PLOS Biology
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.
| 论文编号: | DOI:10.1371/journal.pbio.2004880 |
| 论文题目: | METTL3-mediated m6A Modification is Required for Cerebellar Development |
| 英文论文题目: | METTL3-mediated m6A Modification is Required for Cerebellar Development |
| 第一作者: | 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 |
| 英文第一作者: | 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 |
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| 发表年度: | 2018-06-08 |
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| 摘要: | 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. |
| 英文摘要: | 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. |
| 刊物名称: | PLOS Biology |
| 英文刊物名称: | PLOS Biology |
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| 其它备注: | 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. METTL3-mediated m6A Modification is Required for Cerebellar Development. PLOS Biology. DOI:10.1371/journal.pbio.2004880 |
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