Luo Juan, Zou Hailin, Deng Liang, Sun Xiang, Yuan Ping, Li Peng
Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
Department of General Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
Stem Cells Int. 2021 Feb 22;2021:6674283. doi: 10.1155/2021/6674283. eCollection 2021.
The RNA-binding protein Lin28 regulates neurogliogenesis in mammals, independently of the let-7 microRNA. However, the detailed regulatory mechanism remains obscured. Here, we established Lin28a or Lin28b overexpression mouse embryonic stem cells (ESCs) and found that these cells expressed similar levels of the core pluripotent factors, such as Oct4 and Sox2, and increased Yap1 but decreased lineage-specific markers compared to the control ESCs. Further differentiation of these ESCs to neuronal and glial lineage cells revealed that Lin28a/b overexpression did not affect the expression of neuronal marker III-tubulin, but dramatically inhibited the glial lineage markers, such as Gfap and Mbp. Interestingly, overexpression of Yap1 in mouse ESCs phenocopied Lin28a/b overexpression ESCs by showing defect in glial cell differentiation. Inhibition of Yap1/Tead-mediated transcription with verteporfin partially rescued the differentiation defect of Lin28a/b overexpression ESCs. Mechanistically, we demonstrated that Lin28 can directly bind to mRNA, and the induction of Yap1 by Lin28a in mESCs is independent of Let7. Taken together, our results unravel a novel Lin28-Yap1 regulatory axis during mESC to glial lineage cell differentiation, which may shed light on glial cell generation .
RNA结合蛋白Lin28在哺乳动物中独立于let-7微小RNA调节神经胶质细胞生成。然而，详细的调节机制仍不清楚。在这里，我们建立了Lin28a或Lin28b过表达的小鼠胚胎干细胞（ESC），发现与对照ESC相比，这些细胞表达相似水平的核心多能因子，如Oct4和Sox2，Yap1增加但谱系特异性标记物减少。这些ESC进一步分化为神经元和神经胶质谱系细胞表明，Lin28a/b过表达不影响神经元标记物III-微管蛋白的表达，但显著抑制神经胶质谱系标记物，如Gfap和Mbp。有趣的是，在小鼠ESC中过表达Yap1通过显示神经胶质细胞分化缺陷而模拟了Lin28a/b过表达的ESC。用维替泊芬抑制Yap1/Tead介导的转录部分挽救了Lin28a/b过表达ESC的分化缺陷。从机制上讲，我们证明Lin28可以直接结合mRNA，并且Lin28a在mESC中对Yap1的诱导独立于Let7。综上所述，我们的结果揭示了mESC向神经胶质谱系细胞分化过程中一个新的Lin28-Yap1调节轴，这可能为神经胶质细胞的产生提供线索。
