Heart defects are the most common birth defect requiring medical intervention. The most common heart defects involve septation and alignment of the arterial pole of the heart. The focus of this laboratory is the development of the arterial pole of the heart. For more than 20 years, our group has studied the role of neural crest cells in the functional and structural development of the arterial pole by using several different animal models of human congenital heart defects. Neural crest cells are vital for normal development of the arterial pole as they are required for division of the aorta and pulmonary trunk from a single primordial vessel. Laser ablation of the neural crest cells in chick results in a single outflow vessel or persistent truncus arteriosus, one of the hallmark features of the DiGeorge Syndrome. In addition to normal outflow septation, cells from the neural crest are important in regulating the availability of growth factors in the developing pharynx. In the absence of neural crest cells, fibroblast growth factor (FGF8) is overabundant and interferes with various developmental processes in the heart and pharynx. One of the places where overabundant FGF causes abnormal development is in the induction and differentiation of myocardium from a newly identified secondary heart field. The secondary heart field is the source of the cells that form the myocardium and smooth muscle that comprise the definitive arterial pole of the heart. This secondary source of myocardium in the pharynx, adds to the lengthening outflow tract after initial heart tube formation. Without the addition of myocardium from the secondary heart field, the outflow is shortened and cannot align the aorta and pulmonary arterial trunks with the ventricles appropriately. Defects of outflow alignment such as tetralogy of Fallot and double outlet right ventricle may therefore be the result of abnormal development of the secondary heart field.

In addition to studying the cell biology of the secondary heart field, we are interested in genes that affect their development. We have recently shown that the arterial pole in the zebrafish develops similar to that of the chick and mouse prior to septation. Thus, we are able to perform candidate and forward genetic screens in zebrafish to identify potential genes that are important in normal arterial pole development.