2. Academic Validation
  3. METTL3-mediated m6A modification is required for cerebellar development

METTL3-mediated m6A modification is required for cerebellar development

  • PLoS Biol. 2018 Jun 7;16(6):e2004880. doi: 10.1371/journal.pbio.2004880.
Chen-Xin Wang 1 2,  Guan-Shen Cui 3 4,  Xiuying Liu 5,  Kai Xu 1 2,  Meng Wang 5,  Xin-Xin Zhang 1,  Li-Yuan Jiang 1,  Ang Li 2 3,  Ying Yang 3,  Wei-Yi Lai 2 6,  Bao-Fa Sun 2 3 7,  Gui-Bin Jiang 6,  Hai-Lin Wang 6,  Wei-Min Tong 8,  Wei Li 1 2 7,  Xiu-Jie Wang 2 5 7,  Yun-Gui Yang 2 3 7,  Qi Zhou 1 2 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
  • 4 Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
  • 5 Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  • 6 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
  • 7 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
  • 8 Department of Pathology, Center for Experimental Animal Research, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
PMID: 29879109 DOI: 10.1371/journal.pbio.2004880
Abstract

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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