Journal article
The W-Loop of Alpha-Cardiac Actin Is Critical for Heart Function and Endocardial Cushion Morphogenesis in Zebrafish
Molecular and cellular biology, Vol.32(17), pp.3527-3540
09/2012
DOI: 10.1128/MCB.00486-12
PMCID: PMC3422001
PMID: 22751927
Abstract
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.
Details
- Title: Subtitle
- The W-Loop of Alpha-Cardiac Actin Is Critical for Heart Function and Endocardial Cushion Morphogenesis in Zebrafish
- Creators
- Nicole O Glenn - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USAMelissa McKane - Department of Biochemistry, University of Iowa, Iowa City, Iowa, USAVikram Kohli - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USAKuo-Kuang Wen - Department of Biochemistry, University of Iowa, Iowa City, Iowa, USAPeter A Rubenstein - Department of Biochemistry, University of Iowa, Iowa City, Iowa, USAThomas Bartman - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USASaulius Sumanas - Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Resource Type
- Journal article
- Publication Details
- Molecular and cellular biology, Vol.32(17), pp.3527-3540
- DOI
- 10.1128/MCB.00486-12
- PMID
- 22751927
- PMCID
- PMC3422001
- NLM abbreviation
- Mol Cell Biol
- ISSN
- 0270-7306
- eISSN
- 1098-5549
- Publisher
- American Society for Microbiology; 1752 N St., N.W., Washington, DC
- Language
- English
- Date published
- 09/2012
- Academic Unit
- Stead Family Department of Pediatrics; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984025248102771
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