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Exon-activated functional rescue secures neuronal transcript signatures

ABSTRACT: The production of alternative RNA variants contributes to the tissue-specific regulation of gene expression. In the animal nervous system, a shift towards more distal 3’ processing sites generates hundreds of substantially extended messenger RNAs. These neuronal transcript signatures are crucial for nervous system development and function. However, no clear understanding of the mechanism of systematic 3’ extension in neurons has yet been achieved. Here, we report that the highly conserved RNA-binding protein ELAV globally regulates all events of neuronal 3’ end processing by directly binding to the proximal 3’ end of its target RNAs. We uncover an endogenous strategy of functional gene rescue, by which neuronal RNA signatures are safeguarded in a loss-of-function context. When not directly repressed by ELAV, the transcript encoding the ELAV paralogue FNE acquires a mini‑exon, which equips the new FNE protein with the ability to translocate to the nucleus and rescue neuronal 3’ end processing. We propose that exon-activated functional rescue is a widespread mechanism that ensures robustness of processes that are regulated by a hierarchy, rather than by redundancy, of effectors.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE146986 | GEO | 2020/10/01

REPOSITORIES: GEO

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ELAV/Hu RNA binding proteins determine multiple programs of neural alternative splicing

Project description:ELAV/Hu factors are conserved RNA binding proteins that play diverse roles in mRNA processing and regulation. The founding member, Drosophila Elav, was recognized as a vital neural factor 35 years ago. Nevertheless, still little is known about its impacts on the transcriptome, and potential functional overlap with its paralogs. Building on our recent findings that neural-specific lengthened 3' UTR isoforms are co-determined by ELAV/Hu factors, we address their impacts on splicing. While only a few splicing targets of Drosophila are known, we find that ectopic expression of the three family members (Elav, Fne and Rbp9) induces overlapping changes to hundreds of cassette exon and dozens of alternative last exon (ALE) splicing events. Reciprocally, double mutants of elav/fne, but not elav alone, have opposite effects on both classes of regulated mRNA processing events in the larval CNS. While manipulation of Drosophila ELAV/Hu factors induces both exon skipping and inclusion, motif analysis indicates their major direct effects are to suppress cassette exon usage. Moreover, the roles of ELAV/HU factors in global promotion of distal ALE splicing are mechanistically linked to terminal 3' UTR extensions in neurons, since both involve local suppression of proximal polyadenylation signals via ELAV/Hu binding sites downstream of cleavage sites. The phenotypic impact of combined ELAV/Hu activities in neural mRNA processing is overt, since fne loss strongly enhances neuronal differentiation phenotypes in elav mutants. Finally, we provide evidence for conservation in mammalian neurons, which undergo broad programs of distal ALE and APA lengthening, linked to ELAV/Hu motifs downstream of regulated polyadenylation sites. Overall, ELAV/Hu proteins orchestrate multiple conserved programs of neuronal mRNA processing by suppressing alternative exons and polyadenylation sites.

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Exon-activated functional rescue secures neuronal transcript signatures

Project description:Exon-activated functional rescue secures neuronal transcript signatures

| PRJNA612625 | ENA

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