Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation

Ki Jun Yoon, Francisca Rojas Ringeling, Caroline Vissers, Fadi Jacob, Michael Pokrass, Dennisse Jimenez-Cyrus, Yijing Su, Nam Shik Kim, Yunhua Zhu, Lily Zheng, Sunghan Kim, Xinyuan Wang, Louis C. Doré, Peng Jin, Sergi Regot, Xiaoxi Zhuang, Stefan Canzar, Chuan He, Guo li Ming, Hongjun Song

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)877-889.e17
JournalCell
Volume171
Issue number4
DOIs
StatePublished - Nov 2 2017

Keywords

  • Mettl14
  • RNA methylation
  • autism
  • epitranscriptomics
  • human organoid
  • mA
  • neurogenesis
  • radial glia cell
  • schizophrenia
  • transcriptional prepatterning

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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