DESCRIPTION (Applicant's Description): Research is proposed to decipher how diverse cell types arise within broad fields of heart and kidney potential. Prior studies in my lab have shown that the entire field of cardiogenic mesoderm is specified initially as cardiomyogenic, although non-muscle heart cells also originate from this tissue. Preliminary data in this application reveal that activation of the Notch signaling pathway suppresses cardiomyogenesis in the dorsal regions of the cardiac field and diverts these cells to differentiate as non-muscle cardiac tissue. Similarly, preliminary evidence shows that Notch in the early kidney field regulates the fate of pronephric duct cells and also has striking effects on tubule morphogenesis. Thus, Notch, which is well known to regulate cell fate in the developing nervous system, controls differentiation within at least two mesodermal organs. The first two aims examine how Notch regulates cell fate in the heart. The first will determine if Notch controls the differentiation of a multipotent precursor to adopt myocardial and nonmyocardial fates. The second is based on additional preliminary data suggesting that Notch continues to function after closure of the heart tube. This aim will evaluate the influence of Notch on later determination events, such as acquisition of chamber-specific identity and morphology. The final three aims are to identify novel transcriptional regulators of heart and kidney differentiation. A genetic cascade of bHLH factors that mediate Notch action is conserved in all species. Although a number of homologues mediate Notch function in vertebrate embryos, such as during neurogenesis, relatively few of these are present in the developing heart or kidney and none have been shown to account for Notch function in these tissues. Such proteins are expected to be novel and important regulators of tissue differentiation in the heart and kidney. Knowledge of Notch function and the key downstream regulatory proteins should provide molecular insights that may be of therapeutic benefit for disease and congenital disorders.
NIH ExPorter
NIH ExPorter