MeCP2 controls neural stem cell fate specification through miR-199a-mediated inhibition of BMP-Smad signaling
| Autor: | Hideyuki Okano, Tomoko Andoh-Noda, Kanako Okada, Masataka Ishizu, Keita Tsujimura, Hideyuki Nakashima, Takuya Imamura, Miao Pan, Masahiro Uesaka, Kinichi Nakashima, Koichiro Irie, Kei Aoyagi, Cleber A. Trujillo, Alysson R. Muotri, Hirofumi Noguchi |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities QH301-705.5 Methyl-CpG-Binding Protein 2 SMAD Biology Bone morphogenetic protein miR-199a General Biochemistry Genetics and Molecular Biology MECP2 neural stem cell 03 medical and health sciences Mice 0302 clinical medicine Neural Stem Cells Precursor cell microRNA Rett Syndrome Animals Humans Biology (General) Transcription factor MeCP2 Drosha Smad Cell Differentiation differentiation Bone Morphogenetic Protein Receptors Neural stem cell Cell biology Disease Models Animal 030104 developmental biology 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Cell Reports, Vol 35, Iss 7, Pp 109124-(2021) |
| ISSN: | 2211-1247 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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