Human neurodevelopment requires differentiating neurons to establish large networks of connections in a highly stereotyped manner. Neuronal differentiation in particular requires RNA-binding proteins to spatiotemporally regulate thousands of different mRNAs. Yet how these proteins precisely relate to neuronal development and coordinate the expression of functionally coherent genes in a cell-type specific manner is only partially understood. To address this, we sought to establish how the paradigmatic RNA-binding protein IMP1/IGF2BP1, an essential developmental factor, selects and regulates its RNA targets transcriptome-wide during the differentiation of human neurons. We used a combination of system-wide and targeted molecular analyses to show that IMP1 directly binds to and regulates the expression of a large set of mRNAs that govern microtubule assembly, an essential process and a key driver of neuronal differentiation. We also show that m6A methylation during the transition from neural precursors to neurons drives both the selection of IMP1 mRNA targets and their protein expression. Our findings establish m6A methylation as a key mechanism coordinating the regulatory action of IMP1 on human neuronal architecture.

m6a methylation orchestrates IMP1 regulation of microtubules during human neuronal differentiation