m⁶A RNA methylation-dependent APC translation is required for local translation of beta-actin and axon development

Abstract

Building and maintaining neuronal networks and cognitive functions require mRNA localization and regulated protein synthesis in neurons. RNA modification N6-methyl-adenosine (m6A) has recently been shown in axonal and synaptically localized mRNAs whose local activity is required for axon growth, synaptogenesis, and neuronal plasticity. However, no cellular pathways engaging local epitranscriptomic modulation are known to underlie these post-mitotic neuronal functions. Now we report that cytoplasmic m6A reader YTHDF1 is enriched in neurons and required for axonal, dendritic, and spine development. We show that m6A and YTHDF1 are part of a microtubule plus-end associated RNA granule that contains extensive networks of mRNAs organized by autism risk gene adenomatous polyposis coli (APC). Disrupting m6A signals by knocking down methyltransferase METTL14 or YTHDF1, or overexpressing autism or schizophrenia-associated missense mutations I311V or S399L in human METTL14, reduce expression of APC granule and tubulin, disrupt microtubule assembly and function. These results reveal a novel neuronal subcellular locus for epitranscriptomic regulation to promote post-mitotic neurodevelopment.