MSX2 mediates entry of human pluripotent stem cells into mesendoderm by simultaneously suppressing SOX2 and activating NODAL signaling
MSX2 mediates entry of human pluripotent stem cells into mesendoderm by simultaneously suppressing SOX2 and activating NODAL signaling
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MSX2 通过同时抑制 SOX2 和激活 NODAL 信号传导介导人多能干细胞进入中内胚层
DOI：
10.1038/cr.2015.118
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发表时间：
2015-12-01
期刊：
影响因子：
44.1
通讯作者：
Zhou, Jiaxi
中科院分区：
文献类型：
--
作者：
Wu, Qingqing;Zhang, Leisheng;Zhou, Jiaxi
BMP信号传导如何整合到人多能干细胞（hPSC）的多能性回路中并使其不稳定以启动分化成单个胚层是一个长期存在的难题。本文报道了msh家族同源异型盒转录因子muscle segment homeobox 2（MSX2）作为BMP信号转导的直接靶基因和hPSC向中内胚层分化的主要介导因子。MSX2的强制表达足以消除多能性并诱导hPSC的定向中内胚层分化，而MSX2消耗损害中内胚层诱导。MSX2是hPSC中BMP通路的直接靶基因，并且可以在中内胚层诱导期间通过LEF1被Wnt信号协同激活。此外，MSX2通过直接结合S0X2启动子和抑制S0X2转录来使多能性回路不稳定，而MSX2通过同时抑制S0X2和通过直接结合和激活Nodal启动子诱导NODAL表达来控制中内胚层谱系定型。有趣的是，SOX 2可以促进MSX2蛋白的降解，这表明两种谱系特异性因子在控制干细胞命运中相互拮抗。总之，我们的研究结果揭示了在hPSC中破坏多能性稳定和指导谱系定型的关键新机制。
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.