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

Yi-Lan Weng; Xu Wang; Ran An; Jessica Cassin; Caroline Vissers; Yuanyuan Liu; Yajing Liu; Tianlei Xu; Xinyuan Wang; Samuel Zheng Hao Wong; Jessica Joseph; Louis C Dore; Qiang Dong; Wei Zheng; Peng Jin; Hao Wu; Bin Shen; Xiaoxi Zhuang; Chuan He; Kai Liu; Hongjun Song; Guo-Li Ming

doi:10.1016/j.neuron.2017.12.036

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

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

Authors

Yi-Lan Weng¹, Xu Wang², Ran An³, Jessica Cassin⁴, Caroline Vissers⁵, Yuanyuan Liu⁶, Yajing Liu⁷, Tianlei Xu⁸, Xinyuan Wang⁹, Samuel Zheng Hao Wong¹⁰, Jessica Joseph¹¹, Louis C Dore¹², Qiang Dong¹³, Wei Zheng¹⁴, Peng Jin¹⁵, Hao Wu⁸, Bin Shen⁶, Xiaoxi Zhuang¹⁶, Chuan He¹², Kai Liu², Hongjun Song¹⁷, Guo-Li Ming¹⁸

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives
Adenosine / physiology*
Animals
Axons / physiology*
Epigenesis, Genetic / genetics*
Ganglia, Spinal / metabolism
Gene Ontology
Methyltransferases / deficiency
Methyltransferases / physiology*
Mice, Knockout
Nerve Crush
Nerve Regeneration / genetics*
Nerve Tissue Proteins / physiology*
PTEN Phosphohydrolase / physiology
RNA Processing, Post-Transcriptional*
RNA, Messenger / metabolism
RNA-Binding Proteins / physiology
Sciatic Nerve / injuries
Sciatic Neuropathy / genetics
Sciatic Neuropathy / physiopathology
Sensory Receptor Cells / physiology
Sensory Receptor Cells / ultrastructure
Transcription, Genetic*

Substances

Nerve Tissue Proteins
RNA, Messenger
RNA-Binding Proteins
Ythdf1 protein, mouse
Methyltransferases
Mettl14 protein, mouse
PTEN Phosphohydrolase
Pten protein, mouse
Adenosine

Abstract

Publication types

MeSH terms

Substances

Grants and funding