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

Abstract

N-6-methyladenosine (m(6)A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m(6)A regulates mammalian brain development is unknown. Here, we show that m(6)A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m(6)A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m(6)A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m(6)A tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional prepatterning in cortical neural stem cells. m(6)A signaling also regulates human cortical neurogenesis in fore-brain organoids. Comparison of m(6)A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m(6)A tagging of transcripts related to brain-disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.