An Intrinsic Epigenetic Barrier for Functional Axon Regeneration

Yi-Lan Weng, Ran An, Jessica Cassin, Jessica Joseph, Ruifa Mi, Chen Wang, Chun Zhong, Seung-Gi Jin, Gerd P Pfeifer, Alfonso Bellacosa, Xinzhong Dong, Ahmet Hoke, Zhigang He, Hongjun Song, Guo-Li Ming

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Mature neurons in the adult peripheral nervous system can effectively switch from a dormant state with little axonal growth to robust axon regeneration upon injury. The mechanisms by which injury unlocks mature neurons' intrinsic axonal growth competence are not well understood. Here, we show that peripheral sciatic nerve lesion in adult mice leads to elevated levels of Tet3 and 5-hydroxylmethylcytosine in dorsal root ganglion (DRG) neurons. Functionally, Tet3 is required for robust axon regeneration of DRG neurons and behavioral recovery. Mechanistically, peripheral nerve injury induces DNA demethylation and upregulation of multiple regeneration-associated genes in a Tet3- and thymine DNA glycosylase-dependent fashion in DRG neurons. In addition, Pten deletion-induced axon regeneration of retinal ganglion neurons in the adult CNS is attenuated upon Tet1 knockdown. Together, our study suggests an epigenetic barrier that can be removed by active DNA demethylation to permit axon regeneration in the adult mammalian nervous system.

Original languageEnglish (US)
Pages (from-to)337-346.e6
JournalNeuron
Volume94
Issue number2
DOIs
StatePublished - Apr 19 2017

Keywords

  • 5-Methylcytosine/analogs & derivatives
  • Animals
  • Axons/metabolism
  • Epigenesis, Genetic/drug effects
  • Ganglia, Spinal/cytology
  • Mice, Inbred C57BL
  • Nerve Regeneration/drug effects
  • Peripheral Nerve Injuries/drug therapy

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  • Cite this

    Weng, Y-L., An, R., Cassin, J., Joseph, J., Mi, R., Wang, C., Zhong, C., Jin, S-G., Pfeifer, G. P., Bellacosa, A., Dong, X., Hoke, A., He, Z., Song, H., & Ming, G-L. (2017). An Intrinsic Epigenetic Barrier for Functional Axon Regeneration. Neuron, 94(2), 337-346.e6. https://doi.org/10.1016/j.neuron.2017.03.034