Transcriptional Regulation of Cardiac Development and Function Using Mouse Models

The Epstein laboratory is interested in molecular mechanisms of cardiovascular development and stem cell biology, and the implications of these mechanisms for understanding human disease. Transgenic and knockout mouse models are used. One area of interest is the developmental biology of neural crest. Neural crest cells are multipotent progenitors that give rise to nerve, bone, muscle, melanocytes and other cell types. Hence, they are an attractive model for studying stem cell biology. Neural crest defects are associated with congenital heart disease. Using Cre-lox approaches, we have demonstrated that neural crest cells in mammals give rise to the smooth muscle of the great vessels and portions of the outflow tract of the heart. Semaphorins, molecules that mediate repulsive axon guidance in the central nervous system, also mediate proper neural crest patterning and we have identified novel semaphorin pathways functional in the vasculature. Neural crest patterning is affected in mouse models of DiGeorge syndrome, a common human congenital condition associated with congenital heart disease. We have studied mouse models of DiGeorge syndrome including those with deletions or mutations in the Tbx1 transcription factor gene. Another human disorder associated with neural crest defects is Type I Neurofibromatosis. We have demonstrated that heart defects in Nf1 mutant mice are related to a function for this gene in endothelial cells which is distinct from its role in neural crest. Our lab is also interested in transcriptional regulation of cardiac muscle development and function. We have discovered an unusual homeobox gene that affects heart growth and function. Knockouts in mice and zebrafish have poorly formed hearts, and over-expression in adults causes adult cardiac hypertrophy and heart failure. Chromatin remodeling of cardiac-specific genes is affected. More recent work focuses on the role of chromatin remodeling, histone deacetylation (HDACs) and a small homeodomain protein called Hopx that is expressed in adult stem cells. We have developed several outstanding core facilities for histology, transgenics and mouse physiology to aid students and postdocs in accomplishing research goals and in accelerating productivity.
 

Source: https://www.med.upenn.edu/apps/faculty/index.php/g275/p12834