Genetic and Physiologic Dissection of the Vertebrate Cardiac Conduction System

Chi, N.C., Shaw, R.M., Jungblut, B., Huisken, J., Ferrer, T., Arnaout, R., Scott, I., Beis, D., Xiao, T., Baier, H., Jan, L.Y., Tristani-Firouzi, M., and Stainier, D.Y.
PLoS Biology   6(5): e109 (Journal)
Registered Authors
Baier, Herwig, Beis, Dimitris, Chi, Neil C., Huisken, Jan, Jungblut, Benno, Scott, Ian, Stainier, Didier, Xiao, Tong
Heart, Cardiac ventricles, Zebrafish, Embryos, Myocardium, Cardiac atria, Calcium imaging, Vertebrates
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Cardiac Electrophysiology
  • Connexin 43/genetics
  • Connexin 43/metabolism
  • Connexins/genetics
  • Connexins/metabolism
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/physiology
  • Gene Expression Regulation, Developmental
  • Heart Conduction System/embryology
  • Heart Conduction System/metabolism
  • Heart Conduction System/physiology*
  • Hemodynamics
  • Mutation
  • Myocardium/cytology
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish/physiology*
18479184 Full text @ PLoS Biol.
Vertebrate hearts depend on highly specialized cardiomyocytes that form the cardiac conduction system (CCS) to coordinate chamber contraction and drive blood efficiently and unidirectionally throughout the organism. Defects in this specialized wiring system can lead to syncope and sudden cardiac death. Thus, a greater understanding of cardiac conduction development may help to prevent these devastating clinical outcomes. Utilizing a cardiac-specific fluorescent calcium indicator zebrafish transgenic line, Tg(cmlc2:gCaMP)(s878), that allows for in vivo optical mapping analysis in intact animals, we identified and analyzed four distinct stages of cardiac conduction development that correspond to cellular and anatomical changes of the developing heart. Additionally, we observed that epigenetic factors, such as hemodynamic flow and contraction, regulate the fast conduction network of this specialized electrical system. To identify novel regulators of the CCS, we designed and performed a new, physiology-based, forward genetic screen and identified for the first time, to our knowledge, 17 conduction-specific mutations. Positional cloning of hobgoblin(s634) revealed that tcf2, a homeobox transcription factor gene involved in mature onset diabetes of the young and familial glomerulocystic kidney disease, also regulates conduction between the atrium and the ventricle. The combination of the Tg(cmlc2:gCaMP)(s878) line/in vivo optical mapping technique and characterization of cardiac conduction mutants provides a novel multidisciplinary approach to further understand the molecular determinants of the vertebrate CCS.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes