The Drosophila Nab2 RNA binding protein inhibits m6A methylation and male-specific splicing of Sex lethal transcript in female neuronal tissue

• Type of Material: Article
• Authors: Binta Jalloh, Emory University; Carly L Lancaster, Emory University; J Christopher Rounds, Emory University; Brianna E Brown, Emory University; Sara W Leung, Emory University; Ayan Banerjee, Emory University; Derrick J Morton, Emory University; Rick S Bienkowski, Emory University; Milo B Fasken, Emory University; Isaac J Kremsky, Emory University; Matthew Tegowski, Duke University; Kate Meyer, Duke University; Anita Corbett, Emory University; Ken Moberg, Emory University
• Language: English
• Date: 2023-07-17
• Publisher: eLife Sciences Publications Ltd
• Publication Version: Final Published Version
• Copyright Statement: © 2023, Jalloh, Lancaster et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7554/eLife.64904
• Title of Journal or Parent Work: eLife
• Volume: 12
• Grant/Funding Information: National Institutes of Health F31 HD079226 to Rick S Bienkowski.; National Institutes of Health R01 MH118366 to Kate Meyer; National Institutes of Health R25 GM125598 to Anita Corbett.; National Institutes of Health F32 GM125350 to Derrick J Morton.; National Institutes of Health R01 MH107305 to Ken Moberg, Anita Corbett.; National Institutes of Health F31 NS103595 to Binta Jalloh.; National Institutes of Health RM1 HG011563 to Kate Meyer.; National Institutes of Health F31 HD088043 to J Christopher Rounds.
• Keywords: RNA; Female; Animals; Methylation; Sex lethal; m6A; Drosophila melanogaster; Male; Drosophila Proteins; Drosophila; developmental biology; RNA-Binding Proteins; Alternative Splicing; Nab2; Mettl3; RNA Splicing; brain; D. melanogaster; splicing; Humans; Neurons
• Research Categories: Biology, Genetics; Chemistry, Biochemistry; Biology, Cell; Biology, Molecular; Biology, Neuroscience

Abstract

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 (m6A) modification by the Mettl3 complex. At a molecular level, Nab2 associates with Sxl pre-mRNA in neurons and limits Sxl m6A methylation at specific sites. In parallel, reducing expression of the Mettl3, Mettl3 complex components, or the m6A reader Ythdc1 rescues mutant phenotypes in Nab2 flies. Overall, these data identify Nab2 as an inhibitor of m6A methylation and imply significant overlap between Nab2 and Mettl3 regulated RNAs in neuronal tissue.