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Impact of Intracardiac Neurons on Cardiac Electrophysiology and Arrhythmogenesis in an Ex Vivo Langendorff System
Published on: May 22, 2018
Genetic and physiologic dissection of the vertebrate cardiac conduction system
Neil C Chi1, Robin M Shaw, Benno Jungblut
1Department 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
Insights
Understanding cardiac conduction system (CCS) development is crucial for preventing heart defects. This study identifies novel genetic regulators of CCS formation and function in zebrafish, offering new insights into vertebrate heart development.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Genetics
Background:
- The vertebrate cardiac conduction system (CCS) coordinates heart contractions for efficient blood circulation.
- Defects in the CCS can lead to serious health issues, including sudden cardiac death.
- Understanding CCS development is vital for preventing cardiac abnormalities.
Purpose of the Study:
- To investigate the developmental stages and molecular regulators of the cardiac conduction system (CCS).
- To identify novel genes involved in CCS formation and function using a forward genetic screen.
- To elucidate the role of epigenetic factors in regulating cardiac electrical activity.
Main Methods:
- Utilized a zebrafish transgenic line (Tg(cmlc2:gCaMP)(s878)) for in vivo optical mapping of cardiac electrical activity.
- Performed a physiology-based forward genetic screen to identify mutations affecting cardiac conduction.
- Employed positional cloning to identify specific genes responsible for identified mutations, including tcf2.
Main Results:
- Identified four distinct stages of cardiac conduction development in zebrafish.
- Discovered that hemodynamic flow and contraction act as epigenetic regulators of the CCS.
- Identified 17 novel conduction-specific mutations, including hobgoblin(s634), revealing tcf2 as a regulator of atrioventricular conduction.
Conclusions:
- The combination of in vivo optical mapping and genetic screening provides a powerful approach to study CCS development.
- Identified tcf2 as a novel regulator of cardiac conduction, linking it to known roles in diabetes and kidney disease.
- This research offers new molecular targets and insights into the development and function 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.
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