METTL3-mediated m6A modification is required for cerebellar development
Open accessAbstract
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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METTL3 plays a role in neural development, and its absence causes hypoplasia of the cerebellum in mice, resulting in ataxia.
“As the earliest identified component of m6A methyltransferase-possessing methylation catalysts, METTL3 plays a role in neural development, and its absence causes hypoplasia of the cerebellum in mice, resulting in ataxia.355”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [355]
The Introduction and Results report that brain-specific Mettl3 knockout in mice caused severe cerebellar hypoplasia and produced movement symptoms described as typical of cerebellar ataxia. The Results only speculate that the cerebellar defects might contribute to those symptoms; they do not establish that hypoplasia caused the ataxia. (LLM, conf=0.84)
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References 82 · Cited by 291
- Authors
- Wang, C.-X., Cui, G.-S., Liu, X., Xu, K., Wang, M., Zhang, X.-X., Jiang, L.-Y., Li, A., Yang, Y., Lai, W.-Y., Sun, B.-F., Jiang, G.-B., Wang, H.-L., Tong, W.-M., Li, W., Wang, X.-J., Yang, Y.-G., & Zhou, Q.
- Affiliations
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Zhou, Qi
- Venue
- PLOS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2018-06-07
- Volume
- 16
- Issue
- 6
- Pages
- e2004880
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC6021109
- OpenAlex
- W2805826733
- Cited by
- 291
- References
- 82
- Citations by year
- 2026: 15 · 2025: 27 · 2024: 24 · 2023: 60 · 2022: 46 · 2021: 55 · 2020: 41 · 2019: 20 · 2018: 2
- FWCI
- 10.58
- Type
- journal article
- Language
- en
- Update notices
- new_version (2018-06-27)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (31670824, 31430022, 2016YFC0900300, 2014CB964800, QYZDB-SSW-SMC022, 31625016, 201701, 2017SHZDZX01, 91540204, 31471395)
- National Key Research and Development Program of China (2014CB964800, QYZDB-SSW-SMC022, 2016YFC0900300, 2017SHZDZX01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- METTL3, N6-methyladenosine, RNA methylation, cerebellar development, cerebellar hypoplasia, cerebellar granule cells, apoptosis, external granular layer, RNA half-life, alternative splicing, conditional knockout mice, brain development
- MeSH terms
- Adenosine, Animals, Cells, Cultured, Cerebellum, Developmental Disabilities, Gene Expression Regulation, Methylation, Methyltransferases, Mice, Inbred C57BL, Mice, Inbred DBA, Nervous System Malformations, RNA, Messenger, Apoptosis, Alternative Splicing, Mice, Knockout, RNA Stability, Mice
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