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Proper development of the mammalian cerebral cortex relies on precise gene expression regulation, which is controlled by genetic, epigenetic, and epitranscriptomic factors. Here we generate RNA demethylase  Fto  and methyltransferase  Mettl3  cortical-specific conditional knockout mice, and detect severe brain defects caused by  Mettl3  deletion but not  Fto  knockout. Transcriptomic profiles using RNA sequencing indicate that knockout of  Mettl3  causes a more dramatic alteration on gene transcription than that of  Fto . Interestingly, we conduct ribosome profiling sequencing, and find that knockout of  Mettl3  leads to a more severe disruption of translational regulation of mRNAs than deletion of  Fto  and results in altered translation of crucial genes in cortical radial glial cells and intermediate progenitors. Moreover, Mettl3 deletion causes elevated translation of a significant number of mRNAs, in particular major components in m 6 A methylation. Our findings indicate distinct functions of Mettl3 and Fto in brain development, and uncover a profound role of Mettl3 in regulating translation of major mRNAs that control proper cortical development.

Distinct roles of Fto and Mettl3 in controlling development of the cerebral cortex through transcriptional and translational regulations