@article{c37f272188834031b2afa97c08b7a5cc,
title = "Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation",
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.",
keywords = "Mettl14, RNA methylation, autism, epitranscriptomics, human organoid, mA, neurogenesis, radial glia cell, schizophrenia, transcriptional prepatterning",
author = "Yoon, {Ki Jun} and Ringeling, {Francisca Rojas} and Caroline Vissers and Fadi Jacob and Michael Pokrass and Dennisse Jimenez-Cyrus and Yijing Su and Kim, {Nam Shik} and Yunhua Zhu and Lily Zheng and Sunghan Kim and Xinyuan Wang and Dor{\'e}, {Louis C.} and Peng Jin and Sergi Regot and Xiaoxi Zhuang and Stefan Canzar and Chuan He and Ming, {Guo li} and Hongjun Song",
note = "Funding Information: We thank K.M. Christian and J. Schnoll for comments; members of the Ming and Song laboratories for discussion; L. Liu, Y. Cai, and D.G. Johnson for technical assistance; and T.M. Hyde and D.R. Weinberger for dissected fetal human brain samples. K.-J.Y. was partially supported by a Young Investigator Award from the 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 training grant T32GM007445. The research was supported by grants from the 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.; and RM1HG008935 to C.H., H.S., and P.J), the Simons Foundation (SFARI grant 308988 to H.S. and SFARI grant 401625 to G.-l.M.), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (G.-l.M.). C.H. is a Howard Hughes Medical Institute Investigator. Funding Information: We thank K.M. Christian and J. Schnoll for comments; members of the Ming and Song laboratories for discussion; L. Liu, Y. Cai, and D.G. Johnson for technical assistance; and T.M. Hyde and D.R. Weinberger for dissected fetal human brain samples. K.-J.Y. was partially supported by a Young Investigator Award from the 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 training grant T32GM007445 . The research was supported by grants from the 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.; and RM1HG008935 to C.H., H.S., and P.J), the Simons Foundation (SFARI grant 308988 to H.S. and SFARI grant 401625 to G.-l.M.), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (G.-l.M.). C.H. is a Howard Hughes Medical Institute Investigator. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = nov,
day = "2",
doi = "10.1016/j.cell.2017.09.003",
language = "English (US)",
volume = "171",
pages = "877--889.e17",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}