Cell
Volume 171, Issue 4, 2 November 2017, Pages 877-889.e17
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Article
Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation

https://doi.org/10.1016/j.cell.2017.09.003Get rights and content
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Highlights

  • m6A depletion leads to prolonged cell-cycle progression of cortical neural progenitors

  • m6A promotes decay of tagged neurogenesis-related transcripts

  • Transcriptional prepatterning for normal cortical neurogenesis

  • Conserved and unique m6A landscapes in mouse and human cortical neurogenesis

Summary

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.

Keywords

neurogenesis
epitranscriptomics
RNA methylation
Mettl14
radial glia cell
transcriptional prepatterning
human organoid
schizophrenia
autism
m6A

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These authors contributed equally

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