Dynamic m(6)A modification regulates local translation of mRNA in axons

N-6-methyladenosine (m(6)A) is a reversible modification in mRNA and has been shown to regulate processing, translation and decay of mRNA. However, the roles of m(6)A modification in neuronal development are still not known. Here, we found that the m(6)A eraser FTO is enriched in axons and can be locally translated. Axon-specific inhibition of FTO by rhein, or compartmentalized siRNA knockdown of Fto in axons led to increases of m(6)A levels. GAP-43 mRNA is modified by m(6)A and is a substrate of FTO in axons. Loss-of-function of this non-nuclear pool of FTO resulted in increased m(6)A modification and decreased local translation of axonal GAP-43 mRNA, which eventually repressed axon elongation. Mutation of a predicted m(6)A site in GAP-43 mRNA eliminated its m(6)A modification and exempted regulation of its local translation by axonal FTO. This work showed an example of dynamic internal m(6)A demethylation of non-nuclear localized mRNA by the demethylase FTO. Regulation of m(6)A modification of axonal mRNA by axonal FTO might be a general mechanism to control their local translation in neuronal development.