Abstract
Changes in splicing patterns are a characteristic of the aging transcriptome; however, it is unclear whether these age‐related changes in splicing facilitate the progressive functional decline that defines aging. In Drosophila, visual behavior declines with age and correlates with altered gene expression in photoreceptors, including downregulation of genes encoding splicing factors. Here, we characterized the significance of these age‐regulated splicing‐associated genes in both splicing and visual function. To do this, we identified differential splicing events in either the entire eye or photoreceptors of young and old flies. Intriguingly, aging photoreceptors show differential splicing of a large number of visual function genes. In addition, as shown previously for aging photoreceptors, aging eyes showed increased accumulation of circular RNAs, which result from noncanonical splicing events. To test whether proper splicing was necessary for visual behavior, we knocked down age‐regulated splicing factors in photoreceptors in young flies and examined phototaxis. Notably, many of the age‐regulated splicing factors tested were necessary for proper visual behavior. In addition, knockdown of individual splicing factors resulted in changes in both alternative splicing at age‐spliced genes and increased accumulation of circular RNAs. Together, these data suggest that cumulative decreases in splicing factor expression could contribute to the differential splicing, circular RNA accumulation, and defective visual behavior observed in aging photoreceptors.
Highlights
Normal aging is characterized by progressive and time‐dependent functional decline (Kenyon, 2010)
We identified age‐regulated splicing events in the eye and photoreceptor neurons of Drosophila
Age‐regulated changes in splicing were observed in genes involved in visual function in photoreceptors, but not in the eye, suggesting that cell‐type‐specific transcriptome studies reveal changes in splicing that may be masked in whole tissue RNA‐seq analysis
Summary
Normal aging is characterized by progressive and time‐dependent functional decline (Kenyon, 2010). As many as one‐third of all splicing factors exhibit altered expression with age in human blood (Holly et al, 2013) Despite this correlation between splicing factor levels and splicing outcomes during aging, it is not clear whether the decreased expression of splicing factors causes the observed age‐associated changes in splicing. As other transcriptome studies have shown a correlation between splicing factor expression and splicing during aging (Stegeman & Weake, 2017), we wondered whether age‐associated alterations in splicing could contribute to visual senescence in flies. To examine this question, we sought to characterize the contribution of individual age‐regulated splicing factors to age‐associated changes in alternative splicing and visual function in the Drosophila eye. Our data suggest that decreased levels of splicing factors could potentially contribute to both age‐associated splicing defects and visual senescence
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