A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment
A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment
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DOI：
10.1038/ncb1759
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发表时间：
2008-08-01
影响因子：
21.3
通讯作者：
Wulczyn, F. Gregory
中科院分区：
文献类型：
--
作者：
Rybak, Agnieszka;Fuchs, Heiko;Wulczyn, F. Gregory
miRNA 群体，包括 lin-4 (mir-125) 和 let-7 的哺乳动物同源物，在干细胞分化过程中经历显着转变(1)。 mir-125 和 let-7 最初是根据干细胞成熟过程中的突变表型进行鉴定的，它们在胚胎干 (ES) 细胞和胚胎癌细胞 (EC) 细胞的神经分化过程中被强烈诱导。我们报告胚胎神经干（NS）细胞表达let-7和mir-125，并研究有助于let-7诱导的转录后机制。我们证明多能因子 Lin-28 与 pre-let-7 RNA 结合并抑制 ES 和 EC 细胞中 Dicer 核糖核酸酶的加工。在 NS 细胞中，Lin-28 被 mir-125 和 let-7 下调，从而允许 pre-let-7 的处理继续进行。 NS细胞中let-7或mir-125活性的抑制导致Lin-28的上调和前let-7加工活性的丧失，表明let-7、mir-125和lin-28参与在NS细胞定型期间控制miRNA加工的自动调节回路。
miRNA populations, including mammalian homologues of lin-4 (mir-125) and let-7, undergo a marked transition during stem-cell differentiation(1). Originally identified on the basis of their mutational phenotypes in stem-cell maturation, mir-125 and let-7 are strongly induced during neural differentiation of embryonic stem (ES) cells and embryocarcinoma (EC) cells. We report that embryonic neural stem (NS) cells express let-7 and mir-125, and investigate post-transcriptional mechanisms contributing to the induction of let-7. We demonstrate that the pluripotency factor Lin-28 binds the pre-let-7 RNA and inhibits processing by the Dicer ribonuclease in ES and EC cells. In NS cells, Lin-28 is downregulated by mir-125 and let-7, allowing processing of pre-let-7 to proceed. Suppression of let-7 or mir-125 activity in NS cells led to upregulation of Lin-28 and loss of pre-let-7 processing activity, suggesting that let-7, mir-125 and lin-28 participate in an autoregulatory circuit that controls miRNA processing during NS-cell commitment.