The p53 Family Coordinates Wnt and Nodal Inputs in Mesendodermal Differentiation of Embryonic Stem Cells

被引:133
作者
Wang, Qiong [1 ]
Zou, Yilong [1 ]
Nowotschin, Sonja [2 ]
Kim, Sang Yong [3 ]
Li, Qing V. [2 ,6 ]
Soh, Chew-Li [2 ]
Su, Jie [1 ]
Zhang, Chao [4 ,5 ]
Shu, Weiping [1 ]
Xi, Qiaoran [1 ,7 ]
Huangfu, Danwei [2 ]
Hadjantonakis, Anna-Katerina [2 ]
Massague, Joan [1 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA
[2] Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA
[3] NYU, Rodent Genet Engn Core, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA
[4] Weill Cornell Med, Dept Med, New York, NY 10065 USA
[5] Weill Cornell Med, Inst Computat Biomed, New York, NY 10065 USA
[6] Louis V Gerstner Jr Grad Sch Biomed Sci, New York, NY 10065 USA
[7] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China
关键词
TUMOR-SUPPRESSOR; MESODERM INDUCTION; ICRISPR PLATFORM; MOUSE EMBRYO; DNA-DAMAGE; BETA; PATHWAY; EXPRESSION; PLURIPOTENCY; PROTEIN;
D O I
10.1016/j.stem.2016.10.002
中图分类号
Q813 [细胞工程];
学科分类号
摘要
In this study, we outline a regulatory network that involves the p53 tumor suppressor family and the Wnt pathway acting together with the TGF-beta pathway in mesendodermal differentiation of mouse and human embryonic stem cells. Knockout of all three members, p53, p63, and p73, shows that the p53 family is essential for mesendoderm specification during exit from pluripotency in embryos and in culture. Wnt3 and its receptor Fzd1 are direct p53 family target genes in this context, and induction of Wnt signaling by p53 is critical for activation of mesendodermal differentiation genes. Globally, Wnt3-activated Tcf3 and nodal-activated Smad2/3 transcription factors depend on each other for co-occupancy of target enhancers associated with key differentiation loci. Our results therefore highlight an unanticipated role for p53 family proteins in a regulatory network that integrates essential Wnt-Tcf and nodal-Smad inputs in a selective and interdependent way to drive mesendodermal differentiation of pluripotent cells.
引用
收藏
页码:70 / 86
页数:17
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