Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
Group of Brain Function and Development, Nagoya University Neuroscience Institute of the Graduate School of Science, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan; Research Unit for Developmental Disorders, Institute for Advanced Research, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan.
Cell Rep. 2021 May 18;35(7):109124. doi: 10.1016/j.celrep.2021.109124.
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.
雷特综合征（RTT）是一种严重的神经发育障碍，由 MECP2 基因突变引起大脑发育受损；然而，其潜在的机制仍难以捉摸。我们从之前的工作中了解到，MeCP2 通过与 Drosha 复合物结合来促进特定 microRNA（miR-199a）的加工，从而调节神经元功能。在这里，我们表明 MeCP2/miR-199a 轴调节神经干细胞/前体细胞（NS/PC）分化。由于骨形态发生蛋白（BMP）信号转导的下游转录因子 Smad1 的上调，MeCP2 和 miR-199a 缺陷的 NS/PC 发生从神经元到星形胶质细胞分化的转变。此外，miR-199a 的表达和 BMP 抑制剂的处理分别纠正了 RTT 患者来源的 NS/PC 的分化和脑类器官的发育，这表明促进 BMP 信号转导解释了 RTT 大脑发育受损的原因。我们的研究阐明了 RTT 的分子病理学，并揭示了 MeCP2/miR-199a/Smad1 轴作为 RTT 的潜在治疗靶点。
