Sequential regulatory loops as key gatekeepers for neuronal reprogramming in human cells.
Sequential regulatory loops as key gatekeepers for neuronal reprogramming in human cells.
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顺序调节环作为人类细胞神经元重编程的关键看门人
DOI：
10.1038/nn.4297
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发表时间：
2016-06
影响因子：
25
通讯作者：
Fu XD
中科院分区：
文献类型：
--
作者：
Xue Y;Qian H;Hu J;Zhou B;Zhou Y;Hu X;Karakhanyan A;Pang Z;Fu XD
直接将体细胞转化为神经元对再生医学有很大的前景。然而，与小鼠细胞相比，人类细胞中的神经元转换相对低效。目前还不清楚人类细胞重编程的关键障碍是什么。我们最近阐明了一种由多嘧啶束结合蛋白PTB介导的RNA程序，可将小鼠胚胎成纤维细胞（mef）转化为功能神经元。然而，在人类成纤维细胞（HAFs）中，我们意外地发现，调用记录的PTB-REST-miR-124环只产生未成熟的神经元。我们现在报道，这种功能需要HAFs中PTB和PTB平行nPTB的顺序失活。nPTB失活会触发另一个神经元成熟所必需的自我强化环，其中包括nPTB、转录因子BRN2和miR-9。这些发现表明，两个独立的“守门人”控制着神经元的转换和成熟，连续地克服这些“守门人”可以使haf确定性地重编程为功能性神经元。
Direct conversion of somatic cells into neurons holds great promise for regenerative medicine. However, neuronal conversion is relatively inefficient in human cells compared to mouse cells. It has been unclear what might be the key barriers to reprogramming in human cells. We recently elucidated an RNA program mediated by the polypyrimidine tract binding protein PTB to convert mouse embryonic fibroblasts (MEFs) into functional neurons. In human adult fibroblasts (HAFs), however, we unexpectedly found that invoking the documented PTB–REST–miR-124 loop generates only immature neurons. We now report that the functionality requires sequential inactivation of PTB and the PTB paralog nPTB in HAFs. Inactivation of nPTB triggers another self-enforcing loop essential for neuronal maturation, which comprises nPTB, the transcription factor BRN2, and miR-9. These findings suggest that two separate gatekeepers control neuronal conversion and maturation and consecutively overcoming these gatekeepers enables deterministic reprogramming of HAFs into functional neurons.