Credit: Macmillan Publishers Limited

The regeneration of peripheral axons after injury involves a gene transcription programme that is driven by genetic and epigenetic mechanisms. A new study by Ming and colleagues highlights the role of an additional regulatory mechanism — mRNA methylation — in peripheral axon regeneration in mice.

Methylation of adenosine bases at the nitrogen-6 position generates N6-methyladenosine (m6A), an abundant, dynamic and reversible mRNA modification (or 'tag'). m6A modifications have been linked to regulation of neuronal development and function; however, their influence in the adult nervous system remains unknown. Here, the authors observed an increase in m6A levels in peripheral sensory neurons in the adult dorsal root ganglia (DRG) after a sciatic nerve lesion (SNL), suggesting a role for this modification in the regenerative process.

injury-induced m6A tagging was observed in transcripts that included ... many regeneration-associated genes ... and ... components of the protein translation machinery

Transcriptome-wide m6A profiling revealed that injury-induced m6A tagging was observed in transcripts that included those encoded by many regeneration-associated genes that are upregulated during regeneration and those encoding components of the protein translation machinery.

m6A modifications could function to alter the stability, processing or translation of the tagged mRNAs. In this study, the authors' findings suggested that m6A tagging can influence global protein translation in DRG neurons in response to injury. Indeed, the authors showed that mice in which Mettl14 (encoding a component of the enzymatic complex responsible for m6A tagging) was conditionally deleted in postmitotic neurons, and mice lacking Ythdf1 (encoding an m6A 'reader' protein that is thought to mediate some of the effects of m6A on protein translation) exhibited a clear reduction in SNL-induced protein synthesis in the DRG.

Next, the authors assessed the contribution of the dynamic changes in m6A to axon regeneration. Deletion of Mettl14 in DRG neurons in vivo reduced the extension of regenerating axons, the re-innervation of the epidermis and the recovery of heat-induced paw withdrawal latency after SNL, compared with control animals. The absence of Ythdf1 likewise reduced axon regeneration. Although CNS regeneration is limited, mice lacking Pten exhibit enhanced regeneration of adult retinal ganglion cell (RGC) axons; however, when short hairpin RNA was used to knock down Mettl14 in RGCs in vivo, their regeneration after an optic nerve crush injury was reduced, confirming that m6A tagging is also required for effective CNS regeneration.

These findings widen our understanding of the complex transcriptional, epigenetic and epitranscriptomic mechanisms that regulate axonal regeneration and the contributions of mRNA methylation to adult nervous system function.