REGULATION OF BONE DEVELOPMENT BY FGF SIGNALING

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DESCRIPTION (provided by applicant): The family of fibroblast growth factors (FGFs) and cognate receptors (FGFR) plays an important role in a large number of developmental processes, including sketal development. Activating mutations in FGFR1-3 cause a number of human bone morphogenetic disorders, including dwarfism and craniosynostosis syndromes, by affecting the proliferation and differentiation of chondrocytes and osteoblasts, the two major cell types responsible for bone formation. The main focus of this project is to investigate the mechanisms and identify the key events which detrmine the response of chondrocytes to FGF signaling. Elucidating these mechansims should shed light on the physiological and pathological role of FGF signaling in bone development. Our previous studies have shown that proliferating chondrocytes respond to FGF with growth- inhibition and that this inhibition requires STAT1 function, both in vitro and in vivo. FGF also induces some aspects of hypertrophic differentiation, including apoptosis. In addition to STAT1, we have shown that FGF- mediated growth inhibition also requires the retinoblastoma proteins p107 and p130, and that p107 dephosphorylation is an early critical event in the FGF response of choncrocytes. We have also recently uncovered a novel role for STAT3 in endochondral ossification. The goals of this project are: 1) To study the role and the mechanism of p107 dephosphorylation in the FGF response of chondrocytes, and whether a specific activation of the PP2A phosphatase by FGF is responsible for p107 dephosphorylation. 2) To study further FGF signaling in chondrocytes to understand the role that STAT1 plays in the FGF response. We will determine whether STAT1 regulates the growth-inhibitory response to FGF by a transcriptional or non- transcriptional mechanism and identify the genes whose activation or downregulation of expression by FGF requires STAT1 function. 3) To investigate the role of STATS in bone development and the response of chondrocytes to FGF. We have found that a conditional knockout of STATS in chondrocytes reduces proliferation, and accelerates differentiation and apoptosis in the growth plate. We will study the mechanisms of this effect and the hypothesis that STAT1 and STATS play opposite roles in chondrocyte proliferatin and differentiation.