Abstract 9236: Receptor Tyrosine Kinase Signaling Causes Cardiac Hypertrophy in Adult Drosophila
Abnormalities in receptor tyrosine kinase (RTK) signaling are associated with dilated cardiomyopathies and cardiac hypertrophy in humans and mouse models. We have developed strategies based on fruit fly genetics to identify genes that cause cardiac abnormalities in order to better understand suppressors of cardiomyopathic phenotypes. To characterize the role of RTK pathway in adult Drosophila heart function, we expressed dominant negative or constitutively active EGFR (DN-EGFR or EGFRAct) specifically in the fly heart using tinC-Gal4 drivers. DN-EGFR flies had enlarged hearts and poor systolic function as assessed by optical coherence tomography. Interestingly, the cardiac-specific expression of EGFRAct resulted in significantly reduced eclosion rates and poor survival of adult escapers, which die within 48hrs. Moreover, EGFRAct adult escapers showed abnormal cardiomyocyte myofibrils, smaller heart lumens and significant increases in concentric wall thickness consistent with cardiac hypertrophy. The number of cardiac nuclei among hearts expressing EGFRAct was the same as controls, suggesting the effect was not due to proliferation. Since EGFR stimulation results in the activation of Ras and multiple downstream components including Raf-ERK, Ral-GDS and PI3K-AKT, we examined the effects of cardiac-specific expression of constitutively active Ras85D (Ras85DV12), gain of function Raf (RafGOF) and constitutively active PI3K (PI3KAct). Ras85DV12 and RafGOF, but not PI3KAct phenocopied the effects of EGFRAct resulting in abnormal cardiac myofibrils, smaller heart lumens and thicker concentric wall. To our knowledge, our findings represent the first evident of cardiac hypertrophy in the fruit flies. These results suggest that Ras-mediated activation of Raf-ERK may be a major contributor to the abnormal cardiac hypertrophy phenotype. Our ongoing studies are focused on the rescue of the Ras85DAct phenotype by ERK inhibition and the identification of gene transcripts that correlate with cardiac hypertrophy in adult Drosophila.
- © 2011 by American Heart Association, Inc.