PNAS：转录因子Oct4与Erk/MAPK信号通路在胚胎干细胞分化中的调控机制

细胞海洋

胚胎干细胞（embryonic stem cells, ES细胞）来源于着床前囊胚的内细胞团，具有自我更新和分化多能性的特点，这使得其具有巨大的基础研究和临床应用价值。ES细胞的自我更新和分化受到细胞内转录因子与细胞外分子介导的信号通路的共同调控。
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研究表明，以Oct4为代表的关键转录因子对于ES细胞保持未分化状态至关重要；而Erk/MAPK通路对于ES细胞的分化是必不可少的。然而，细胞内转录因子与细胞外信号通路之间是如何调控的，它们对于ES细胞分化命运的决定有何意义，关于这方面的研究报道还较少。
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& L) N( W4 Y" \3 }/ c1 g中科院上海生命科学研究院/上海交通大学医学院健康科学研究所干细胞生物学重点实验室金颖课题组最新研究发现了Oct4的新的靶基因Stk40（serine/threonie kinase 40）。他们的研究证明Stk40能够激活Erk/MAPK通路，并能诱导小鼠ES细胞向胚外内胚层（extraembryonic endoderm, ExEn）方向分化。当Stk40高表达的细胞注入小鼠囊胚时，这些细胞能整合并进一步参与嵌合胚胎中胚外内胚层的发育；而Stk40缺失则导致ES 细胞向胚外内胚层方向分化的能力显著降低。进一步的研究表明，Stk40能够与Rcn2相互作用。Rcn2表达于早期发育中的胚外内胚层区域，并作为重要的调控分子参与Erk/MAPK通路的激活以及胚外内胚层分化。抑制Rcn2的表达，能够阻止Stk40对Erk1/2的激活和ES细胞的分化。这表明，二者相互作用，协同参与了胚外内胚层的分化调控。该研究不但发现了胚外内胚层分化的新的调控因子，并进一步将多能性转录因子Oct4与Erk/MAPK信号通路建立起了联系；Oct4通过调控Erk/MAPK信号通路组分的表达水平参与胚外内胚层分化的调控。这为深入理解ES细胞自我更新与分化，以及胚胎早期发育的调控机制提供了新的思路。

细胞海洋

PNAS January 4, 2010, doi: 10.1073/pnas.0905657107
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Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation
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) p, R; P+ V6 {/ k! ~: uLingjie 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+ C, \" I! |) B, {, w

$ `2 Y. _' E- u$ v. F! Y( V9 ]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;/ l. }: R9 Z4 t( O( s( C& P# A
bLaboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;* H; n& A( t$ R$ ], A7 A
cShanghai Stem Cell Institute, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China; and
' D7 G/ b" Y! sdBen May Department for Cancer Research, University of Chicago, Chicago, IL 606375 V- @5 d9 p/ ?8 R/ ]

  T5 k$ D2 W3 s) L0 f2 [" M( fSelf-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.

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