title: Genetic and physiologic dissection of the vertebrate cardiac conduction system.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biophysics and Programs in Developmental Biology, Genetics, and Human Genetics, University of California San Francisco, San Francisco, California, United States of America. Neil.Chi@ucsf.edu
authors.forename: Neil C
authors.initials: NC
authors.lastname: Chi
authors.forename: Robin M
authors.initials: RM
authors.lastname: Shaw
authors.forename: Benno
authors.initials: B
authors.lastname: Jungblut
authors.forename: Jan
authors.initials: J
authors.lastname: Huisken
authors.forename: Tania
authors.initials: T
authors.lastname: Ferrer
authors.forename: Rima
authors.initials: R
authors.lastname: Arnaout
authors.forename: Ian
authors.initials: I
authors.lastname: Scott
authors.forename: Dimitris
authors.initials: D
authors.lastname: Beis
authors.forename: Tong
authors.initials: T
authors.lastname: Xiao
authors.forename: Herwig
authors.initials: H
authors.lastname: Baier
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Jan
authors.forename: Martin
authors.initials: M
authors.lastname: Tristani-Firouzi
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D054849:Cardiac Electrophysiology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006329:Heart Conduction System / Q000196:embryology / Q000378:metabolism / Q000502:physiology*; D006439:Hemodynamics; D009154:Mutation; D009206:Myocardium / Q000166:cytology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000502:physiology*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D018031:Connexin 43; D017630:Connexins; D000097003:Gap Junction alpha-5 Protein