Elav-Mediated Exon Skipping and Alternative Polyadenylation of the Dscam1 Gene Are Required for Axon Outgrowth

Zhang, Zhiping; So, Kevin Kam Fung; Peterson, R. Price; Bauer, Matthew; Ng, Henry; Zhang, Yong; Kim, Jung Hwan; Kidd, Thomas; Miura, Pedro

doi:10.1016/j.celrep.2019.05.083

Cited by 34 publications

(44 citation statements)

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“…Indeed, by visual inspection, the magnitude of changes in alternatively spliced exons are frequently much larger in L1-CNS than in whole embryos, and many that were splicing annotated only in embryos fell below the cutoffs we used in our study and/or had marginal changes (S3 Fig) . Overall, although we used more stringent criteria in our efforts, we detect nearly an order of magnitude more ELAV/Hu-dependent alternatively spliced exons in our mutant L1-CNS datasets than were reported from embryos (Fig 2K and 2L and S3). The complete cassette exon splicing analyses are provided in S1 Table . Taken together, these analyses reveal that beyond a couple of loci studied over the past 20 years [42,43], Drosophila ELAV/Hu factors are global regulators of alternative neural splicing.…”

Section: Plos Geneticsmentioning

confidence: 85%

“…This applies to both ubiquitously expressed HuR [46,47] as well as neuronally restricted HuB/C/D [19,48]. However, even though Drosophila Elav was shown to be involved in splicing [49] before its mammalian counterparts [50], until recently, the internal splicing of only two Drosophila genes (Dscam1 and arm) was known to be dependent on Elav [42,43]. Thus, it was unclear if splicing is a diverged regulatory function for ELAV/Hu RBPs.…”

Section: All Drosophila Elav/hu Factors Can Induce Broad Programs Of mentioning

confidence: 99%

“…Mammalian ELAV/Hu RBPs have been extensively connected to alternative splicing of cassette exons [19,[46][47][48]50], but only to selected APA events [39,65,66]. In contrast, only a handful of Drosophila genes were known to be alternative splicing targets of Elav [40,42,43,67], of which only two loci (Dscam1 and arm) harbor regulated cassette exons. Thus, it was unclear to what extent there are conserved utilities of this RBP family in mRNA processing.…”

Section: Combined Activities Of Drosophila Elav/hu Rbps Specify the Nmentioning

confidence: 99%

“…The first direct target of Elav characterized was erect wing (ewg), and it controls splicing of its alternative last exons [40]. Elav also regulates the splicing of certain internal exons [42,43], but unlike other strategies for splicing control mentioned above, Elav controls neural-specific ewg by modulating cleavage and polyadenylation. In particular, Elav suppresses cleavage at the 3' end of an internal ewg terminal exon isoform, thereby permitting transcription to extend to the distal terminal exon.…”

Section: Introductionmentioning

confidence: 99%

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

Lee

Zhang

et al. 2021

PLoS Genet

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ELAV/Hu factors are conserved RNA binding proteins (RBPs) 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, little was 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, ectopic expression of each of the three family members (Elav, Fne and Rbp9) alters hundreds of cassette exon and alternative last exon (ALE) splicing choices. Reciprocally, double mutants of elav/fne, but not elav alone, exhibit opposite effects on both classes of regulated mRNA processing events in larval CNS. While manipulation of Drosophila ELAV/Hu RBPs induces both exon skipping and inclusion, characteristic ELAV/Hu motifs are enriched only within introns flanking exons that are suppressed by ELAV/Hu factors. 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 processes involve bypass of proximal polyadenylation signals linked to ELAV/Hu motifs downstream of cleavage sites. We corroborate the direct action of Elav in diverse modes of mRNA processing using RRM-dependent Elav-CLIP data from S2 cells. 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 RBPs orchestrate multiple broad programs of neuronal mRNA processing and isoform diversification in Drosophila and mammalian neurons.

