Loss of Mob1a/b impairs the differentiation of mouse embryonic stem cells into the three germ layer lineages
Loss of Mob1a/b impairs the differentiation of mouse embryonic stem cells into the three germ layer lineages
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DOI：
10.1038/s12276-019-0342-z
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发表时间：
2019-11-14
影响因子：
12.8
通讯作者：
Lee, Ho
中科院分区：
文献类型：
--
作者：
Bae, June Sung;Kim, Sun Mi;Lee, Ho
Hippo通路在细胞增殖和凋亡中起着至关重要的作用，并可以调节干细胞的维持和胚胎发育。MOB激酶激活物1A和1B（Mob 1a/B）是Hippo通路的关键组分，其在小鼠中的纯合缺失导致植入前阶段的早期胚胎死亡。为了研究Mob 1a/B在干细胞维持和分化中的作用，产生并表征了其中Mob 1a/B可以被条件性耗尽的胚胎干细胞（ESC）克隆。虽然Mob 1a/B缺失不影响小鼠胚胎干细胞的干细胞性或增殖，但这种缺失导致向三个胚层分化的缺陷。雅普基因敲低挽救了由Mob 1a/B缺失引起的体外和体内分化缺陷，表明由Mob 1a/B缺失引起的分化缺陷是Yap依赖性的。在畸胎瘤实验中，雅普基因敲低Mob 1a/b缺失的ESC部分恢复了分化缺陷，表明Hippo通路的另一个效应子Taz的过度激活抑制了向三个胚层的分化。综上所述，这些结果表明，Mob 1a/B或Hippo信号在小鼠ESCs分化为三个胚层中起着关键作用，这依赖于雅普。Hippo通路与干细胞分化的这些密切关系支持其作为再生医学治疗靶点的潜力。
The Hippo pathway plays a crucial role in cell proliferation and apoptosis and can regulate stem cell maintenance and embryonic development. MOB kinase activators 1A and 1B (Mob1a/b) are key components of the Hippo pathway, whose homozygous deletion in mice causes early embryonic lethality at the preimplantation stage. To investigate the role of Mob1a/b in stem cell maintenance and differentiation, an embryonic stem cell (ESC) clone in which Mob1a/b could be conditionally depleted was generated and characterized. Although Mob1a/b depletion did not affect the stemness or proliferation of mouse ESCs, this depletion caused defects in differentiation into the three germ layers. Yap knockdown rescued the in vitro and in vivo defects in differentiation caused by Mob1a/b depletion, suggesting that differentiation defects caused by Mob1a/b depletion were Yap-dependent. In teratoma experiments, Yap knockdown in Mob1a/b-depleted ESCs partially restored defects in differentiation, indicating that hyperactivation of Taz, another effector of the Hippo pathway, inhibited differentiation into the three germ layers. Taken together, these results suggest that Mob1a/b or Hippo signaling plays a critical role in the differentiation of mouse ESCs into the three germ layers, which is dependent on Yap. These close relationship of the Hippo pathway with the differentiation of stem cells supports its potential as a therapeutic target in regenerative medicine.