Cardiovascular defects are the most common defects in human infants, affecting one of two hundred live births. Although many of these cardiac malformations have well defined phenotypes, currently very few candidate genes have been identified as playing a role in these heart malformations. Recent studies suggest that the connexin 43 (Cx43) gap junction gene may be one such candidate gene. Cx43 knockout (KO) mice die at birth as a result of conotruncal defects associated with pulmonary stenosis and ventricular septal defects. Given that previous ablation studies have shown the importance of occipital neural crest cells in conotruncal development, we suggest that perturbation of neural crest cells may underlie the cardiovascular malformations resulting from Cx43 perturbation. Consistent with this possibility is the fact that neural crest cells express the Cx43 gap junction gene, and are functionally coupled via gap junctions. Furthermore, Cx43 expression in the CMV43 transgenic mice is driven by the cytomegaloviral promoter, a promoter which restricts transgene expression to the dorsal neural tube, and a subpopulation of neural crest cells, including neural crest cells that migrate to the heart outflow tract. In light of these observations, we propose experiments to further examine whether perturbation of neural crest cells may underlie the cardiovascular malformations seen in mice harboring the loss of Cx43 function. We will characterize cardiovascular morphogenesis in the Cx43 KO and CMV43 transgenic mice using histology, echocardiography, and MRI analyses. We will perform echocardiography on live embryos (in-utero), send the pregnant female to Duke, perfuse the embryos with BSA-DTPA-Gd, perform a quick survey scan of each embryo, and then perform a 3D spin echo scan on homozygote KO embryos that looked promising in the survey scans. We anticipate preparing 4 litters of embryos, and performing 3D scans on 6-8 of the embryos on the 9T magnet.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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Duke University
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