Schizophrenia and autism associated mutations and disrupted m⁶A signal by YTHDF1 cause defects in microtubule function and neurodevelopment

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.