Pattern Formation in the Cardiac His-Purkinje System

Medical University Of South Carolina, Charleston SC

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Abstract

The rhythmic generation and coordinated and coordinate of electrical excitation in the heart is dependent on its pacemaking and conduction system. The developmental mechanisms governing molecular induction and pattern is mounting evidence that embryonic structural malformations and dysfunction of the conduction system are clinically important in the morbidity and mortality associated with congenital heart disease. In published studies on chick embryos, we have shown i) that embryonic myocytes are recruited to conductive Purkinje fiber lineages on chick embryos, we have shown i) that embryonic myocytes are recruited to conductive Purkinje fiber lineages in close association with developing coronary arteries and ii) that endothelin-1 (ET), a cytokine expressed by a number of extracardiac mesenchymal-derived cell types (including neural crest and arteriogenic EPDCs), prompts differentiation of Purkinje fibers from embryonic myocytes in vitro. Recently, we have obtained evidence that a WNT-based mechanisms, down stream of ET, is involved in restricting the recruitment of myocytes to the developing conduction system. To build on these findings we will determine the roles of; (1) WNT-signaling in localized, inductive recruitment to the His-Purkinje system. We will also undertaken intensive gene expression profiling to determine if regulatory pathways involved in the molecular induction of conductive lineages in chick are conserved in the mouse embryo. The experimental strategies and animal models outlined herein include use of avian retroviral gene vectors and a binary CRE-Lox transgenic construct. Gene chip microarray screening of FACS sorted cells from transgenic mice encoding GFP-based reporter restricted to specific conduction system lineages will also be used. Pursuit of the aims of this study will lead to better understanding of the cellular, molecular and genetic mechanisms underpinning normal and abnormal pattern formation in the cardiac conduction system of humans.