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
Affiliations
Hideyuki Nakashima
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
Keita Tsujimura
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; Corresponding author
Koichiro Irie
Center for Medical Research and Education, Graduate School of Medicine, Osaka University, Suita, 565-0871 Osaka, Japan
Takuya Imamura
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
Cleber A. Trujillo
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
Masataka Ishizu
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
Masahiro Uesaka
Laboratory for Evolutionary Morphology, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan
Miao Pan
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
Hirofumi Noguchi
Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
Kanako Okada
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
Kei Aoyagi
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
Tomoko Andoh-Noda
Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Hideyuki Okano
Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Alysson R. Muotri
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
Kinichi Nakashima
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; Corresponding author
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.
