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

• Type of Material: Article
• 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
• Language: English
• Date: 2018-01-17
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuron.2017.12.036
• Title of Journal or Parent Work: Neuron
• ISSN: 0896-6273
• Volume: 97
• Issue: 2
• Start Page: 313
• End Page: +
• Grant/Funding Information: This work was supported by grants from AMRF (to G-l.M.), National Institutes of Health (P01NS097206 and RM1HG008935 to H.S., J.P., and C.H., R37NS047344 to H.S., and R35NS097370 to G-l.M.), Hong Kong Research Grants Council (16103315 and 16149316 to K.L.), and National Natural Science Foundation of China (81671214 to K.L.).; C.H. is an HHMI investigator.
• Keywords: MESSENGER-RNA METHYLATION; Neurosciences & Neurology; GROWTH; HITS-CLIP; SENSORY NEURONS; Neurosciences; EPIGENETIC REGULATION; MECHANISMS; STEM; DISTINCT MODES; FAT MASS; Life Sciences & Biomedicine; Science & Technology; SINGLE-NUCLEOTIDE-RESOLUTION
• Research Categories: Chemistry, Biochemistry; Biology, Genetics; Biology, Neuroscience

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.