METTL3-mediated m6A modification is required for cerebellar development.
2018
Chen-Xin Wang | Guan-Shen Cui | Xiuying Liu | Kai Xu | Meng Wang | Xin-Xin Zhang | Li-Yuan Jiang | Ang Li | Ying Yang | Wei-Yi Lai | Bao-Fa Sun | Gui-Bin Jiang | Hai-Lin Wang | Wei-Min Tong | Wei Li | Xiu-Jie Wang | Yun-Gui Yang | Qi Zhou
N6-methyladenosine (m6A) RNA methylation is the most abundant modification on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex including methyltransferase-like 3 (METTL3) as a key factor. However, the in vivo functions of METTL3 and m6A modification in mammalian development remain unclear. Here, we show that specific inactivation of Mettl3 in mouse nervous system causes severe developmental defects in the brain. Mettl3 conditional knockout (cKO) mice manifest cerebellar hypoplasia caused by drastically enhanced apoptosis of newborn cerebellar granule cells (CGCs) in the external granular layer (EGL). METTL3 depletion-induced loss of m6A modification causes extended RNA half-lives and aberrant splicing events, consequently leading to dysregulation of transcriptome-wide gene expression and premature CGC death. Our findings reveal a critical role of METTL3-mediated m6A in regulating the development of mammalian cerebellum.
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