Neural Crest and Heart Development

Abstract

Ablation of cardiac neural crest results in a unique set of morphologic and function changes in cardiovascular development. The most dramatic morphologic changes are seen after the embryonic period is completed and include defective septation of the cardiac outflow tract and mispatterning (or interruption) of the great arteries, which is associated with hypoplastic development of the pharyngeal glands. These phenotypic changes are accompanied by myocardial functional alterations that include defective excitation-contraction coupling from the earliest time of myocardial function, resulting in heart failure. Abnormal ventricular function begins prior to the time when neural crest cells normally reach the heart in an intact embryo. Because the cardiac neural crest cells migrate initially into the pharyngeal region, where they support normal development of the aortic arch arteries, it was initially thought that abnormal development of the aortic (pharyngeal) arch arteries was likely to impact on ventricular development and would thus explain poor myocardial function. The pharyngeal arteries carry all of the cardiac output during a significant portion of early heart development. Loss of neural crest cells that support the endothelial walls of these vascular channels could change the properties of their walls. However, several attempts to document hemodynamic abnormalities in the aortic arch arteries following cardiac neural crest ablation have failed. Coculture of myocardium with endoderm leads to myocardial functional abnormalities similar to those seen in neural crest–ablated embryos. This has led to the hypothesis that an interaction of neural crest cells with pharyngeal endoderm may be required for inhibition or sequestration of a fibroblast growth factor (FGF)-like factor that is deleterious to myocardial development. This recent finding has produced a dramatic revision in classical thinking about the function of cardiac neural crest cells and the interactions that influence normal heart development.