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

Area of Science:

• Neuroscience
• Molecular Biology
• Epitranscriptomics

Background:

• N6-methyladenosine (m6A) is a key RNA modification impacting mRNA metabolism and development.
• The role of m6A in the adult mammalian nervous system, particularly after injury, remains largely unexplored.

Purpose of the Study:

• To investigate the role of m6A in the adult mammalian nervous system following nerve injury.
• To elucidate the impact of m6A on gene expression, protein translation, and axon regeneration after sciatic nerve lesion.

Main Methods:

• Sciatic nerve lesion model in adult mice.
• m6A-CLIP (crosslinking immunoprecipitation) with single-base resolution to map m6A sites.
• Analysis of m6A-tagged transcripts, protein translation, and axon regeneration.
• Genetic manipulation of m6A regulators (Mettl14, Ythdf1) and Pten deletion.

Main Results:

• Sciatic nerve injury increases m6A-modified transcripts related to regeneration and translation in dorsal root ganglia (DRG).
• Dynamic changes in the m6A landscape were observed in the DRG post-injury.
• Loss of Mettl14 or Ythdf1 significantly reduced injury-induced protein synthesis and functional axon regeneration in vivo.
• Mettl14 knockdown attenuated Pten deletion-induced axon regeneration in the central nervous system.

Conclusions:

• m6A RNA modification is a critical regulator of injury-induced protein synthesis and axon regeneration in the adult mammalian nervous system.
• This study reveals a novel epitranscriptomic mechanism essential for nerve repair and functional recovery.