Abstract 2269: Deficiency in Rhomboid-3 Causes a Dilated Cardiomyopathy in Adult Drosophila
The identification of genes that cause or modify cardiac dysfunction is required to understand the complex biology that is responsible for dilated cardiomyopathy and heart failure in humans. Model systems of human heart failure facilitate the screening and identification of genetic mutants that affect cardiac function. We hypothesized that a genome wide-screen in Drosophila would identify mutations that cause dilated cardiomyopathy. As part of a systematic, genome wide screen in Drosophila to identify candidate genes that cause dilated cardiomyopathy we employed optical coherence tomography (OCT) to examine the cardiac function in awake, adult Drosophila. We examined flies with molecularly-defined genomic deficiencies along the 3L chromosome from the Dros-Del and Excelixis collections and identified a set of mutants that had dilated cardiomyopathy manifest as enlarged end-diastolic dimension (EDD), end-systolic dimension (ESD) and impaired fractional shortening (FS). Strains Df(3L)4238, Df(3L)ED4196, Df(3L)ED207, and Df(3L)ED4191, that had dilated cardiomyopathy and further analysis suggested that rhomboid 3 (dRho3) was the candidate gene. Next, we examined available mutants that spanned the candidate region and identified a cardiac abnormality in rhoughoid (ru1) a mutant that is localized to dRho3 locus. We determined that ru1 encodes a truncated form of dRho3. To validate our findings, we determined that the cardiac expression of dRho3 rescued the abnormal phenotype observed in Df(3L)4238 and ru1 mutants. Since dRho3 is involved in the processing of Spitz, a fly ortholog of epidermal growth factor (EGF), we examined the effects of downstream components of the dRho3 pathway. The cardiac expression of active, but not inactive, Spitz, or EGF receptor (EGFR) rescued the abnormal cardiac phenotype observed in Df(3L)4238 and ru1 mutants. Furthermore, the post-developmental cardiac specific expression of a dominant negative EGFR resulted in a progressive deterioration of cardiac function. Our results demonstrate that abnormalities in dRho3 or the EGFR signaling pathway causes dilated cardiomyopathy and suggests that EGFR signaling is necessary to maintain post-developmental cardiac function in adult Drosophila.
This research has received full or partial funding support from the American Heart Association, National Center.