FE1.bw

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 <i>Fto </i>and methyltransferase <i>Mettl3 </i>cortical specific conditional knockout mice, and detect severe brain defects caused by <i>Mettl3 </i>deletion but not <i>Fto </i>knockout. Transcriptomic profiles using RNA sequencing (RNAseq) indicate that knockout of <i>Mettl3 </i>causes a more dramatic alteration on gene transcription than that of <i>Fto</i>. Interestingly, we conduct ribosome profiling sequencing (Ribo-Seq), and find that knockout of <i>Mettl3 </i>leads to a more severe disruption of translational regulation of mRNAs than deletion of <i>Fto</i>, 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 m6A 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 <br>