Fibroblast Growth Factors (FGF), together with their high affinity receptors constitute a complex signaling pathway involved in the regulation of cell proliferation, differentiation and neoplastic transformation. The fourteen ligands and four receptors in this family display unique expression patterns and have specific binding interactions. Alternative mRNA splicing leads to several forms of each receptor which have distinct ligand binding specificities. Additionally, heparin or heparan sulfate proteoglycans, which are required for FGFs to bind to high affinity receptors, constitute another level in which FGF biologic activity may be modulated. Keratinocyte growth factor (FGF-7), a potent mitogen for keratinocytes, was though to be an essential molecule for epidermal development. However, the targeted disruption of the FGF-7 gene revealed a relatively minor phenotype. This suggests possible redundant function within the FGF family and the existence of another FGF ligand with similar properties to that of FGF-7. The proposed research will examine the biology of FGF-10, a newly discovered member of the FGF family, and FGF receptor 2, a likely physiological target for both FGF-7 and FGF-10. Preliminary data suggests that FGF-10 is closely related to keratinocyte growth factor (FGF-7) and is expressed throughout mouse embryogenesis and in adult animals. The hypothesis, that FGF-10 and FGF receptor 2 are important for epidermal development and for wound healing will be examined by determining the relative expression patterns of FGF-7 and FGF-10 throughout embryonic development. Mice will be engineered in which the FGF-10 gene is disrupted and in which the FGF receptor 2 gene is replaced by a conditional allele which can be inactivated specifically in the epidermis. These animals will be analyzed for skin pathology and for possible defects in wound healing.
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