MeCP2 controls neural stem cell fate specification through miR-199a-mediated inhibition of BMP-Smad signaling
MeCP2 controls neural stem cell fate specification through miR-199a-mediated inhibition of BMP-Smad signaling
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DOI：
10.1016/j.celrep.2021.109124
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发表时间：
2021-05-18
期刊：
影响因子：
8.8
通讯作者：
Nakashima, Kinichi
中科院分区：
文献类型：
--
作者：
Nakashima, Hideyuki;Tsujimura, Keita;Nakashima, Kinichi
Rett综合征（RTT）是一种严重的神经系统疾病，由MECP 2突变引起的大脑发育受损;然而，其潜在机制仍然难以捉摸。我们从以前的工作中知道，MeCP 2通过与Drosha复合物结合来调节神经元功能，从而促进特定microRNA miR-199 a的加工。在这里，我们表明MeCP 2/miR-199 a轴调节神经干/前体细胞（NS/PC）分化。由于miR-199 a靶点Smad 1（骨形态发生蛋白（BMP）信号传导的下游转录因子）的上调，MeCP 2和miR-199 a缺陷NS/PC发生了从神经元到星形胶质细胞分化的转变。此外，miR-199 a表达和BMP抑制剂处理分别纠正RTT患者来源的NS/PC的分化和脑类器官的发育，表明BMP信号传导的促进导致RTT脑发育受损。我们的研究阐明了RTT的分子病理学，并揭示了MeCP 2/miR-199 a/Smad 1轴作为RTT的潜在治疗靶点。
Rett syndrome (RTT) is a severe neurological disorder, with impaired brain development caused by mutations in MECP2; however, the underlying mechanism remains elusive. We know from previous work that MeCP2 facilitates the processing of a specific microRNA, miR-199a, by associating with the Drosha complex to regulate neuronal functions. Here, we show that the MeCP2/miR-199a axis regulates neural stem/precursor cell (NS/PC) differentiation. A shift occurs from neuronal to astrocytic differentiation of MeCP2- and miR-199a-deficient NS/PCs due to the upregulation of a miR-199a target, Smad1, a downstream transcription factor of bone morphogenetic protein (BMP) signaling. Moreover, miR-199a expression and treatment with BMP inhibitors rectify the differentiation of RTT patient-derived NS/PCs and development of brain organoids, respectively, suggesting that facilitation of BMP signaling accounts for the impaired RTT brain development. Our study illuminates the molecular pathology of RTT and reveals the MeCP2/miR-199a/Smad1 axis as a potential therapeutic target for RTT.