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The small heart Mutation Reveals Novel Roles of Na⁺/K⁺-ATPase in Maintaining Ventricular Cardiomyocyte Morphology and Viability in Zebrafish

From the Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass.

Correspondence to Shipeng Yuan, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, 149 13th St, Charlestown, MA 02129. E-mail yuan{at}cvrc.mgh.harvard.edu

Forward genetic screens in zebrafish have been used to identify mutations in genes with important roles in organogenesis. One of these mutants, small heart, develops a diminutive and severely malformed heart and multiple developmental defects of the brain, ears, eyes, and kidneys. Using a positional cloning approach, we identify that the mutant gene encodes the zebrafish Na⁺/K⁺-ATPase 1B1 protein. Disruption of Na⁺/K⁺-ATPase 1B1 function via morpholino "knockdown" or pharmacological inhibition with ouabain phenocopies the mutant phenotype, in a dose-dependent manner. Heterozygosity for the mutation sensitizes embryos to ouabain treatment. Our findings present novel genetic and morphological details on the function of the Na⁺/K⁺-ATPase 1B1 in early cardiac morphogenesis and the pathogenesis of the small heart malformation. We demonstrate that the reduced size of the mutant heart is caused by dysmorphic ventricular cardiomyocytes and an increase in ventricular cardiomyocyte apoptosis. This study provides a new insight that Na⁺/K⁺-ATPase 1B1 is required for maintaining ventricular cardiomyocyte morphology and viability.

Key Words: apoptosis • cardiac • development • heart failure • organogenesis • Na⁺/K⁺-ATPase • Danio rerio

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