TY - JOUR T1 - The Nab2 RNA binding protein promotes sex-specific splicing of <em>Sex lethal</em> in <em>Drosophila</em> neuronal tissue JF - bioRxiv DO - 10.1101/2020.11.13.382168 SP - 2020.11.13.382168 AU - Binta Jalloh AU - J. Christopher Rounds AU - Brianna E. Brown AU - Isaac J. Kremsky AU - Ayan Banerjee AU - Derrick J. Morton AU - Rick S. Bienskowski AU - Milo B. Fasken AU - Anita H. Corbett AU - Kenneth H. Moberg Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/11/14/2020.11.13.382168.abstract N2 - The Drosophila polyadenosine RNA binding protein Nab2, which is orthologous to a human protein lost in a form of inherited intellectual disability, controls axon projection, locomotion, and memory. Here we define an unexpectedly specific role for Nab2 in regulating splicing of ~150 exons/introns in the head transcriptome and link the most prominent of these, female retention of a male-specific exon in the sex determination factor Sex-lethal (Sxl), to a role in m6A-dependent mRNA splicing. Genetic evidence indicates that aberrant Sxl splicing underlies multiple phenotypes in Nab2 mutant females. At a molecular level, Nab2 associates with Sxl pre-mRNA and ensures proper female-specific splicing by preventing m6A hypermethylation by Mettl3 methyltransferase. Consistent with these results, reducing Mettl3 expression rescues developmental, behavioral and neuroanatomical phenotypes in Nab2 mutants. Overall these data identify Nab2 as a required regulator of m6A-regulated Sxl splicing and imply a broader link between Nab2 and Mettl3-regulated brain RNAs.Competing Interest StatementThe authors have declared no competing interest. ER -