@article{61331ba4a9624e37b158944675a91a7a,
title = "MeCP2 controls neural stem cell fate specification through miR-199a-mediated inhibition of BMP-Smad signaling",
abstract = "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.",
keywords = "BMP, MeCP2, Rett syndrome, Smad, differentiation, human organoid, miR-199a, neural stem cell",
author = "Hideyuki Nakashima and Keita Tsujimura and Koichiro Irie and Takuya Imamura and Trujillo, {Cleber A.} and Masataka Ishizu and Masahiro Uesaka and Miao Pan and Hirofumi Noguchi and Kanako Okada and Kei Aoyagi and Tomoko Andoh-Noda and Hideyuki Okano and Muotri, {Alysson R.} and Kinichi Nakashima",
note = "Funding Information: We thank M.E. Greenberg and Z. Zhou for sharing reagents; I. Smith for editing the manuscript; and all of the members of the Laboratory of Basic Stem Cell Biology, Department of Stem Cell Biology and Medicine, Kyushu University. We appreciate the technical assistance from the Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Sciences. This work was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI (JP17H01390, JP16H06527, JP16K21734, and JP16H06279 [PAGS]), AMED (JP25mg1310008), and an Intramural Research Grant (27-7 and 30-9) for Neurological and Psychiatric Disorders of NCNP Grant to K.N.; JSPS KAKENHI (JP19H05211, JP18K06484, and JP16K18391) and AMED (JP21ek0109411) to K.T.; and JSPS KAKENHI (JP16J03827 and JP19K16918) to H. Nakashima. This research was also supported by NPO the Rett Syndrome Support Organization to H. Nakashima and K.T. (2019-01-09 and 2019-2-10). H. Nakashima wrote the paper and performed the majority of the experiments, with participation from K.T. K.I. M.I. M.P. H. Noguchi, K.O. and K.A. T.I. and M.U. contributed to the bioinformatic analysis. T.A.-N. and H.O. contributed to the analysis of RTT patient NS/PCs and iPSCs. H. Nakashima, M.I. C.A.T. and A.R.M. generated and analyzed the cortical organoids. K.T. and K.N. supervised the whole project and wrote the paper. The authors declare no competing interests. Funding Information: We thank M.E. Greenberg and Z. Zhou for sharing reagents; I. Smith for editing the manuscript; and all of the members of the Laboratory of Basic Stem Cell Biology, Department of Stem Cell Biology and Medicine, Kyushu University. We appreciate the technical assistance from the Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Sciences. This work was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI ( JP17H01390 , JP16H06527 , JP16K21734 , and JP16H06279 [PAGS]), AMED ( JP25mg1310008 ), and an Intramural Research Grant ( 27-7 and 30-9 ) for Neurological and Psychiatric Disorders of NCNP Grant to K.N.; JSPS KAKENHI ( JP19H05211 , JP18K06484 , and JP16K18391 ) and AMED ( JP21ek0109411 ) to K.T.; and JSPS KAKENHI ( JP16J03827 and JP19K16918 ) to H. Nakashima. This research was also supported by NPO the Rett Syndrome Support Organization to H. Nakashima and K.T. ( 2019-01-09 and 2019-2-10 ). Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = may,
day = "18",
doi = "10.1016/j.celrep.2021.109124",
language = "English",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}