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Section: Plos Geneticsmentioning

confidence: 85%

Section: All Drosophila Elav/hu Factors Can Induce Broad Programs Of mentioning

confidence: 99%

Section: Combined Activities Of Drosophila Elav/hu Rbps Specify the Nmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Lee

Zhang

et al. 2021

PLoS Genet

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“…This connectivity of an exon skipping event and an alternative long 3 UTR could be explained simply by the co-regulation by Elav. However, it was found that Elav could only exert its influence on the exon skipping event when the Dscam1 long 3 UTR was present [160] (Figure 4E).…”

Section: Coordination Of Alternative Splicing and Apamentioning

confidence: 99%

Emerging Roles for 3′ UTRs in Neurons

Bae

Miura

2020

IJMS

Self Cite

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The 3′ untranslated regions (3′ UTRs) of mRNAs serve as hubs for post-transcriptional control as the targets of microRNAs (miRNAs) and RNA-binding proteins (RBPs). Sequences in 3′ UTRs confer alterations in mRNA stability, direct mRNA localization to subcellular regions, and impart translational control. Thousands of mRNAs are localized to subcellular compartments in neurons—including axons, dendrites, and synapses—where they are thought to undergo local translation. Despite an established role for 3′ UTR sequences in imparting mRNA localization in neurons, the specific RNA sequences and structural features at play remain poorly understood. The nervous system selectively expresses longer 3′ UTR isoforms via alternative polyadenylation (APA). The regulation of APA in neurons and the neuronal functions of longer 3′ UTR mRNA isoforms are starting to be uncovered. Surprising roles for 3′ UTRs are emerging beyond the regulation of protein synthesis and include roles as RBP delivery scaffolds and regulators of alternative splicing. Evidence is also emerging that 3′ UTRs can be cleaved, leading to stable, isolated 3′ UTR fragments which are of unknown function. Mutations in 3′ UTRs are implicated in several neurological disorders—more studies are needed to uncover how these mutations impact gene regulation and what is their relationship to disease severity.

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On the function and relevance of alternative 3′‐UTRs in gene expression regulation

Pereira-Castro

Moreira

2021

WIREs RNA

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Messanger RNA (mRNA) isoforms with alternative 3 0 -untranslated regions (3 0 -UTRs) are produced by alternative polyadenylation (APA), which occurs during transcription in most eukaryotic genes. APA fine-tunes gene expression in a cell-type-and cellular state-dependent manner. Selection of an APA site entails the binding of core cleavage and polyadenylation factors to a particular polyadenylation site localized in the pre-mRNA and is controlled by multiple regulatory determinants, including transcription, pre-mRNA cis-regulatory sequences, and protein factors. Alternative 3 0 -UTRs serve as platforms for specific RNA binding proteins and microRNAs, which regulate gene expression in a coordinated manner by controlling mRNA fate and function in the cell.Genome-wide studies illustrated the full extent of APA prevalence and revealed that specific 3 0 -UTR profiles are associated with particular cellular states and diseases. Generally, short 3 0 -UTRs are associated with proliferative and cancer cells, and long 3 0 -UTRs are mostly found in polarized and differentiated cells. Fundamental new insights on the physiological consequences of this widespread event and the molecular mechanisms involved have been revealed through single-cell studies. Publicly available comprehensive databases that cover all APA mRNA isoforms identified in many cellular states and diseases reveal specific APA signatures. Therapies tackling APA mRNA isoforms or APA regulators may be regarded as innovative and attractive tools for diagnostics or treatment of several pathologies. We highlight the function of APA and alternative 3 0 -UTRs in gene expression regulation, the control of these mechanisms, their physiological consequences, and their potential use as new biomarkers and therapeutic tools.

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Elav-Mediated Exon Skipping and Alternative Polyadenylation of the Dscam1 Gene Are Required for Axon Outgrowth

Abstract: Highlights d Elav regulates Dscam1 long 3 0 UTR (Dscam1-L) biogenesis d Long-read sequencing reveals connectivity of long 3 0 UTR to skipping of upstream exon 19 d Loss of Dscam1-L impairs axon outgrowth d Dscam1 long 3 0 UTR is required for correct splicing of exon 19

Cited by 34 publications

References 50 publications

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

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

Emerging Roles for 3′ UTRs in Neurons

On the function and relevance of alternative 3′‐UTRs in gene expression regulation

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