MSX2 mediates entry of human pluripotent stem cells into mesendoderm by simultaneously suppressing SOX2 and activating NODAL signaling

Qingqing Wu, Leisheng Zhang, Pei Su, Xiaohua Lei, Xin Liu, Hongtao Wang, Lisha Lu, Yang Bai, Tao Xiong, Dong Li, Zhengmao Zhu, Enkui Duan, Erlie Jiang, Sizhou Feng, Mingzhe Han, Yuanfu Xu, Fei Wang, Jiaxi Zhou

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1314-1332
Number of pages19
JournalCell Research
Volume25
Issue number12
DOIs
StatePublished - Dec 1 2015

Keywords

  • MSX2
  • NODAL
  • SOX2
  • hPSC
  • mesendoderm

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Wu, Q., Zhang, L., Su, P., Lei, X., Liu, X., Wang, H., Lu, L., Bai, Y., Xiong, T., Li, D., Zhu, Z., Duan, E., Jiang, E., Feng, S., Han, M., Xu, Y., Wang, F., & Zhou, J. (2015). MSX2 mediates entry of human pluripotent stem cells into mesendoderm by simultaneously suppressing SOX2 and activating NODAL signaling. Cell Research, 25(12), 1314-1332. https://doi.org/10.1038/cr.2015.118