Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Jonathan A. Epstein

Abstract

Development of the heart is an intricate and complex process. Crucial to this process is vascular patterning and the signals that properly guide developing vessels. Consequences of improper patterning can be severe, including life-threatening congenital heart defects. In this dissertation, I investigate the role of the secreted guidance molecule semaphorin 3d (Sema3d) in cardiovascular patterning during development, and attempt to dissect the molecular mechanisms involved in Sema3d signaling. Using loss-of-function genetic experiments in mice, I model multiple forms of congenital heart defects such as total anomalous pulmonary venous connections, transposition of the great arteries, and congenital abnormalities of the coronary vessels. These mouse models are powerful tools, which I use to investigate the etiology and morphogenesis of these disorders. Critical to understanding these congenital defects in these models is precisely deciphering the cellular and molecular mechanisms involved. I show how Sema3d affects the motility, migration, and adhesion of endothelial cells through a process of cytoskeletal reorganization, and I identify multiple molecules in the Sema3d signaling pathway, including a novel holoreceptor comprised of the receptor tyrosine kinase ErbB2 and semaphorin receptor neuropilin 1. Elucidating the precise mechanisms of normal vascular development along with pathologic processes is a necessary step towards future interventions and possible therapeutics.

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