Fibroblast growth factors (FGFs) are essential molecules for mammalian development. Several human genetic diseases have been identified that are caused by point mutations in the genes encoding FGF receptors (FGFRs), 1, 2 and 3. These disorders result in craniofacial and skeletal dysplasias (craniosynostosis syndromes) and chondrodysplasia syndromes and demonstrate that FGF signaling pathways are essential regulators of chondrogenesis and osteogenesis. FGFR is expressed in proliferating and proliferating and pre-hypertrophic chrondrocytes. FGFR1 is expressed in hypertrophic chrondrocytes in an adjacent domain to that of FGFR3. FGFR2 is expressed in mesenchymal condensations, the perichondrium and in the osteoblast compartment of developing bone. These very defined and non-overlapping expression patterns suggest that different FGFRs have unique signaling properties required for different stages of bone development and/or that different FGFRs are utilized to take advantage of unique responsiveness to specific ligands. Additionally, the identity and function of the FGF ligand(s) that activate three different FGFRs throughout bone growth and development is not known. The experiments proposed here will test the hypotheses that unique signaling and unique ligand binding properties of FGFRs are essential to their function at different stages of bone development. In addressing this hypothesis we will elucidate the specific roles for FGFRs in the development of the proliferating and hypertrophic compartment of the growth plate and the perichondrium/periosteum. These studies will also provide insight into the mechanisms underlying human genetic diseases. To accomplish these goals we will specifically disrupt FGFR signaling in each compartment of developing bone versus tissue-specifically expressed cre recombinase and conditionally targeted FGFRs. To test for signaling differences versus ligand specificity differences we will expand the domain of FGFR1 expression in the growth plate to encompass that of FGFR3. Additionally objectives will be to identify physiologically relevant FGF ligands involved in chondrogenesis, cranial suture growth and perichondrium/periosteum growth and to examine the biochemical function of a mutation in FGFR2 that causes Aperts syndrome.
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