Retinoic acid promotes stem cell differentiation and embryonic development by transcriptionally activating CFTR
Retinoic acid promotes stem cell differentiation and embryonic development by transcriptionally activating CFTR
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视黄酸通过转录激活 CFTR 促进干细胞分化和胚胎发育
DOI：
10.1016/j.bbamcr.2018.01.005
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发表时间：
2018-04-01
影响因子：
5.1
通讯作者：
Chan, Hsiao Chang
中科院分区：
文献类型：
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作者：
Li, Xiaofeng;Fok, Kin Lam;Chan, Hsiao Chang
维甲酸(RA)在许多细胞过程中起着关键作用，但其介导作用的信号机制尚不完全清楚。在这里，我们证明了RA通过促进其受体RARα与小鼠精原细胞和胚胎干细胞中的囊性纤维化跨膜传导调节因子启动子的直接结合而在转录上上调囊性纤维化跨膜传导调节因子。RA/CFTR途径参与了非洲爪哇胚胎发育过程中精原细胞的分化和器官的发生。SiRNA介导的基因敲除导致CFTR的缺失可钝化RA诱导的精原细胞分化。CFTR的过表达模拟了RA诱导精原细胞分化的作用，或修复了精原细胞和非洲爪哇RARα基因敲除所导致的发育缺陷。对人类数据库的分析表明，CFTR的表达与RARα在脑组织、干细胞和癌症中的表达呈正相关，支持RA/CFTR途径在人类不同发育过程中的作用。总之，我们的研究发现CFTR在调节RA依赖的信号转导干细胞分化和胚胎发育方面发挥着重要作用。
Retinoic acid (RA) plays a pivotal role in many cellular processes; however, the signaling mechanisms mediating the effect of RA are not fully understood. Here, we show that RA transcriptionally upregulates cystic fibrosis transmembrane conductance regulator (Cftr) by promoting the direct binding of its receptor RAR alpha to Cftr promoter in mouse spermatogonia and embryonic stem (ES) cells. The RA/CFTR pathway is involved in the differentiation of spermatogonia and organogenesis during the embryo development of Xenopus laevis. Loss of CFTR by siRNA-mediated knockdown blunts the RA-induced spermatogonial differentiation. Overexpression of CFTR mimics the effect of RA on the induction of spermatogonial differentiation or restores the developmental defects induced by the knockdown of RAR alpha in spermatogonial cells and Xenopus laevis. Analysis of the human database shows that the expression of CFTR positively correlates with RAR alpha in brain tissues, stem cells as well as cancers, supporting the role of RA/CFTR pathway in various developmental processes in humans. Together, our study discovers an essential role of CFTR in mediating the RA-dependent signaling for stem cell differentiation and embryonic development.