Deletion of Siah-interacting protein gene in Drosophila causes cardiomyopathy

Abstract

Drosophila is a useful model organism in which to study the genetics of human diseases, including recent advances in identification of the genetics of heart development and disease in the fly. To identify novel genes that cause cardiomyopathy, we performed a deficiency screen in adult Drosophila. Using optical coherence tomography to phenotype cardiac function in awake adult Drosophila, we identified Df(1)Exel6240 as having cardiomyopathy. Using a number of strategies including customized smaller deletions, screening of mutant alleles, and transgenic rescue, we identified CG3226 as the causative gene for this deficiency. CG3226 is an uncharacterized gene in Drosophila possessing homology to the mammalian Siah-interacting-protein (SIP) gene. Mammalian SIP functions as an adaptor protein involved in one of the β-catenin degradation complexes. To investigate the effects of altering β-catenin/Armadillo signaling in the adult fly, we measured heart function in flies expressing either constitutively active Armadillo or transgenic constructs that block Armadillo signaling, specifically in the heart. While increasing Armadillo signaling in the heart did not have an effect on adult heart function, decreasing Armadillo signaling in the fly heart caused the significant reduction in heart chamber size. In summary, we show that deletion of CG3226, which has homology to mammalian SIP, causes cardiomyopathy in adult Drosophila. Alterations in Armadillo signaling during development lead to important changes in the size and function of the adult heart.

Mechanical Regulation of Cardiac Aging in Model Systems

“…57 Recent work showed that while β-CAT overexpression has no measurable effects, its knockdown induces significant dysfunction. 58 While β-CAT could have a role in pathological disease, we have recently demonstrated that its counterpart–α-catenin–was upregulated in aged, non-diseased simian and fly hearts using proteomic and genetic analyses. Data suggest that α-CAT appears upregulated with physiological aging 51 and may precede pathological remodeling (Figure 1, red).…”

Disruption of Methionine Metabolism inDrosophila melanogasterImpacts Histone Methylation and Results in Loss of Viability

“…While we do not have a definitive reason to explain how reduction of a gene with low RNA expression results in an observable phenotype, we note that other important developmental genes show the same pattern. For example, expression of Pan is low in S2 cells and during development ( Graveley et al 2011 ) and yet its reduction leads to heart development defects ( Casad et al 2012 ). Collectively, the results presented here indicate that methionine metabolism and histone methylation are critical for Drosophila development.…”