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.