title: Galactokinase is a novel modifier of calcineurin-induced cardiomyopathy in Drosophila.
abstract: Activated/uninhibited calcineurin is both necessary and sufficient to induce cardiac hypertrophy, a condition that often leads to dilated cardiomyopathy, heart failure, and sudden cardiac death. We expressed constitutively active calcineurin in the adult heart of Drosophila melanogaster and identified enlarged cardiac chamber dimensions and reduced cardiac contractility. In addition, expressing constitutively active calcineurin in the fly heart using the Gal4/UAS system induced an increase in heart wall thickness. We performed a targeted genetic screen for modifiers of calcineurin-induced cardiac enlargement based on previous calcineurin studies in the fly and identified galactokinase as a novel modifier of calcineurin-induced cardiomyopathy. Genomic deficiencies spanning the galactokinase locus, transposable elements that disrupt galactokinase, and cardiac-specific RNAi knockdown of galactokinase suppressed constitutively active calcineurin-induced cardiomyopathy. In addition, in flies expressing constitutively active calcineurin using the Gal4/UAS system, a transposable element in galactokinase suppressed the increase in heart wall thickness. Finally, genetic disruption of galactokinase suppressed calcineurin-induced wing vein abnormalities. Collectively, we generated a model for discovering novel modifiers of calcineurin-induced cardiac enlargement in the fly and identified galactokinase as a previously unknown regulator of calcineurin-induced cardiomyopathy in adult Drosophila.
authors: Department of Cell Biology, Duke University, Durham, North Carolina 27710.
authors: Teresa E
authors: TE
authors: Lee
authors: Department of Medicine, Duke University, Durham, North Carolina 27710.
authors: Lin
authors: L
authors: Yu
authors: Department of Medicine, Duke University, Durham, North Carolina 27710 Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina 27710.
authors: Matthew J
authors: MJ
authors: Wolf
authors: Department of Cell Biology, Duke University, Durham, North Carolina 27710 Department of Medicine, Duke University, Durham, North Carolina 27710 Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina 27710 h.rockman@duke.edu.
authors: Howard A
authors: HA
authors: Rockman
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000201:enzymology*; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster; D005260:Female; D005686:Galactokinase / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009206:Myocardium / Q000201:enzymology*
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; C472859:tinc protein, Drosophila; D005686:Galactokinase; D019703:Calcineurin
keywords: Drosophila melanogaster; calcineurin; cardiomyopathy; galactokinase