Epitranscriptomic m(6)A Regulation of Axon Regeneration in the Adult Mammalian Nervous System

• Authors: Yi-Lan Weng, University of Pennsylvania; Xu Wang, Emory University; Ran An, University of Pennsylvania; Jessica Cassin, Johns Hopkins University; Caroline Vissers, Johns Hopkins University; Yuanyuan Liu, Nanjing Medical University; Yajing Liu, ShanghaiTech University; Tianlei Xu, Emory University; Xinyuan Wang, University of Pennsylvania; Samuel Zheng Hao Wong, University of Pennsylvania; Jessica Joseph, Johns Hopkins University; Louis C. Dore, University of Chicago; Qiang Dong, Fudan University; Wei Zheng, National Institutes of Health; Peng Jin, Emory University; Hao Wu, Emory University; Bin Shen, Nanjing Medical University; Xiaoxi Zhuang, University of Chicago; Chuan He, University of Chicago; Kai Liu, Hong Kong University of Science & Technology; Hongjun Song, University of Pennsylvania; Guo-Li Ming, University of Pennsylvania
• Journal Title: Neuron
• Volume: Volume 97, Number 2
• Publisher: Elsevier (Cell Press): 12 month embargo | 2018-01-17, Pages 313-+
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.neuron.2017.12.036
• Subjects: Biology, Neuroscience; Biology, Genetics; Chemistry, Biochemistry
• Keywords: Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; MESSENGER-RNA METHYLATION; SINGLE-NUCLEOTIDE-RESOLUTION; EPIGENETIC REGULATION; SENSORY NEURONS; DISTINCT MODES; HITS-CLIP; FAT MASS; GROWTH; MECHANISMS; STEM

Abstract

N6-methyladenosine (m6A) affects multiple aspects of mRNA metabolism and regulates developmental transitions by promoting mRNA decay. Little is known about the role of m6A in the adult mammalian nervous system. Here we report that sciatic nerve lesion elevates levels of m6A-tagged transcripts encoding many regeneration-associated genes and protein translation machinery components in the adult mouse dorsal root ganglion (DRG). Single-base resolution m6A-CLIP mapping further reveals a dynamic m6A landscape in the adult DRG upon injury. Loss of either m6A methyltransferase complex component Mettl14 or m6A-binding protein Ythdf1 globally attenuates injury-induced protein translation in adult DRGs and reduces functional axon regeneration in the peripheral nervous system in vivo. Furthermore, Pten deletion-induced axon regeneration of retinal ganglion neurons in the adult central nervous system is attenuated upon Mettl14 knockdown. Our study reveals a critical epitranscriptomic mechanism in promoting injury-induced protein synthesis and axon regeneration in the adult mammalian nervous system. N6-methyladenosine (m6A) occurs in many mRNAs. Weng et al. uncovered an epitranscriptomic mechanism wherein axonal injury elevates m6A levels and signaling to promote protein translation, including regeneration-associated genes, which is essential for functional axon regeneration of peripheral sensory neurons.