Temporal Control of Mammalian Cortical Neurogenesis by m(6)A Methylation

• Type of Material: Article
• Authors: Ki-Jun Yoon, University of Pennsylvania; Francisca Rojas Ringeling, Johns Hopkins University; Caroline Vissers, Johns Hopkins University; Fadi Jacob, Johns Hopkins University; Michael Pokrass, Johns Hopkins University; Dennisse Jimenez-Cyrus, Johns Hopkins University; Yijing Su, University of Pennsylvania; Nam-Shik Kim, University of Pennsylvania; Yunhua Zhu, Johns Hopkins University; Lily Zheng, Johns Hopkins University; Sunghan Kim, Johns Hopkins University; Xinyuan Wang, University of Pennsylvania; Louis C. Dore, University of Chicago; Peng Jin, Emory University; Sergi Regot, Johns Hopkins University; Xiaoxi Zhuang, University of Chicago; Stefan Canzar, Ludwig Maximilians Universitat Munchen; Chuan He, University of Chicago; Guo-li Ming, University of Pennsylvania; Hongjun Song, University of Pennsylvania
• Language: English
• Date: 2017-11-02
• Publisher: IOS Press
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2017.09.003
• Title of Journal or Parent Work: Analytical Cellular Pathology / Cellular Oncology
• ISSN: 1570-5870
• Volume: 171
• Issue: 4
• Start Page: 877
• End Page: +
• Grant/Funding Information: The research was supported by grants from NIH (R37NS047344 to H.S., U19MH106434 to H.S and G-l.M., P01NS097206 to H.S., G-l.M., P.J and C.H., R01MH105128 and R35NS097370 to G-l.M., U19AI131130 to G-l.M. and P.J., R01NS051630 and R01MH102690 to P.J, RM1HG008935 to C.H., H.S and P.J), Simons Foundation (to H.S. and G-l.M.), and The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to G-l.M.).; C.H. is a Howard Hughes Medical Institute Investigator.; K-J.Y. was partially supported by a Young Investigator Award from Brain & Behavior Research Foundation and a postdoctoral fellowship from Maryland Stem Cell Research Found (MSCRF); C.V. was partially supported by an NSF pre-doctoral fellowship and NIH T32GM007445.
• Keywords: NEWBORN; Life Sciences & Biomedicine; SCHIZOPHRENIA; MODEL; SUITE; RNA METHYLATION; NEURONS; EXPRESSION; Biochemistry & Molecular Biology; Cell Biology; MECHANISMS; Science & Technology; IDENTIFICATION; CELLS
• Research Categories: Biology, Molecular; Biology, Neuroscience; Chemistry, Biochemistry

Abstract

N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m6A regulates mammalian brain development is unknown. Here, we show that m6A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m6A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m6A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m6A tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional prepatterning in cortical neural stem cells. m6A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m6A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m6A tagging of transcripts related to brain-disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis. m6A-dependent mRNA decay is critical for proper transcriptional prepatterning in mammalian cortical neurogenesis.