Adjunct Faculty

Christopher Brown, Ph.D.

Adjunct Assistant Professor of Pharmacology

VUMC 9435-A MRB4 Langford 2213 Garland Ave, Nashville, TN, 37232

Research Description

The goal of our laboratory is to understand the molecular mechanisms governing cardiac development and remodeling. The early linear heart tube is connected to a symmetrical system of aortic arch arteries. This primitive structure is remodeled into the mature cardiovascular system with separate high and low pressure circulation connected to the heart through a single aortic arch and pulmonary trunk. This remodeling is mediated by a population of migratory cells known as the cardiac neural crest. These cells directly contribute to the aortic arch arteries by differentiating into smooth muscle cells. Additional roles of the cardiac neural crest in determining which primitive arteries contribute to the mature vessels are less clearly understood.

Using the mouse as a model system we are examining the role of a class of signaling proteins known as semaphorins in neural crest mediated cardiovascular remodeling. Semaphorins were initially characterized as neural pathfinding molecules. Intriguingly, targeted ablation of Semaphorin 3C (Sema3C) results in cardiovascular malformations and not neural pathfinding defects. Sema3C homozygous null embryos exhibit interruption of the aorta and a condition called persistent truncus arteriosus in which the aorta and pulmonary artery fail to fully separate. We hypothesize that the cardiac defects observed are secondary to defects in the cardiac neural crest. Preliminary experiments indicate that neural crest migration, while perturbed, is not grossly deficient in Sema3C null animals. This suggests that the neural crest defect is not in migration but in differentiation, proliferation, or survival. We are currently assessing these aspects in the Sema3C null embryos.

Semaphorins signal through receptor complexes composed of two classes of transmembrane proteins called Neuropilins and Plexins. We have identified PlexinA2 as a putative co-receptor for Sema3C in cardiac neural crest cells. In order to demonstrate a requirement for PlexinA2 in the neural crest, we are taking advantage of dominant negative receptor expression to assess the role of Plexin signaling in neural crest cells. These experiments will allow us to determine the global requirement for functional plexin signaling in the cardiac neural crest. We are also generating conditional alleles of Sema3C and PlexinA2 to determine the tissue specific requirements for each gene.

Our long term goal is to better understand the complex role of neural crest cells in cardiac development and disease. The importance of these experiments is underscored by the observation that cardiovascular developmental defects are among the most prevalent developmental defects seen in children, occurring at rates as high as 1 in 100 births.
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Selected Publications