Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation

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 Mettl14 deletion in the embryonic mouse brain diminishes m6A levels, prolongs cell cycle of radial glia cells, and extends cortical neurogenesis into postnatal stages. Mettl3 knockdown also prolongs neural progenitor cell cycle and promotes radial glia cell maintenance. m6A-sequencing of the embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, cell cycle and neuron differentiation, and Mettl14 deletion attenuates their decay. Notably, Mettl14-/- radial glia cells precociously express neuronal proteins. Further analysis uncovers previously unappreciated transcriptional pre-patterning in cortical neural stem cells. Comparison of m6A-mRNA landscapes between mouse and human cortical neural progenitors identifies human-specific tagging of transcripts related to epigenetic regulation and brain disorder risk genes. Our study reveals an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.