IP3R-mediated Ca2+ signals govern hematopoietic and cardiac divergence of Flk1+ cells via the calcineurin-N FATc3-Etv2 pathway  被引量:3

IP3R-mediated Ca2+ signals govern hematopoietic and cardiac divergence of Flk1+ cells via the calcineurin-N FATc3-Etv2 pathway

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作  者:Yi-Jie Wang Jijun Huang Wenqiang Liu Xiaochen Kou Huayuan Tang Hong Wang Xiujian Yu Shaorong Gao Kunfu Ouyang Huang-Tian Yang 

机构地区:[1]Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai liao Tong University School of Medicine, Shanghai 200031, China [2]Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China [3]Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China [4]Second Affiliated Hospital/Zhejiang University, Hangzhou 310009, China

出  处:《Journal of Molecular Cell Biology》2017年第4期274-288,共15页分子细胞生物学报(英文版)

基  金:This study was supported by grants from the National Natural Science Foundation of China (31030050, 81520108004, and 81470422 to H.-T.Y.), the Strategic Priority Research Program of Chinese Academy of Sciences (XDA01020204 to H.-T.Y.), the National Basic Research Program of China (2014CB965100 to H.-T.Y.), the National Science and Technology Major Project (2012ZX09501001 to H.-T.Y.), and the Shenzhen Science, Technology and Innovation Committee OCYI 20160428154108239 to K.O.).

摘  要:Ca2+ signals participate in various cellular processes with spatial and temporal dynamics, among which, inositol 1,4,5-trisphosphate receptors (IP3Rs)-mediated Ca2+ signals are essential for early development. However, the underlying mechanisms of IP3R- regulated cell fate decision remain largely unknown. Here we report that IP3Rs are required for the hematopoietic and cardiac fate divergence of mouse embryonic stem cells (mESCs). Deletion of IP3Rs (IP3R-tKO) reduced FIkl+/PDGFRα- hematopoietic mesoderm, c-Kit+/CD41+ hematopoietic progenitor ceil population, and the colony-forming unit activity, but increased cardiac progenitor markers as well as cardiomyocytes. Concomitantly, the expression of a key regulator of hematopoiesis, Ely2, was reduced in IP3R-tKO cells, which could be rescued by the activation of Ca2+ signals and calcineurin or overexpression of constitutively active form of NFATc3. Furthermore, IP3R-tKO impaired specific targeting of Ely2 by NFATc3 via its evolutionarily conserved cis-element in differentiating ESCs. Importantly, the activation of Ca2+-calcineurin-NFAT pathway reversed the phenotype of IP3R-tKO cells. These findings reveal an unrecognized governing role of IP3Rs in hematopoietic and cardiac fate commitment via IP3Rs-Ca2+-calcineurin-NFATc3- Etv2 pathway.

关 键 词:IP3Rs Ca2+ signals mesoderm specification hematopoietic and cardiac fate Etv2 

分 类 号:Q813.1[生物学—生物工程] U491.51[交通运输工程—交通运输规划与管理]

 

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