Cardiac neural crest ablation inhibits compaction and electrical function of conduction system bundles

Abstract

Retroviral and transgenic lineage-tracing studies have shown that neural crest cells associate with the developing bundles of the ventricular conduction system. Whereas this migration of cells does not provide progenitors for the myocardial cells of the conduction system, the question of whether neural crest affects the differentiation and/or function of cardiac specialized tissues continues to be of interest. Using optical mapping of voltage-sensitive dye, we determined that ventricles from chick embryos in which the cardiac neural crest had been laser ablated did not progress to apex-to-base activation by the expected stage [i.e., Hamburger and Hamilton (HH) 35] but instead maintained basal breakthroughs of epicardial activation consistent with immature function of the conduction system. In direct studies of activation, waves of depolarization originating from the His bundle were found to be uncommon in control hearts from HH34 and HH35 embryos. However, activations propagating from septal base, at or near the His bundle, occurred frequently in hearts from HH34 and HH35 neural crest-ablated embryos. Consistent with His bundle cells maintaining electrical connections with adjacent working myocytes, histological analyses of hearts from neural crest-ablated embryos revealed His bundles that had not differentiated a lamellar organization or undergone a process of compaction and separation from surrounding myocardium observed in controls. Furthermore, measurements on histological sections from optically mapped hearts indicated that, whereas His bundle diameter in control embryos thinned by almost one-half between HH30 and HH34, the His bundle in ablated embryos underwent no such compaction in diameter, maintaining a thickness at HH30, HH32, and HH34 similar to that observed in HH30 controls. We conclude that the cardiac neural crest is required in a novel function involving lamellar compaction and electrical isolation of the basally located His bundle from surrounding myocardium.

Biphasic Development of the Mammalian Ventricular Conduction System

“…6,31,32 In parallel, inductive signals from the NCC have been proposed to regulate the development and maturation of the central conduction system. 33,34 Our Cx40-Cre lineage study suggests that VCS lineage restriction occurs by E16.5 in both ventricles, indicating that temporal as well as spatial regulation of inductive signals may be involved in the transition to lineage restriction and the control of VCS outgrowth. Indeed, previous work has revealed a late role for Nkx2.5 in maturation of Purkinje fiber network.…”

Prenatal Zinc Deficiency: Influence on Heart Morphology and Distribution of Key Heart Proteins in a Rat Model

“…However, a number of recent studies using transgenic mice with NCC specific cre recombinase activity have shown that NCC not only migrate within the cells of the conduction system lineage but that they play a significant role in their final maturation [38,40,41]. Gurjarpadhye et al [34] have also observed abnormal conductivity in hearts of chick embryos after the ablation of their cardiac NCC. Thus, consistent with the above, we postulate that Zn deficiency could affect either the development of the conduction system directly or the ability of NCC to participate in CCS maturation and innervation; either effect would result in impaired heart formation.…”

“…NCC are essential to support normal heart morphogenesis [28][29][30][31] and alterations in the population, the developmental migration, or metabolism of NCC by surgical ablation, genetic deletion, or teratogenic insults lead to a panoply of cardiovascular defects [32][33][34][35][36][37][38]. Cardiac NCC originate from the lateral ridges of the neuroectoderm that span between the mid-otic placode and the caudal end of the third somite and contribute ectomesenchymal cells towards the development of the pharyngeal arches, the carotid, subclavian, innominate and coronary arteries, the aorticopulmonary septum, the conotruncal cushions, the distal portion of the ventricular septum, the walls of the ascending aorta, and the pulmonary trunk [28,29,39] and participate in the maturation of the cardiac conduction system [29,38,40,41].…”

Developmental Basis for Electrophysiological Heterogeneity in the Ventricular and Outflow Tract Myocardium As a Substrate for Life-Threatening Ventricular Arrhythmias

“…Ablation of CNC in chicken results in defects of the atrioventricular bundle, Purkinje fiber, and OFT. 134,135,137,138 OFT misalignment and persistent truncus arteriosus, abnormal patterning of the great arteries, and abnormal myocardial function are part of these defects. Thus, congenital defects in the OFT or the great vessels mediated by CNC may affect cardiac electrophysiology indirectly.…”