Abstract 3057: Gene Deletion Screen for Cardiomyopathy in Adult Drosophila Identifies Weary (Wry): A New Notch Ligand
We performed a screen of genomic-deficiency mutants to identify genes that cause dilated cardiomyopathy by phenotyping cardiac function in awake adult Drosophila using optical coherence tomography. Our screen identified a deletion mutant, Df(2L)Exel7007 (see figure A1⇓) that encompassed 23 annotated genes. Using multiple approaches including the cardiac examination of overlapping deficiency stocks, transposon insertion stocks, and transgenic RNAi lines, we identify CG31665, which we name weary (wry), as a candidate gene responsible for dilated cardiomyopathy. Cardiac-specific expression of transgenic Wry rescues cardiomyopathic phenotype of Df(2L)Exel7007 (see figure A2⇓). Bioinformatic analysis suggests that Wry contains multiple EGF repeats and a transmembrane domain that are similar to motifs in proteins involved in Notch signaling. We examined the effects of disrupting Notch signaling components and show that alteration in Notch signaling components causes dilated cardiomyopathy (see figure B⇓). Furthermore, cardiac specific expression of Notch signaling components such as Delta (see figure A3⇓), Serrate, N, and Su(H) rescues the abnormal phenotype of our original deletion mutant Df(2L)Exel7007. A cell culture based ligand-dependent reporter assay indicates that Wry transactivates Notch signaling pathway. In conclusion, we identify Weary, a novel Notch ligand in Drosophila that is important for maintenance of normal heart function. These data suggest that gene orthologues involved in Notch signaling may be important in the pathogenesis of human dilated cardiomyopathy.
This research has received full or partial funding support from the American Heart Association, Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).