Abstract
Most eukaryotic genes express multiple transcripts and proteins, and a sophisticated gene expression strategy plays a crucial role in ensuring the cell-specificity of genetic information and the correctness of phenotypes. The Drosophila melanogaster gene shaggy encodes several isoforms of the conserved glycogen synthase kinase 3 (GSK3), which is vitally important for multiple biological processes. To characterize the phenotypic effects of differential shaggy expression, we explored how the multidirectional modulation of the expression of the main GSK3 isoform, Shaggy-PB, in different tissues and cells affects lifespan. To this end, we used lines with transgenic constructs that encode mutant variants of the protein. The effect of shaggy misexpression on lifespan depended on the direction of the presumed change in GSK3 activity and the type of tissue/cell. The modulation of GSK3 activity in motor and dopaminergic neurons improved female lifespan but caused seemingly negative changes in the structural (mitochondrial depletion; neuronal loss) and functional (perturbed locomotion) properties of the nervous system, indicating the importance of analyzing the relationship between lifespan and healthspan in invertebrate models. Our findings provide new insights into the molecular and cellular bases of lifespan extension, demonstrating that the fine-tuning of transcript-specific shaggy expression in individual groups of neurons is sufficient to provide a sex-specific increase in survival and slow aging.
Highlights
According to both genome annotation data and experimental evidence, most Drosophila melanogaster genes express multiple transcripts and proteins1
The question of how the enzyme is regulated so that it can participate in so many diverse processes, in particular, how the activity of the enzyme is distributed between different regulatory cascades and metabolic pathways, arises
Within a cell, small amounts of the enzyme can be distributed between different subcellular domains and in such a way are coupled to distinct signaling pathways (Patel and Woodgett, 2017). This does not elucidate the molecular mechanisms of the cellular specificity of glycogen synthase kinase 3 (GSK3) function when the same change in GSK3 activity in different types of cells leads to opposite cellular and phenotypic effects
Summary
According to both genome annotation data and experimental evidence, most Drosophila melanogaster genes express multiple transcripts and proteins. Little is known about why such sophisticated organization of gene structure and expression strategy is needed, it becomes clear that transcriptome burdening may play a crucial role in the implementation of information encoded in the genome. There are many indications of significant sex-specific usage of alternative splicing and sexspecific transcription in D. melanogaster (Jin et al, 2001; Ranz et al, 2003; Telonis-Scott et al, 2009), and most sex-specific splicing is restricted to the gonads (Brown et al, 2014). Extensive alternative promoter usage and a great number of splicing events have been found in nervous tissue (Brown et al, 2014). It was demonstrated that most transcriptionally complex genes play significant tissue- and sex-specific roles (Huang et al, 2015). The exact and excessive regulation of gene expression reflects evolutionary and functional similarity between D. melanogaster and higher organisms such as mammals, which makes the fruit fly a practical model for functional genomics studies
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