METTL3-mediated m6A modification is required for cerebellar development

PLoS Biol. 2018 Jun 7;16(6):e2004880. doi: 10.1371/journal.pbio.2004880. eCollection 2018 Jun.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Alternative Splicing / genetics
  • Animals
  • Apoptosis / genetics
  • Cells, Cultured
  • Cerebellum / abnormalities
  • Cerebellum / embryology*
  • Cerebellum / pathology
  • Developmental Disabilities / genetics
  • Developmental Disabilities / pathology
  • Gene Expression Regulation / genetics
  • Methylation
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Nervous System Malformations / genetics
  • Nervous System Malformations / pathology
  • RNA Stability / genetics
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism

Substances

  • RNA, Messenger
  • N-methyladenosine
  • Methyltransferases
  • Mettl3 protein, mouse
  • Adenosine

Supplementary concepts

  • Cerebellar Hypoplasia

Grants and funding

National Natural Science Foundation of China https://isisn.nsfc.gov.cn/egrantindex/funcindex/prjsearch-list (grant number 91540204). Received by X. -J. W. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation of China https://isisn.nsfc.gov.cn/egrantindex/funcindex/prjsearch-list (grant number 31430022). Received by Y. -G. Y. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation of China https://isisn.nsfc.gov.cn/egrantindex/funcindex/prjsearch-list (grant number 31471395). Received by Q. Z. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation of China https://isisn.nsfc.gov.cn/egrantindex/funcindex/prjsearch-list (grant number 31625016). Received by Y. -G. Y. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation of China https://isisn.nsfc.gov.cn/egrantindex/funcindex/prjsearch-list (grant number 31670824). Received by B. -F. S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Basic Research Program of China http://program.most.gov.cn/ (grant number 2014CB964800). Received by W. L. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Basic Research Program of China https://www.360zhyx.com/home-research-index-rid-66144.shtml (grant number 2016YFC0900300). Received by Y. -G. Y. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CAS Strategic Priority Research Program http://www.cas.cn/kxyj/index.shtml#xdzx (grant number XDB14030300). Received by Y. -G. Y. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CAS Key Research Projects of the Frontier Science http://www.cas.cn/jh/201701/t20170117_4588584.shtml (grant number QYZDY-SSW-SMC027). Received by Y. -G. Y. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CAS Key Research Projects of the Frontier Science http://www.cas.cn/jh/201701/t20170117_4588584.shtml (grant number QYZDB-SSW-SMC022). Received by W. L. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Shanghai Municipal Science and Technology Major Project http://czkj.shic.gov.cn/czkjtr/ (grant number 2017SHZDZX01). Received by Y. -G. Y. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.