Abstract 1245: Temporal Ablation of Neural Crest in the Mouse Results in Cardiovascular Defects
Conotruncal heart defects account for about 50 – 60% of cardiac malformations found in neonates, and are associated with high morbidity and mortality. Neural crest cells are thought to play a critical role in the morphogenesis of the human conotruncus and in the pathogenesis of conotruncal defects. In avian embryos, ablation of this population of cells results in cardiac outflow tract defects and aortic arch patterning abnormalities. However, chicken and mammalian cardiovascular patterning differs in several important respects. While fate mapping experiments in mice suggest a conservation of function, the functional requirement for these cells in cardiovascular development in mammals has not been formally tested. We therefore set out to test the hypotheses that the murine neural crest plays an important role in the remodeling of the cardiac outflow tract and that its ablation would result in conotruncal heart defects. We used the PuΔTK selector mouse line, which expresses a truncated version of the herpes simplex virus-1 thymidine kinase (TK) after Cre-recombination. Mitotic cells that express TK convert Gancyclovir (GCV) to a toxic metabolite that induces cell death. We crossed this line with the Wnt-1 Cre line, which expresses Cre-recombinase in pre-migratory neural crest cells. By administering intraperitoneal GCV to pregnant dams between 7.5 and 8 days post coitum we were able to ablate neural crest cells. Affected embryos displayed a spectrum of outflow tract and aortic arch defects including truncus arteriosus, double outlet right ventricle and right aortic arch. Interestingly, in some of the most severely affected embryos we also found coronary artery patterning defects. To our knowledge, this is the first report of a neural crest ablation experiment in mammals. We conclude that the neural crest in the mouse plays an important role in the remodeling of the outflow tract and great arteries, as well as in the formation of the coronary arteries. This data provides important insight into the role of the mammalian neural crest during cardiovascular development, and further support for the theory that abnormalities in neural crest cell migration or function play a critical role in the pathogenesis of conotruncal abnormalities in humans.