METTL3-mediated m6A modification is required for cerebellar development.

Chen-Xin Wang,Wei Li,Bao-Fa Sun,Xiuying Liu,Qi Zhou,Ying Yang,Guan-Shen Cui,Ang Li,Li-Yuan Jiang,Hai-Lin Wang,Meng Wang,Xin-Xin Zhang,Gui-Bin Jiang,Wei-Min Tong,Xiu-Jie Wang,Wei-Yi Lai,Yun-Gui Yang,Kai Xu,Chuan He

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.

Highlights

Multiple layers of epigenetic modifications play essential roles in neuronal development and brain function in mammals through highly coordinated epigenetic regulatory mechanisms [1,2,3,4,5], such as DNA methylation and demethylation [6,7,8], histone modifications [9, 10], and noncoding RNAs [11,12,13]
Adenosine methylation is regulated by a large methyltransferase complex and by demethylases, as well as by other binding proteins
methyltransferase-like 3 (METTL3) is one of the core subunits of the methyltransferase complex catalyzing m6A formation

Summary

Introduction

Multiple layers of epigenetic modifications play essential roles in neuronal development and brain function in mammals through highly coordinated epigenetic regulatory mechanisms [1,2,3,4,5], such as DNA methylation and demethylation [6,7,8], histone modifications [9, 10], and noncoding RNAs [11,12,13]. Nerve lesion induces the elevation of m6A level, and loss of METTL14 or m6A binding protein YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) inhibits axonal regeneration [31]. All these studies indicate the important roles of m6A signaling in neuronal development and neurogenesis

Methods

Results

Discussion

Conclusion