The Nab2 RNA Binding Protein Inhibits MA Methylation and Male-specific Splicing of Transcript in Female Neuronal Tissue

The polyadenosine RNA binding protein Nab2, which is orthologous to a human protein lost in a form of inherited intellectual disability, controls adult locomotion, axon projection, dendritic arborization, and memory through a largely undefined set of target RNAs. Here, we show a specific role for Nab2 in regulating splicing of ~150 exons/introns in the head transcriptome and focus on retention of a male-specific exon in the sex determination factor () that is enriched in female neurons. Previous studies have revealed that this splicing event is regulated in females by N6-methyladenosine (mA) modification by the Mettl3 complex. At a molecular level, Nab2 associates with pre-mRNA in neurons and limits mA methylation at specific sites. In parallel, reducing expression of the Mettl3, Mettl3 complex components, or the mA reader Ythdc1 rescues mutant phenotypes in flies. Overall, these data identify Nab2 as an inhibitor of mA methylation and imply significant overlap between Nab2 and Mettl3 regulated RNAs in neuronal tissue.