| Popis: |
TheDrosophilapolyadenosine 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 factorSex-lethal(Sxl), to a role in m6A-dependent mRNA splicing. Genetic evidence indicates that aberrantSxlsplicing underlies multiple phenotypes inNab2mutant females. At a molecular level, Nab2 associates withSxlpre-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 inNab2mutants. Overall these data identify Nab2 as a required regulator of m6A-regulatedSxlsplicing and imply a broader link between Nab2 and Mettl3-regulated brain RNAs. |
