MeCP2 controls neural stem cell fate specification through miR-199a-mediated inhibition of BMP-Smad signaling

Hideyuki Nakashima, Keita Tsujimura, Koichiro Irie, Takuya Imamura, Cleber A. Trujillo, Masataka Ishizu, Masahiro Uesaka, Miao Pan, Hirofumi Noguchi, Kanako Okada, Kei Aoyagi, Tomoko Andoh-Noda, Hideyuki Okano, Alysson R. Muotri, Kinichi Nakashima

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


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.

Original languageEnglish
Article number109124
JournalCell Reports
Issue number7
Publication statusPublished - 2021 May 18


  • BMP
  • MeCP2
  • Rett syndrome
  • Smad
  • differentiation
  • human organoid
  • miR-199a
  • neural stem cell

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology


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