m⁶A RNA methylation-mediated control of global APC expression is required for local translation of β-actin and axon development

The spatial regulation of mRNAs in neurons, including their localization and translation, is controlled by RNA-binding proteins and is critical for neuronal development. In this study, we present evidence that the multifunctional RNA-binding protein adenomatous polyposis coli (APC) is encoded by an mRNA modified with N6-methyladenosine (m⁶A). This modification facilitates the translation of APC in neuronal somata via YTH domain-containing family (YTHDF) m⁶A reader proteins. Disrupted APC expression, caused by reduced expression of the m⁶A writer METTL14 or reader YTHDF1, or by overexpression of METTL14 mutants carrying human missense mutations linked to autism and schizophrenia, impairs the transport and local translation of APC-regulated target mRNA β-actin in axons and growth cones. Such disruptions consequently hinder axon development both in vitro and in vivo. These findings reveal a mechanism by which m⁶A-regulated global expression of the RNA-binding protein APC governs axonal mRNA translation and development.