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

N ⁶-methyladenosine (m ⁶A) affects multiple aspects of mRNA metabolism and regulates developmental transitions by promoting mRNA decay. Little is known about the role of m ⁶A in the adult mammalian nervous system. Here we report that sciatic nerve lesion elevates levels of m ⁶A-tagged transcripts encoding many regeneration-associated genes and protein translation machinery components in the adult mouse dorsal root ganglion (DRG). Single-base resolution m ⁶A-CLIP mapping further reveals a dynamic m ⁶A landscape in the adult DRG upon injury. Loss of either m ⁶A methyltransferase complex component Mettl14 or m ⁶A-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. N ⁶-methyladenosine (m ⁶A) occurs in many mRNAs. Weng et al. uncovered an epitranscriptomic mechanism wherein axonal injury elevates m ⁶A levels and signaling to promote protein translation, including regeneration-associated genes, which is essential for functional axon regeneration of peripheral sensory neurons.