Notch signaling in cardiac development.

摘要

Development of the vertebrate heart is a complex process involving the interaction of multiple different cell types. Failure to properly coordinate many aspects of cardiac morphogenesis can result in congenital heart defects. Disruptions in the Notch signaling pathway have been implicated as a genetic cause of several types of cardiovascular disease in humans. However, many of the mechanisms by which Notch functions during heart development are still unclear. In this dissertation, I combine mouse genetics and ex vivo tissue culture assays to analyze the role of Notch and one of its ligands, Jagged1, in heart development. Using Cre/loxP technology, I have generated a series of tissue-specific mutant mouse models to study the roles of Notch and Jagged1 in the major cell types that contribute to the outflow tract of the heart, including cardiac neural crest cells, endothelial cells, and cardiac progenitors from the secondary heart field. These studies reveal critical roles for Notch in cardiac neural crest cells and secondary heart field. In addition, they implicate Jagged1 as a critical Notch ligand in this process, with essential roles in vascular endothelium and secondary heart field cells. These findings provide a framework for understanding the role of Jagged1 and Notch in the etiology of several common forms of congenital heart disease.