Genetic and physiologic dissection of the vertebrate cardiac conduction system.
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.
Chi
Neil C
NC
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
Shaw
Robin M
RM
Jungblut
Benno
B
Huisken
Jan
J
Ferrer
Tania
T
Arnaout
Rima
R
Scott
Ian
I
Beis
Dimitris
D
Xiao
Tong
T
Baier
Herwig
H
Jan
Lily Y
LY
Tristani-Firouzi
Martin
M
Stainier
Didier Y R
DY
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
D018031:Connexin 43; D017630:Connexins; D000097003:Gap Junction alpha-5 Protein