Jalloh, B., Lancaster, C.L., Rounds, J.C., Brown, B.E., Leung, S.W., Banerjee, A., Morton, D.J., Bienkowski, R.S., Fasken, M.B., Kremsky, I.J., Tegowski, M., Meyer, K., Corbett, A., Moberg, K. (2023). The Drosophila Nab2 RNA binding protein inhibits m[6]A methylation and male-specific splicing of Sex lethal transcript in female neuronal tissue.  eLife 12(): e64904.

FBrf0257037

Research paper

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.

PMC10351920 (PMC) (EuropePMC)