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The W-loop of alpha-cardiac actin is critical for heart function and endocardial cushion morphogenesis in zebrafish.

Mutations in cardiac actin (ACTC) have been associated with different cardiac abnormalities in humans, including dilated cardiomyopathy and septal defects. However, it is still poorly understood how altered ACTC structure affects cardiovascular physiology and results in the development of distinct congenital disorders. A zebrafish mutant (s434 mutation) was identified that displays blood regurgitation in a dilated heart and lacks endocardial cushion (EC) formation. We identified the mutation as a single nucleotide change in the alpha-cardiac actin 1a gene (actc1a), resulting in a Y169S amino acid substitution. This mutation is located at the W-loop of actin, which has been implicated in nucleotide sensing. Consequently, s434 mutants show loss of polymerized cardiac actin. An analogous mutation in yeast actin results in rapid depolymerization of F-actin into fragments that cannot reanneal. This polymerization defect can be partially rescued by phalloidin treatment, which stabilizes F-actin. In addition, actc1a mutants show defects in cardiac contractility and altered blood flow within the heart tube. This leads to downregulation or mislocalization of EC-specific gene expression and results in the absence of EC development. Our study underscores the importance of the W-loop for actin functionality and will help us to understand the structural and physiological consequences of ACTC mutations in human congenital disorders.

Pubmed ID: 22751927

Authors

  • Glenn NO
  • McKane M
  • Kohli V
  • Wen KK
  • Rubenstein PA
  • Bartman T
  • Sumanas S

Journal

Molecular and cellular biology

Publication Data

September 14, 2012

Associated Grants

  • Agency: NIDCD NIH HHS, Id: DC8803

Mesh Terms

  • Actins
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Embryo, Nonmammalian
  • Endocardium
  • Heart
  • Heart Defects, Congenital
  • Models, Molecular
  • Molecular Sequence Data
  • Morphogenesis
  • Mutation
  • Myocardium
  • Myofibrils
  • Phalloidine
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Zebrafish