The focus of this laboratory is the development of the arterial pole of the heart, which is involved in some of the most common birth defects.
Heart defects are the most common birth defect requiring medical intervention, and the most common heart defects involve septation and the arterial pole of the heart.
Current Projects in the Lab
- Mechanisms of fibroblast growth factor 8 modulation in the pharynx by cardiac neural crest cells
- Intracellular pathways activated by fibroblast growth factor 8
- Other signaling pathways important in secondary heart field development
- Dynamics and signaling involved in development of the tubular heart from the heart fields
- Evolutionary conservation of the secondary heart field
- Genetic basis of conotruncal malformations
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 chicks 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. We have described that 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 undergo the rotation necessary to make appropriate connections from the ventricles to the aorta and pulmonary arterial trunks. Defects of outflow alignment such as tetralogy of Fallot and double outlet right ventricle may therefore be the result of problems with the addition of myocardium from the secondary heart field. Moreover, the secondary heart field adds smooth muscle component to the outflow above the myocardium at the semilunar valves and may be important for normal coronary artery patterning.
Because the zebrafish has an unseptated outflow tract, we are able to study addition of the cells from the secondary heart field in a simpler system. We are currently using zebrafish to identify genes that are required for normal development of the secondary heart field.
Margaret L. Kirby, PhD
Professor, Departments of Pediatrics and Cell Biology
Office: Room 403, Jones Building, Durham, NC, 27708
Campus mail: Box 103105, Durham, NC, 27710