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© The Rockefeller University Press, 0021-9525/1998//1725 $5.00
The Journal of Cell Biology, Volume 143, Number 6, , 1998 1725-1734

Article

Gap Junction–mediated Cell–Cell Communication Modulates Mouse Neural Crest Migration



G.Y. Huang*, E.S. Cooper*, K. Waldo{ddagger}, M.L. Kirby{ddagger}, N.B. Gilula§, and C.W. Lo*

* Biology Department, University of Pennsylvania, Philadelphia, Pennsylvania 19104; {ddagger} Developmental Biology Program, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912-2640; and § Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037

Previous studies showed that conotruncal heart malformations can arise with the increase or decrease in {alpha}1 connexin function in neural crest cells. To elucidate the possible basis for the quantitative requirement for {alpha}1 connexin gap junctions in cardiac development, a neural crest outgrowth culture system was used to examine migration of neural crest cells derived from CMV43 transgenic embryos overexpressing {alpha}1 connexins, and from {alpha}1 connexin knockout (KO) mice and FC transgenic mice expressing a dominant-negative {alpha}1 connexin fusion protein. These studies showed that the migration rate of cardiac neural crest was increased in the CMV43 embryos, but decreased in the FC transgenic and {alpha}1 connexin KO embryos. Migration changes occurred in step with connexin gene or transgene dosage in the homozygous vs. hemizygous {alpha}1 connexin KO and CMV43 embryos, respectively. Dye coupling analysis in neural crest cells in the outgrowth cultures and also in the living embryos showed an elevation of gap junction communication in the CMV43 transgenic mice, while a reduction was observed in the FC transgenic and {alpha}1 connexin KO mice. Further analysis using oleamide to downregulate gap junction communication in nontransgenic outgrowth cultures showed that this independent method of reducing gap junction communication in cardiac crest cells also resulted in a reduction in the rate of crest migration. To determine the possible relevance of these findings to neural crest migration in vivo, a lacZ transgene was used to visualize the distribution of cardiac neural crest cells in the outflow tract. These studies showed more lacZ-positive cells in the outflow septum in the CMV43 transgenic mice, while a reduction was observed in the {alpha}1 connexin KO mice. Surprisingly, this was accompanied by cell proliferation changes, not in the cardiac neural crest cells, but in the myocardium— an elevation in the CMV43 mice vs. a reduction in the {alpha}1 connexin KO mice. The latter observation suggests that cardiac neural crest cells may have a role in modulating growth and development of non–neural crest– derived tissues. Overall, these findings suggest that gap junction communication mediated by {alpha}1 connexins plays an important role in cardiac neural crest migration. Furthermore, they indicate that cardiac neural crest perturbation is the likely underlying cause for heart defects in mice with the gain or loss of {alpha}1 connexin function.

Key Words: neural crest • gap junction • connexin 43 • oleamide • cardiac

Abbreviations used in this paper: BrdU, bromodeoxyuridine; KO, knockout; PCNA, proliferating cell nuclear antigen.


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