Communication between Migrating Cardiac Neural Crest Cells

Although we think of neural crest cells migrating as individual mesenchymal cells, there is evidence that the cardiac crest cells are literally "in contact" with each other during their migrations. Studies of transgenic and knockout mice with perturbations in gap junction protein connexin 43 (Cx43) have revealed an important role for gap junctions in cardiac development.

Waldo and her colleagues (1999) constructed transgenic mice in which the promoter sequence for connexin 43 was fused to a lacZ reporter and was expressed in neural crest (but not in myocardial) cells. The pattern of cardiac neural crest cells expressing the lacZ transgene in the caudal pharyngeal arches and cardiac outflow tracts was similar to that of cardiac neural crest cells in quail-chick chimeras. There were slight differences between the chick and the mouse in the contribution made to the cardiac outflow tracts, but the overall pattern was the same.

Huang and colleagues (1998a) showed that Connexin 43 knockout mice and transgenic mice that overexpressed the Cx43 gap junction gene (by putting it on a viral promoter) exhibited heart defects that involving the conotruncus and right ventricle. Based on the heart phenotype and Cx43 gene and transgene expression pattern, it appeared that interfering with the gap junctions altered the neural crest-derived structures of the heart. Magnetic resonance microscopy showed in some of the overexpressing and Cx43 knockout mice an attenuation of the ductus arteriosus, a phenotype indicative of outflow tract obstruction. Histological examination of these hearts showed abnormal myocardial development in the conotruncus, a neural crest derived structure (Figure 1). Therefore, the dosage of Cx43 appears critical in conotruncal heart development and suggests that this involves a role for Cx43 gap junctions in cardiac neural crest development.

Figure 1 Heart malformations in the Cx43 knockout heart. Trypan blue dye was injected into the right ventricular chamber of wild-type (A) or Cx43 knockout (B) embryonic (17.5d) mice. The trypan blue in the wild-type mouse delineates the right ventricular cavity of the wild-type mouse, but in the knockout mouse, it extends through a broken conotruncal wall. The arrow points to a morphological abnormality in the heart. ra, right atrium; la, left atrium. (From Huang et al., 1998a; courtesy of C. Lo.)

Using a neural crest outgrowth culture system, Huang and colleagues (1998b) showed that the migration of the cardiac neural crest cells was altered by the dosage of Cx43. These studies showed that the migration rate of cardiac neural crest was increased in the Cx43-overexpressing embryos, but decreased in the Cx43 knockout embryos. Dye coupling analysis in neural crest cells (wherein a low molecular weight dye is placed into one cell and transferred through gap junctions to other cells), in outgrowth cultures and in living embryos, showed an elevation of gap junction communication in the Cx43- overexpressing transgenic mice, while a reduction was observed in the Cx43 knockout mice.

By labeling cardiac neural crest cells with the LacZ transgene, Huang and colleagues (1998b) showed that the Cx43-overexpressing mice had more lacZ-positive neural crest cells in the outflow septum, while a reduction was observed in the Cx43 knockout mice. Surprisingly, the greater number of neural crest cells in the heart was accompanied by an increase in the cell proliferation of the myocardium—heart muscle (that is not neural crest-derived). Similarly, there was a decrease in the proliferation rate of heart muscle in the Cx43 knockout mice. This suggests that cardiac neural crest cells may have a role in modulating the growth and development of non-neural crest- derived cardiac tissues.

It appears, then, that cardiac neural crest cells communicate with each other as they migrate to the heart. Moreover, when they arrive at the heart, they not only form the septa and cardiac outflow derivatives, but also help promote cell division in the developing heart musculature.

Literature Cited

Huang, G. Y., Wessels, A., Smith, B. R., Linask, K. K., Ewart, J. L., and Lo, C. W. 1998a. Alteration in connexin 43 gap junction gene dosage impairs conotruncal heart development. Dev. Biol. 198:32-44.

Huang, G. Y., Cooper, E. S., Waldo, K., Kirby, M. L., Gilula, N. B., and Lo, C. W. 1998b. Gap junction-mediated cell-cell communication modulates mouse neural crest migration. J Cell Biol. 143: 1725-1734.

Waldo, K. L., Lo, C. W., Kirby, M. L. 1999. Connexin 43 expression reflects neural crest patterns during cardiovascular development. Dev. Biol. 208: 307-323.

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