Development of the cardiac conduction system

The heterogeneous tissues of the cardiac pacemaking and conduction system are responsible for setting, maintaining and coordinating the rhythmic pumping of the heart (reviewed Thompson et al., 1995; Moorman et al., 1998; Gourdie et al., 1999). Anomalous development of this specialized network has been implicated in pediatric arrhythmia and other congenital abnormalities of cardiac activation (Schott et al., 1998). In earlier retroviral lineage-tracing work in chick (Gourdie et al., 1995), it was reported that periarterial Purkinje fibers, the most peripheral cells of the developing conduction system (Davies, 1930), share common cardiomyogenic origins with working myocytes. Owing to the close proximity of these Purkinje fiber cells to coronary arteries, it was furthermore suggested that this selection of a specialized phenotype within myocardial clones occurred as a result of paracrine signals from vascular tissues (Gourdie et al., 1995; reviewed Gourdie et al., 1999). Consistent with this, it was subsequently reported that endothelin-1 (ET1), a shear stress-induced cytokine prominently expressed by the coronary arterial bed (Yanagisawa et al., 1988; Masaki et al., 1991), prompts embryonic myocytes to express Purkinjefiber like characteristics in vitro (Gourdie et al., 1998). While there has been some progress on understanding the mechanisms governing development of peripheral Purkinje fibers, the cellular origins of other components of the conduction system (e.g. the nodes and bundles of the central conduction system), and the molecular signaling processes giving rise to such tissues remain almost entirely uncharacterized. Indeed, this area is distinguished by a number of long-standing controversies (reviewed Gorza et al., 1988; Moorman et al., 1998; Gourdie et al., 1999). First, debate continues as to whether specialized 5041 Development 126, 5041-5049 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 DEV4208