Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

Torres-Méndez, Antonio; Pop, Sînziana; Bonnal, Sophie; Almudí, Isabel; Avola, Alida; Roberts, Ruairí J.V.; Paolantoni, Chiara; Alcaina-Caro, Ana; Anduaga, Ane Martín; Haussmann, Irmgard U.; Morín, Violeta; Casares, Fernando; Soller, Matthias; Kadener, Sebastián; Roignant, Jean‐Yves; Prieto-Godino, Lucía L.; Irimia, Manuel

doi:10.1126/sciadv.abk0445

Cited by 20 publications

(17 citation statements)

References 85 publications

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“…The coincidence of events in orthologous genes is considerably more than was detected in a similar analysis of mouse and D. melanogaster microexons ( Torres-Méndez et al 2022 ). In this study, the authors found microexons in 156 D. melanogaster genes and 2,731 mouse genes.…”

Section: Resultsmentioning

confidence: 67%

Origins and Evolution of Human Tandem Duplicated Exon Substitution Events

Martínez-Gómez

Cerdán-Vélez

Abascal

et al. 2022

Genome Biology and Evolution

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The mutually exclusive splicing of tandem duplicated exons produces protein isoforms that are identical save for a homologous region that allows for the fine tuning of protein function. Tandem duplicated exon substitution events are rare, yet highly important alternative splicing events. Most events are ancient, their isoforms are highly expressed, and they have significantly more pathogenic mutations than other splice event. Here we analysed the physicochemical properties and functional roles of the homologous polypeptide regions produced by the 236 tandem duplicated exon substitutions annotated in the human gene set. We find that most important structural and functional residues in these homologous regions are maintained and that most changes are conservative rather than drastic. Three quarters of the isoforms produced from tandem duplicated exon substitution events are tissue specific, particularly in nervous and cardiac tissues, and tandem duplicated exon substitution events are enriched in functional terms related to structures in the brain and skeletal muscle. We find considerable evidence for the convergent evolution of tandem duplicated exon substitution events in vertebrates, arthropods and nematodes. Twelve human gene families have orthologues with tandem duplicated exon substitution events in both Drosophila melanogaster and Caenorhabditis elegans. Six of these gene families are ion transporters, suggesting that tandem exon duplication in genes that control the flow of ions into the cell has an adaptive benefit. The ancient origins, the strong indications of tissue-specific functions, and the evidence of convergent evolution suggest that these events may have played important roles in the evolution of animal tissues and organs.

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Section: Resultsmentioning

confidence: 67%

Origins and Evolution of Human Tandem Duplicated Exon Substitution Events

Martínez-Gómez

Cerdán-Vélez

Abascal

et al. 2022

Genome Biology and Evolution

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“…In Drosophila, about 15–20% of genes that undergo neuronal APA are affected at the protein‐coding level: ELAV‐mediated CDS‐APA is required for the expression of often essential neuron‐specific protein isoforms, including those of Ewg, Neuroglian, Zelda, and giant Ankyrin. One recent study particularly highlighted ELAV's direct and indirect effects on the neuronal proteome: Disruption of the ELAV‐dependent CDS‐APA of the gene Srrm234 impaired the expression of the neuron‐specific enhancer of microexons (eMIC) domain, and caused genome‐wide microexon skipping and pervasive neurological defects in flies (Torres‐Méndez et al, 2022).…”

Section: Elav‐mediated Alternative Polyadenylationmentioning

confidence: 99%

“…of the neuron-specific enhancer of microexons (eMIC) domain, and caused genome-wide microexon skipping and pervasive neurological defects in flies (Torres-Méndez et al, 2022).…”

Section: Physiological Consequences Of Loss Of Elav-mediated Apamentioning

confidence: 99%

Regulation of neuronal RNA signatures by ELAV/Hu proteins

Hilgers

2022

WIREs RNA

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The RNA-binding proteins encoded by the highly conserved elav/Hu gene family, found in all metazoans, regulate the expression of a wide range of genes, at both the co-transcriptional and posttranscriptional level. Nervoussystem-specific ELAV/Hu proteins are prominent for their essential role in neuron differentiation, and mutations have been associated with human neurodevelopmental and neurodegenerative diseases. Drosophila ELAV, the founding member of the protein family, mediates the synthesis of neuronal RNA signatures by promoting alternative splicing and alternative polyadenylation of hundreds of genes. The recent identification of ELAV's direct RNA targets revealed the protein's central role in shaping the neuronal transcriptome, and highlighted the importance of neuronal transcript signatures for neuron maintenance and organism survival. Animals have evolved multiple cellular mechanisms to ensure robustness of ELAV/Hu function. In Drosophila, elav autoregulates in a 3 0 UTR-dependent manner to maintain optimal protein levels. A complete absence of ELAV causes the activation and nuclear localization of the normally cytoplasmic paralogue FNE, in a process termed EXon-Activated functional Rescue (EXAR). Other species, including mammals, seem to utilize different strategies, such as protein redundancy, to maintain ELAV protein function and effectively safeguard the identity of the neuronal transcriptome.

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“…By increasing genetic versatility in cells that are particularly morphologically and functionally complex, neuronal RNA isoforms are thought to contribute to the robust coordination of neuronal processes ( Hilgers, 2015 ; Miura et al., 2014 ; Pereira-Castro and Moreira, 2021 ; Turner et al., 2018 ). For example, dysregulation of neural splicing programs causes widespread neurological alterations in animal models and has been associated with human neurological conditions including autism spectrum disorder, intellectual disability, and neurodegenerative diseases ( Furlanis and Scheiffele, 2018 ; Irimia et al., 2014 ; Nik and Bowman, 2019 ; Torres-Méndez et al., 2022 ).…”

Section: Introductionmentioning

confidence: 99%