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

doi:10.1016/j.celrep.2021.109124

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

Cell Rep. 2021 May 18;35(7):109124. doi: 10.1016/j.celrep.2021.109124.

Authors

Affiliations

¹ 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.
² 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. Electronic address: tsujimura.keita@e.mbox.nagoya-u.ac.jp.
³ Center for Medical Research and Education, Graduate School of Medicine, Osaka University, Suita, 565-0871 Osaka, Japan.
⁴ 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; Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526, Japan.
⁵ Department of Pediatrics and Cellular and Molecular Medicine/Rady Children's Hospital San Diego, School of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
⁶ Laboratory for Evolutionary Morphology, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan.
⁷ Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
⁹ 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. Electronic address: kin1@scb.med.kyushu-u.ac.jp.

PMID: 34010654
DOI: 10.1016/j.celrep.2021.109124

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Morphogenetic Protein Receptors / metabolism*
Cell Differentiation
Disease Models, Animal
Humans
Methyl-CpG-Binding Protein 2 / metabolism*
Mice
Neural Stem Cells / metabolism*
Rett Syndrome / genetics*
Signal Transduction

Substances

Mecp2 protein, mouse
Methyl-CpG-Binding Protein 2
Bone Morphogenetic Protein Receptors