MECP2
诺金
骨形态发生蛋白
雷特综合征
SMAD公司
神经干细胞
细胞生物学
小RNA
干细胞
生物
转录因子
细胞分化
神经科学
信号转导
癌症研究
遗传学
基因
表型
作者
Hideyuki Nakashima,Keita Tsujimura,Kouji Irie,Takuya Imamura,Cleber A. Trujillo,Masataka Ishizu,Masahiro Uesaka,Miao Pan,Hirofumi Noguchi,Kazuko Okada,Kei Aoyagi,Tomoko Andoh-Noda,Hideyuki Okano,Alysson R. Muotri,Kinichi Nakashima
出处
期刊:Cell Reports
[Cell Press]
日期:2021-05-01
卷期号:35 (7): 109124-109124
被引量:16
标识
DOI:10.1016/j.celrep.2021.109124
摘要
Summary
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.
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