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
  • Animals, Genetically Modified
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/physiology*
  • Molecular Sequence Data
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • Mice, Knockout
  • Animals
  • Mice
  • Electrocardiography
  • Connexins/classification
  • Connexins/genetics
  • Connexins/metabolism
  • Microscopy, Confocal
  • Amino Acid Sequence
  • Heart Conduction System/physiology*
  • Gene Knockdown Techniques
  • Embryo, Mammalian/embryology
  • Embryo, Mammalian/metabolism
  • Embryo, Mammalian/physiology
  • Mutation
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Phylogeny
  • Heart/embryology
  • Heart/physiology*
  • In Situ Hybridization
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Myocardium/metabolism*
  • Sequence Homology, Amino Acid
(all 33)
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
Figure Gallery (5 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b109
    Small Deletion
    s226
      Point Mutation
      s843TgTransgenic Insertion
        s878TgTransgenic Insertion
          s879TgTransgenic Insertion
            s882TgTransgenic Insertion
              s883TgTransgenic Insertion
                s896TgTransgenic Insertion
                  s925TgTransgenic Insertion
                    1 - 9 of 9
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                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    Target Reagent Reagent Type
                    gja3MO1-gja3MRPHLNO
                    1 - 1 of 1
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                    Fish
                    Antibodies
                    No data available
                    Orthology
                    Gene Orthology
                    gja3
                    1 - 1 of 1
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                    Engineered Foreign Genes
                    Marker Marker Type Name
                    DsRedEFGDsRed
                    EGFPEFGEGFP
                    GCaMPEFGGCaMP
                    mCherryEFGmCherry
                    1 - 4 of 4
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                    Mapping
                    Entity Type Entity Symbol Location
                    Features226Chr: 9 Details
                    GENEgja3Chr: 9 Details
                    SSLPz34824Chr: 9 Details
                    1 - 3 of 3
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