Format

Send to

Choose Destination
Neuron. 2018 Jan 17;97(2):313-325.e6. doi: 10.1016/j.neuron.2017.12.036.

Epitranscriptomic m6A Regulation of Axon Regeneration in the Adult Mammalian Nervous System.

Author information

1
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China.
3
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China.
4
Human Genetic Pre-graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
7
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
8
Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
9
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; School of Basic Medical Sciences, Fudan University, Shanghai 200040, China.
10
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
11
Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
12
Department of Chemistry, University of Chicago, Chicago, IL 60637, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
13
Department of Neurology, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China.
14
National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
15
Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
16
Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA.
17
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Human Genetic Pre-graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
18
Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: gming@pennmedicine.upenn.edu.

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.

KEYWORDS:

CNS axon regeneration; DRG; Mettl14; PNS axon regeneration; RGC; YTHDF1; epitranscriptomics; mRNA methylation; protein synthesis

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center