Mettl3 promotes reprogramming and axonogenesis of induced retinal ganglion cells.

Direct somatic cell-to-neuronal fate reprogramming (induced neurons, iNs) is valuable for translational and basic research. N(6)-Methyladenosine (m(6)A), the most prevalent mRNA epitranscriptomic modification, is critical for neural biology, but its role in iN reprogramming remains elusive. Using our induced retinal ganglion cell-like neuron (iRGC) system, we found dynamic m(6)A epitranscriptomic adjustments during iRGC reprogramming. Mettl3, the core component of the m(6)A methyltransferase complex, promoted iRGC fate reprogramming and axon development. Integrated RNA-seq/MeRIP-seq analyses and gene function interrogations identified three m(6)A-modified genes (Prokr1, Rspo1, and Fmo2) as key mediators of Mettl3 effects. Collectively, our study elucidated the essential roles and molecular mechanisms of the m(6)A epitranscriptomic modification in neuronal fate reprogramming and axon development. These findings could aid future investigations designed to improve neuronal fate and axon regeneration outcomes for therapeutic purposes to treat neurodegenerative diseases.