title: Actin binding GFP allows 4D in vivo imaging of myofilament dynamics in the zebrafish heart and the identification of Erbb2 signaling as a remodeling factor of myofibril architecture.
abstract: BACKGROUND
  Dilated cardiomyopathy is a leading cause of congestive heart failure and a debilitating complication of antineoplastic therapies. Despite disparate causes for dilated cardiomyopathy, maladaptive cardiac remodeling and decreased systolic function are common clinical consequences, begging an investigation of in vivo contractile dynamics in development and disease, one that has been impossible to date.
  
  
  OBJECTIVE
  To image myocardial contractile filament dynamics in vivo and to assess potential causes of dilated cardiomyopathy in antineoplastic therapies targeting the epidermal growth factor receptor Erbb2.
  
  
  RESULTS
  We generated a transgenic zebrafish line expressing an actin-binding green fluorescent protein in cardiomyocytes, allowing an in vivo imaging of myofilaments. Analysis of this line revealed architectural differences in myofibrils of the distinct cardiomyocyte subtypes. We used this model to investigate the effects of Erbb2 signaling on myofibrillar organization because drugs targeting ERBB2 (HER2/NEU) signaling, a mainstay of breast cancer chemotherapy, cause dilated cardiomyopathy in many patients. High-resolution in vivo imaging revealed that Erbb2 signaling regulates a switch between a dense apical network of filamentous myofibrils and the assembly of basally localized myofibrils in ventricular cardiomyocytes.
  
  
  CONCLUSIONS
  Using this novel line, we compiled a reference for myofibrillar microarchitecture among myocardial subtypes in vivo and at different developmental stages, establishing this model as a tool to analyze in vivo cardiomyocyte contractility and remodeling for a broad range of cardiovascular questions. Furthermore, we applied this model to study Erbb2 signaling in cardiomyopathy. We show a direct link between Erbb2 activity and remodeling of myofibrils, revealing an unexpected mechanism with potentially important implications for prevention and treatment of cardiomyopathy.
authors.affiliation: From the Department of Biochemistry and Biophysics (S.R., D.Y.R.S.) and Division of Cardiology, Department of Medicine, Cardiovascular Research Institute (R.A.), University of California, San Francisco; and Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.R., R.R., D.Y.R.S.). sven.reischauer@mpi-bn.mpg.de didier.stainier@mpi-bn.mpg.de.
authors.forename: Sven
authors.initials: S
authors.lastname: Reischauer
authors.affiliation: From the Department of Biochemistry and Biophysics (S.R., D.Y.R.S.) and Division of Cardiology, Department of Medicine, Cardiovascular Research Institute (R.A.), University of California, San Francisco; and Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.R., R.R., D.Y.R.S.).
authors.forename: Rima
authors.initials: R
authors.lastname: Arnaout
authors.affiliation: From the Department of Biochemistry and Biophysics (S.R., D.Y.R.S.) and Division of Cardiology, Department of Medicine, Cardiovascular Research Institute (R.A.), University of California, San Francisco; and Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.R., R.R., D.Y.R.S.).
authors.forename: Radhan
authors.initials: R
authors.lastname: Ramadass
authors.affiliation: From the Department of Biochemistry and Biophysics (S.R., D.Y.R.S.) and Division of Cardiology, Department of Medicine, Cardiovascular Research Institute (R.A.), University of California, San Francisco; and Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.R., R.R., D.Y.R.S.). sven.reischauer@mpi-bn.mpg.de didier.stainier@mpi-bn.mpg.de.
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000199:Actins / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000378:metabolism*; D006321:Heart / Q000033:anatomy & histology / Q000502:physiology*; D021621:Imaging, Three-Dimensional / Q000379:methods*; D008969:Molecular Sequence Data; D009210:Myofibrils / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D015027:Zebrafish
chemical_list: D000199:Actins; D049452:Green Fluorescent Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: Erbb2 protein, human; cardiomyopathies; growth & development; heart contractility; myocardial contraction; myofibrils; sarcomeres