Src-Yap1 signaling axis controls the trophectoderm and epiblast lineage differentiation in mouse embryonic stem cells
Src-Yap1 signaling axis controls the trophectoderm and epiblast lineage differentiation in mouse embryonic stem cells
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DOI：
10.1016/j.scr.2021.102413
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发表时间：
2021-05-31
影响因子：
1.2
通讯作者：
Li，Peng
中科院分区：
文献类型：
--
作者：
Luo，Juan;Zou，Hailin;Li，Peng
酪氨酸激酶Src在胚胎干细胞和胚胎干细胞分化的细胞中高度表达，然而，其功能作用仍然不清楚。在这里，我们组成型表达Srcin小鼠ESC，发现这些细胞保留了相当水平的核心多能因子，如Oct 4和Sox 2，同时与对照ESC相比，促进了上胚层谱系标记物的表达，抑制了滋养层谱系标记物的表达。敲低Srcin小鼠ESC显示出相反的效果。这些ESCs直接分化为上胚层和滋养层细胞系细胞显示Src激活显着加速上胚层样细胞的产生，并抑制滋养层样细胞的诱导。从机制上讲，我们发现Src激活通过特异性上调Yap 1酪氨酸磷酸化增强了Yap 1-Tead相互作用及其在小鼠ESCs中的转录输出。随后，我们发现Yap 1在小鼠ESCs中的过表达在表型上模仿了Sr过表达细胞的体外分化模式。此外，通过达沙替尼或Yap 1/Tead介导的Verteporfin转录抑制Src激酶活性逆转了Srcoverexpressing ESCs的分化模式。总之，我们的研究结果揭示了一种新的Src-Yap 1调节轴在小鼠胚胎干细胞分化为滋养外胚层和外胚层谱系细胞在体外。
The tyrosine kinase Src is highly expressed in embryonic stem cells (ESCs) and ESC-differentiated cells, however, its functional role remains obscured. Here, we constitutively expressedSrcin mouse ESCs and found these cells retained comparable levels of the core pluripotent factors, such as Oct4 and Sox2, while promoted the expression of epiblast lineage markers and restrained trophoblast lineage markers compared to the control ESCs. Knockdown ofSrcin mouse ESCs showed the opposite effect. Directly differentiation of these ESCs to epiblast and trophoblast lineage cells revealed that Src activation dramatically accelerated the production of epiblast-like cells and inhibited the induction of trophoblast-like cellsin vitro. Mechanistically, we found Src activation enhanced the Yap1-Tead interaction and their transcriptional output in mouse ESCs through specially upregulating Yap1 tyrosine phosphorylation. Subsequently, we found that overexpression ofYap1in mouse ESCs phenocopied the differentiation patterns ofSrcoverexpressing cellsin vitro. Moreover, inhibition of Src kinase activity by Dasatinib or Yap1/Tead-mediated transcription with Verteporfin reversed the differentiation patterns ofSrcoverexpressing ESCs. Taken together, our results unravel a novel Src-Yap1 regulatory axis during mouse ESC differentiation to trophectoderm and epiblast lineage cellsin vitro.