表明,，二者相互作用，協(xié)同參與了胚外內(nèi)胚層的分化調(diào)控,。該研究不但發(fā)現(xiàn)了胚外內(nèi)胚層分化的新的調(diào)控因子,，并進(jìn)一步將多能性轉(zhuǎn)錄因子Oct4與Erk/MAPK信號(hào)通路建立起了聯(lián)系；Oct4通過(guò)調(diào)控Erk/MAPK信號(hào)通路組分的表達(dá)水平參與胚外內(nèi)胚層分化的調(diào)控,。這為深入理解ES細(xì)胞自我更新與分化,，以及胚胎早期發(fā)育的調(diào)控機(jī)制提供了新的思路,。（生物谷Bioon.com）
2010年4月15日-16日金穎老師將赴上海好望角大酒店參加“2010年干細(xì)胞技術(shù)與應(yīng)用講座”，詳細(xì)情況請(qǐng)登陸：http://www.stemcellasia.net/
生物谷推薦原始出處：
PNAS January 4, 2010, doi: 10.1073/pnas.0905657107
Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation
Lingjie Lia,1, Lei Suna,1, Furong Gaoa, Jing Jiangb, Ying Yanga, Chunliang Lia, Junjie Gua,c, Zhe Weia, Acong Yanga,c, Rui Lua, Yu Maa,c, Fan Tanga,c, Sung Won Kwond, Yingming Zhaod, Jinsong Lib, and Ying Jina,c,2
aKey Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, Shanghai 200025, China;
bLaboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
cShanghai Stem Cell Institute, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China; and
dBen May Department for Cancer Research, University of Chicago, Chicago, IL 60637
Self-renewal and differentiation of embryonic stem cells (ESCs) are controlled by intracellular transcriptional factors and extracellular factor-activated signaling pathways. Transcription factor Oct4 is a key player maintaining ESCs in an undifferentiated state, whereas the Erk/MAPK pathway is known to be important for ESC differentiation. However, the manner in which intracellular pluripotency factors modulate extracellular factor-activated signaling pathways in ESCs is not well understood. Here, we report identification of a target gene of Oct4, serine/threonine kinase 40 (Stk40), which is able to activate the Erk/MAPK pathway and induce extraembryonic–endoderm (ExEn) differentiation in mouse ESCs. Interestingly, cells overexpressing Stk40 exclusively contribute to the ExEn layer of chimeric embryos when injected into host blastocysts. In contrast, deletion of Stk40 in ESCs markedly reduces ExEn differentiation in vitro. Mechanistically, Stk40 interacts with Rcn2, which also activates Erk1/2 to induce ExEn specification in mouse ESCs. Moreover, Rcn2 proteins are specifically located in the cytoplasm of the ExEn layer of early mouse embryos. Importantly, knockdown of Rcn2 blocks Stk40-activated Erk1/2 and ESC differentiation. Therefore, our study establishes a link between the pluripotency factor Oct4 and the Erk/MAPK signaling pathway, and it uncovers cooperating signals in the Erk/MAPK activation that control ExEn differentiation.
