Heart disease is a major cause of morbidity and mortality in developed nations. Although tremendous progress has been made in the treatment of heart disease, there is currently no cure: the cells that compose the heart are irreplaceable, having terminally differentiated late in development. Identifying the molecular mechanisms that specify cardiac cell fates may allow the development of regenerate therapies for damaged, diseased or malformed heart tissue. Cardiogenic transcription factors regulate constellations of downstream genes in order to effect cardiac cell fates. In particular, the two transcriptional activators MEF2C and dHAND are both required for the development of the right ventricular chamber in mice. Identifying the genes that are direct targets of MEF2C and dHAND will show how cardiac cell fates are effected and may describe deeper motifs on the nature of cell fate in general. Specifically, this project will use microarray analyses to identify genes that are down regulated in MEF2C and dHAND mutant hearts. Cellular cardiogenesis assays will then be used to identify the subset of downstream genes that are required for cardiac cell fates. Finally, the roles of these cardiogenic effector genes will be studied in vivo, using loss-of-function and gain-of-function mutant alleles and genetic interaction tests.
