title: Intracardiac flow dynamics regulate atrioventricular valve morphogenesis.
abstract: OBJECTIVE
  Valvular heart disease is responsible for considerable morbidity and mortality. Cardiac valves develop as the heart contracts, and they function throughout the lifetime of the organism to prevent retrograde blood flow. Their precise morphogenesis is crucial for cardiac function. Zebrafish is an ideal model to investigate cardiac valve development as it allows these studies to be carried out in vivo through non-invasive imaging. Accumulating evidence suggests a role for contractility and intracardiac flow dynamics in cardiac valve development. However, these two factors have proved difficult to uncouple, especially since altering myocardial function affects the intracardiac flow pattern.
  
  
  RESULTS
  Here, we describe novel zebrafish models of developmental valve defects. We identified two mutant alleles of myosin heavy chain 6 that can be raised to adulthood despite having only one functional chamber-the ventricle. The adult mutant ventricle undergoes remodelling, and the atrioventricular (AV) valves fail to form four cuspids. In parallel, we characterized a novel mutant allele of southpaw, a nodal-related gene involved in the establishment of left-right asymmetry, which exhibits randomized heart and endoderm positioning. We first observed that in southpaw mutants the relative position of the two cardiac chambers is altered, affecting the geometry of the heart, while myocardial function appears unaffected. Mutant hearts that loop properly or exhibit situs inversus develop normally, whereas midline, unlooped hearts exhibit defects in their transvalvular flow pattern during AV valve development as well as defects in valve morphogenesis.
  
  
  CONCLUSIONS
  Our data indicate that intracardiac flow dynamics regulate valve morphogenesis independently of myocardial contractility.
authors.affiliation: Developmental Biology, Biomedical Research Foundation Academy of Athens, Soranou Ephessiou 4, 11527 Athens, Greece.
authors.forename: Stamatia
authors.initials: S
authors.lastname: Kalogirou
authors.affiliation: Developmental Biology, Biomedical Research Foundation Academy of Athens, Soranou Ephessiou 4, 11527 Athens, Greece.
authors.forename: Nikos
authors.initials: N
authors.lastname: Malissovas
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Moro
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Argenton
authors.affiliation: Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology and Cardiovascular Research Institute, University of San Francisco, Sans Francisco, CA, USA Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.affiliation: Developmental Biology, Biomedical Research Foundation Academy of Athens, Soranou Ephessiou 4, 11527 Athens, Greece dbeis@bioacademy.gr.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Beis
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D016275:Atrial Function; D003326:Coronary Circulation; D004694:Endocardial Cushion Defects / Q000196:embryology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D054089:Endocardial Cushions / Q000196:embryology* / Q000378:metabolism / Q000503:physiopathology; D005838:Genotype; D006351:Heart Valves / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics; D040542:Mechanotransduction, Cellular; D009024:Morphogenesis; D009154:Mutation; D009200:Myocardial Contraction; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D029961:Zebrafish Proteins; C481025:myh6 protein, zebrafish; D018995:Myosin Heavy Chains
keywords: Adult models of cardiomyopathies; Cardiac valves; Contractility; Intracardiac flow pattern; Zebrafish
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