PUBLICATION

Cardiac conduction is required to preserve cardiac chamber morphology

Authors
Chi, N.C., Bussen, M., Brand-Arzamendi, K., Ding, C., Olgin, J.E., Shaw, R.M., Martin, G.R., and Stainier, D.Y.
ID
ZDB-PUB-100806-12
Date
2010
Source
Proceedings of the National Academy of Sciences of the United States of America   107(33): 14662-14667 (Journal)
Registered Authors
Chi, Neil C., Stainier, Didier
Keywords
connexin, development, electrophysiology, genetics, heart
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Connexins/classification
  • Connexins/genetics
  • Connexins/metabolism
  • Electrocardiography
  • Embryo, Mammalian/embryology
  • Embryo, Mammalian/metabolism
  • Embryo, Mammalian/physiology
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/physiology*
  • Gene Knockdown Techniques
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • Heart/embryology
  • Heart/physiology*
  • Heart Conduction System/physiology*
  • In Situ Hybridization
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Molecular Sequence Data
  • Mutation
  • Myocardium/metabolism*
  • Phylogeny
  • Sequence Homology, Amino Acid
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
20675583 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Electrical cardiac forces have been previously hypothesized to play a significant role in cardiac morphogenesis and remodeling. In response to electrical forces, cultured cardiomyocytes rearrange their cytoskeletal structure and modify their gene expression profile. To translate such in vitro data to the intact heart, we used a collection of zebrafish cardiac mutants and transgenics to investigate whether cardiac conduction could influence in vivo cardiac morphogenesis independent of contractile forces. We show that the cardiac mutant dco(s226) develops heart failure and interrupted cardiac morphogenesis following uncoordinated ventricular contraction. Using in vivo optical mapping/calcium imaging, we determined that the dco cardiac phenotype was primarily due to aberrant ventricular conduction. Because cardiac contraction and intracardiac hemodynamic forces can also influence cardiac development, we further analyzed the dco phenotype in noncontractile hearts and observed that disorganized ventricular conduction could affect cardiomyocyte morphology and subsequent heart morphogenesis in the absence of contraction or flow. By positional cloning, we found that dco encodes Gja3/Cx46, a gap junction protein not previously implicated in heart formation or function. Detailed analysis of the mouse Cx46 mutant revealed the presence of cardiac conduction defects frequently associated with human heart failure. Overall, these in vivo studies indicate that cardiac electrical forces are required to preserve cardiac chamber morphology and may act as a key epigenetic factor in cardiac remodeling.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping