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Author Notes:

Lead Contact: gming@pennmedicine.upenn.edu.

Y.L.W. led the project and was involved in all aspects of the study.

Xu W., and K.L. performed in vitro neurite outgrowth of DRG neurons and optic nerve injury studies.

R.A. performed surgical procedures and data quantification for DRG studies.

T.X., P.J. and H.W. helped with some of the bioinformatics analyses, J.C., C.V., Xinyuan W., Z.H.S.W., J.J., Q.D., and W.Z. contributed to other data collection.

L.C.D., X.Z. and C.H. provided Mettl14f/f mice.

Yuanyuan L., Yajing L., B.S., X.Z., and C.H. provided Ythdf1−/− mice.

Y.L.W., H.S. and G-l.M. designed the project, analyzed the data and wrote the paper.

All authors helped prepare the manuscript.

We thank members of Ming and Song laboratories, and The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF) investigators for discussion, J. Schnoll and K. Christian for comments, and Y. Cai, L. Liu, and D. Johnson for technical support.

The authors declare no competing financial interests.

Subjects:

Research Funding:

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:

  • 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

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

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Journal Title:

Neuron

Volume:

Volume 97, Number 2

Publisher:

, Pages 313-+

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2017 Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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