Volume 25, No 12, Dec 2015
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 25 Issue 12, December 2015: 1314-1332
ORIGINAL ARTICLES
MSX2 mediates entry of human pluripotent stem cells into mesendoderm by simultaneously suppressing SOX2 and activating NODAL signaling
Qingqing Wu1,2, Leisheng Zhang1,2, Pei Su1,2, Xiaohua Lei3, Xin Liu1,2, Hongtao Wang1,2, Lisha Lu4, Yang Bai1,2, Tao Xiong4, Dong Li5, Zhengmao Zhu6, Enkui Duan3, Erlie Jiang1,2, Sizhou Feng1,2, Mingzhe Han1,2, Yuanfu Xu1,2, Fei Wang7 and Jiaxi Zhou1,2
1State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China
2Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Beijing, China
3State Key Laboratory of Reproductive Biology, Institute of Zoology, CAS, Beijing 100101, China
4College of Life Sciences at Yangtze University, Jingzhou, Hubei 434025, China
5Department of Oncology, Shanghai Third People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201900, China
6College of Life Sciences, Nankai University, Tianjin 300071, China
7Department of Cell and Developmental Biology and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Correspondence: Jiaxi Zhou, Tel: +86-22-23909412; Fax: +86-22-23909412.(zhoujx@ihcams.ac.cn)
How BMP signaling integrates into and destabilizes the pluripotency circuitry of human pluripotent stem cells (hPSCs) to initiate differentiation into individual germ layers is a long-standing puzzle. Here we report muscle segment homeobox 2 (MSX2), a homeobox transcription factor of msh family, as a direct target gene of BMP signaling and a master mediator of hPSCs' differentiation to mesendoderm. Enforced expression of MSX2 suffices to abolish pluripotency and induce directed mesendoderm differentiation of hPSCs, while MSX2 depletion impairs mesendoderm induction. MSX2 is a direct target gene of the BMP pathway in hPSCs, and can be synergistically activated by Wnt signals via LEF1 during mesendoderm induction. Furthermore, MSX2 destabilizes the pluripotency circuitry through direct binding to the SOX2 promoter and repression of SOX2 transcription, while MSX2 controls mesendoderm lineage commitment by simultaneous suppression of SOX2 and induction of NODAL expression through direct binding and activation of the Nodal promoter. Interestingly, SOX2 can promote the degradation of MSX2 protein, suggesting a mutual antagonism between the two lineage-specifying factors in the control of stem cell fate. Together, our findings reveal crucial new mechanisms of destabilizing pluripotency and directing lineage commitment in hPSCs.
10.1038/cr.2015.118
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