m6A methylation regulates RNA axonal localisation and translation in developing neurons

Abstract

Methylation on adenosine N6 (m6A) is an abundant post-transcriptional modification of the RNA that regulates almost the entire lifespan of RNA transcripts, from splicing and nuclear export to RNA stability and translation. Peripheral localisation of RNA is an event common to most cells and especially relevant in neurons where transcripts are trafficked to subcellular compartments to promote growth and differentiation in axons, and synaptic functions in dendrites. Here we show that in developing sympathetic neurons, m6A modification regulates RNA transport and local translation in axons. Critically, Nerve Growth Factor (NGF), a neurotrophin essential for axon growth and neuronal survival, promotes the axonal localisation of methylated transcripts and inhibits protein synthesis of trafficking RNAs, preventing premature protein expression. Noticeably, the translation of the bifunctional mRNA Trp53Inp2 depended on the methylation of the 3UTR, further supporting the key role of m6A modification in determining mRNA fate. Mutation of Trp53Inp2 m6A elements resulted in ectopic translation, defects of axon extension and neuronal death. Together, these data show that m6A is critical for RNA peripheral localisation and spatial regulation of protein expression.