The Drosophila Nab2 RNA binding protein inhibits m 6 A methylation and male-specific splicing of Sex lethal transcript in female neuronal tissue.

The Drosophila 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 Sex-lethal ( Sxl ) that is enriched in female neurons. Previous studies have revealed that this splicing event is regulated in females by N6-methyladenosine (m 6 A) modification by the Mettl3 complex. At a molecular level, Nab2 associates with Sxl pre-mRNA in neurons and limits Sxl m 6 A methylation at specific sites. In parallel, reducing expression of the Mettl3, Mettl3 complex components, or the m 6 A reader Ythdc1 rescues mutant phenotypes in Nab2 flies. Overall, these data identify Nab2 as an inhibitor of m 6 A methylation and imply significant overlap between Nab2 and Mettl3 regulated RNAs in neuronal tissue.