Oct4的新的靶基因Stk40

weiwei

PNAS January 4, 2010, doi: 10.1073/pnas.0905657107
  e; A* _  D& J  Z% |% G
2 q. X. A( A5 ~0 z0 \Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation
2 K2 i& s1 f) ?4 |6 E7 W! t9 ~, w3 i% G- F: `' x
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
' [+ G- X2 h6 N, v8 T2 S' n* R! O' ?  o, r& }/ g
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;
" `6 L) A9 v8 y- WbLaboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
- O; y0 O+ r. [- x6 NcShanghai Stem Cell Institute, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China; and3 |  H5 {/ t, @
dBen May Department for Cancer Research, University of Chicago, Chicago, IL 60637
* R! F/ e0 [2 n. t# J# J- d0 k( o9 D+ [& I
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.
- z4 N! x% X+ S6 X& Z: J金颖课题组最新研究发现了Oct4的新的靶基因Stk40。Stk40能激活Erk/MAPK通路，能诱导小鼠ES细胞向胚外内胚层方向分化。Stk40高表达的细胞注入小鼠囊胚时，这些细胞能整合进一步参与嵌合胚胎中胚外内胚层的发育；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。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。