Cellular and molecular mechanisms of FGF8 signaling in cardiac outflow tract development and remodeling

Congenital heart defects occur in nearly 1% of live-born infants and are estimated to cause 10% of spontaneous abortions. Many congenital heart defects are caused by abnormal development of the outflow tract of the heart. Thus, investigating the mechanisms underlying normal and abnormal outflow tract development and remodeling will improve our understanding of the cause of many congenital heart defects. Although it is known that FGF8 is expressed in multiple domains relevant to cardiac development in the mouse embryo and is crucial for normal cardiovascular development, the molecular mechanisms of how FGF8 signaling regulates outflow formation and remodeling have not yet been fully characterized.;Taken together, these studies refine our understanding of the Fgf8-dependent molecular and cellular events required for outflow tract development and remodeling in the mouse. This could contribute to designing novel molecular and genetic therapies for prevention and treatment of cardiovascular disease.;I used a Cre-loxP system, a tool for tissue specific conditional ablations of gene function, in the mouse model to overcome the early embryonic lethality of FGF loss of function and investigate gene functions in a specific tissue. First, I investigated how FGF8 signals from discrete temporospatial domains regulate outflow tract formation and remodeling. During the course of that study, I developed and optimized an inducible CRE expressing system for controlling the activity of floxed alleles in endoderm to study the function of Fgf signaling in the endoderm. Next, I determined target tissues of the Fgf8 signal required for outflow tract septation by conditional ablation of Fgf receptors and overexpression of an Fgf antagonist in different potential target tissues. I also identified and characterized Fgf signal dependent cellular defects and a molecular pathway that supports normal outflow tract development. Finally, I explored Fgf8 signaling dependent development of the outflow tract myocardium using the Fgf8 conditional mutant with the most reproducible phenotype.