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

N-6 -methyladenosine (m(6)A) affects multiple aspects of mRNA metabolism and regulates developmental transitions by promoting mRNA decay. Little is known about the role of m(6)A in the adult mammalian nervous system. Here we report that sciatic nerve lesion elevates levels of m(6)A-tagged transcripts encoding many regeneration-associated genes and protein translation machinery components in the adult mouse dorsal root ganglion (DRG). Single-base resolution m(6)A-CLIP mapping further reveals a dynamic m(6)A landscape in the adult DRG upon injury. Loss of either m(6)A methyltransferase complex component Mettl14 or m(6)A-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.