Temporal Control of Mammalian Cortical Neurogenesis by mA Methylation.

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