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EDITORIAL FOCUS
1Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska; and 2Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas
THIS YEAR IS THE 113TH ANNIVERSARY of two publications whose relationship was not obvious initially: the observation that neural crest cells migrate away from the neural ectoderm and assume a wide variety of phenotypes (11) and the initial description of what became known as the pacemaking/conduction system of the heart (6). Both of these observations have been expanded logarithmically by advancing technology, and the accumulated data have shown their extraordinary developmental and functional importance.
The contribution of cells from the neural ectodermal to the formation of face mesenchyme (11) confounded fundamentalist believers in the germ layer theory of development, and the next century of research showed that the developmental potential of the neural crest was even more diverse. Neural crest cells contribute to several other mesenchymal cell types, and they may be directed to differentiate into melanocytes, neurons, and glia and into a variety of highly specialized endocrine and paraendocrine cells. This remarkable plasticity has been reviewed several times, e.g., by Le Douarin et al. (10), Sauka-Spengler and Bronner-Fraser (13), and Vickaryous and Hall (16), in whose proposed 21st-century revision of the theory, neural crest becomes the fourth germ layer.
In an important expansion of our understanding of the multiple roles of the neural crest, Kirby et al. (8) used the chicken embryo model of heart development to show that mesenchymal cells from the cranial neural crest were required for normal aorticopulmonary septation, and, in their absence, the heart developed with structural defects of the outflow tract. Conway et al. (2) and others [reviewed by Hutson and Kirby (7)] have carried out a number of experiments that confirmed the role of the cardiac neural crest in mammalian heart development. Indeed, following the seminal discovery by Kirby et al. (8), the potential importance of neural crest impairment in the formation of heart defects was quickly extrapolated to humans [e.g., Lammer et al. (9)], and the region of the cephalic neural crest that gives vertebrates the four-chambered heart now is so well appreciated that it has been named the "cardiac neural crest" [reviewed by Hutson and Kirby (7) and Stoller and Epstein (15)]. Cardiac neural crest-derived heart defects are a distinct, well-recognized, and etiologically useful category for pediatric cardiologists.
Further experiments have demonstrated that the importance of the cardiac neural crest to heart development transcends its chameleon-like ability to assume diverse cellular phenotypes. Hutson and Kirby (7) discuss its "indirect participation" in cardiovascular development, and Stoller and Epstein (15) cite the cardiac neural crest in complex inductive interactions that are vital to heart development. Of particular significance in the present context is the convergence of the inductive influence of the cardiac neural crest with the development of the cardiac pacemaking/conduction system. Gourdie and his colleagues [e.g., Cheng et al. (1) and Gourdie et al. (3, 4)] found that the pacemaking and conduction system was neither derived from a pool of specialized progenitor cells nor derived from the cardiac neural crest; however, they had inferred an inductive effect of the cardiac neural crest on myocardial cells, an effect supported by experimental evidence in both the chicken embryo model (12) and the mouse embryo model (14).
Recently, a research team with outstanding credentials in the development of both the cardiac neural crest and the pacemaking/conduction system carried out a technically sophisticated collaboration that is reported in this issue of the American Journal of Physiology-Heart and Circulatory Physiology (5). In summary, hearts from chicken embryos that had undergone ablation of their cardiac neural crest showed significant deficits in the functional development of the pacemaking/conduction system. Ventricular activation normally proceeds base to apex, and then, as the system develops, activation progresses to the apex-to-basal mode required for normal heart function. However, in the hearts from embryos with ablated cardiac neural crest, progression to the apex-to-basal mode was retarded. Furthermore, cardiac neural crest ablation resulted in reduced electrical isolation of the pacemaking/conduction system. This failure of the system to become functionally insulated from the working myocardium is consistent with the observation by Gurjarpadhye et al. (5) that, in the absence of the normal population of neural crest cells in the heart, the His bundles do not assume their normal compact, lamellar structure. These new data are a significant step toward understanding the mechanisms of induction of various components of the pacemaking/conduction system.
In addition to their providing significant new information regarding heart development, to carry out these experiments, Gurjarpadhye et al. (5) introduced new technical approaches that are likely to be useful to others as well, for example, a new system for optical mapping via fluorescence of the depolarization signal, a method to provide objective measurement of the maturity of ventricular activation, and a new protocol to observe and assess ventricular activations that originate in the His bundle.
GRANTS
For work in the development of the cardiac neural crest, T. Rosenquist and R. Finnell are supported by National Heart, Lung, and Blood Institute Grant HL-66398.
FOOTNOTES
Address for reprint requests and other correspondence: T. H. Rosenquist, Univ. of Nebraska Medical Center, 987878 Nebraska Medical Center, Omaha, NE 68198-7878 (e-mail: throsenq{at}unmc.edu)
REFERENCES
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