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

eLife | 2023

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.

Pubmed ID: 37458420 RIS Download

Associated grants

  • Agency: NIMH NIH HHS, United States
    Id: R01 MH118366
  • Agency: NIH HHS, United States
    Id: R01 MH107305
  • Agency: NICHD NIH HHS, United States
    Id: F31 HD088043
  • Agency: NINDS NIH HHS, United States
    Id: F31 NS103595
  • Agency: NHGRI NIH HHS, United States
    Id: RM1 HG011563
  • Agency: NIH HHS, United States
    Id: F31 NS103595
  • Agency: NICHD NIH HHS, United States
    Id: F31 HD079226
  • Agency: NIH HHS, United States
    Id: R25 GM125598
  • Agency: NIGMS NIH HHS, United States
    Id: R25 GM125598
  • Agency: NIH HHS, United States
    Id: F32 GM125350
  • Agency: NIGMS NIH HHS, United States
    Id: F32 GM125350
  • Agency: NIH HHS, United States
    Id: F31 HD088043
  • Agency: NIH HHS, United States
    Id: RM1 HG011563
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS125768
  • Agency: NIH HHS, United States
    Id: P40 OD018537
  • Agency: NIH HHS, United States
    Id: F31 HD079226
  • Agency: NIMH NIH HHS, United States
    Id: R01 MH107305
  • Agency: NINDS NIH HHS, United States
    Id: F31 NS127545
  • Agency: NIH HHS, United States
    Id: R01 MH118366
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM135060

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