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

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.

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