The fast conduction system of the ventricles is the last element of the PCS to differentiate. In chick, this is marked by an apparent reversal in the sequence of ventricular activation (Chuck et al., 1997a). Specifically, an immature base-to-apex pattern of epicardial activation switches to a mature apex-to-base pattern between the 6th to 9th day of chick embryonic development. Fundamentally, the immature pattern is a maintenance of the sequence of activation seen at earlier looped, tubular stages of development. The mature “apex-first” pattern coincides with completion of ventricular septation, and is likely to result from epicardial break-through near the termini of the right and left branches of the His-Purkinje system. Rentschler and co-workers (2001) have reported that apical activation in mouse is initiated around 10.5 days of embryonic development, a timing prior to completion of ventricular septation. Until recently, it was thought that lower vertebrates did not possess a fast conduction system. However, work in Xenopus and zebrafish have now confirmed that these species also demonstrate a functional equivalent of this specialized network (Sedmera et al., 2002). This observation opens up the use of models such as the zebrafish for investigations of the mechanisms underlying His-Purkinje development.
Retroviral lineage-tracing studies in chick indicated that central elements of the PCS (e.g., the His bundle) differentiated independently of distally located PCS components, such as the peripheral network of Purkinje fibers (Gourdie et al., 1995). This raised the prospect that certain PCS elements may form separately and link together as development proceeds. While it remains to be established that such a linkage process accounts for the switch in activation sequence, addressing this question may be important, as it could inform the origins of congenital AV block in humans, such as that occurring in autoimmune lupus (Askanase et al., 2002). There are other data that may have bearing on this aspect of His-Purkinje development. Work in humans has indicated that the remodeling of an initially ring-like domain, present in the looped, tubular heart, may be key to morphogenesis of the conduction system (Wessels et al., 1992). Two molecules linked to intercellular interactions, PSA-NCAM and connexin40 have been reported to show increasingly retrograde patterns of expression along the axis of atrioventricular conduction in the developing chick heart (Chuck et al., 1997; Gourdie et al., 1993). Interestingly, PSA-NCAM has been implicated in neuronal guidance (Durbec and Cremer, 2001). The gap junction protein connexin40 is highly up-regulated during development of the conduction system in birds (Gourdie et al., 1993) and mammals (Delorme et al., 1995). Coupling mediated by this high conductance channel is thought to be key to emergence of fast activation spread in the His-Purkinje system (reviewed Lo, 2000; Severs et al., 2001). Finally, lineage marking studies in chick have revealed patterns of association between extracardiac-derived populations of cells and specific parts of the developing conduction system (Gittenberger deGroot et al., 1998; Cheng et al., 1999; Poelmann and Gittenberger-de Groo, 1999). In particular, the timing of neural crest migration into the embryonic heart and its subsequent interaction with forming central conduction fascicles appears to correlate with maturation of function of the His-Purkinje system (Cheng et al., 1999; Poelmann and Gittenberger-de Groot, 1999). A caveat to note here is that such associations should not be taken as implying that PCS tissues have an extracardiac origin. Indeed, as will be discussed, lineage analyses from different groups have suggested that significant contributions by migratory cohorts, such as the neural crest, to the conduction system are unlikely, at least in higher vertebrates.