This is a five year RO1 proposal to study the role of FGFR3 and FGF9 in bone development. The objectives of this proposal are to determine how FGFR3 regulates chondrogenesis and how it interacts with other signalling molecules thought to be important for endochondral ossification and to identify the physiological ligands that activate FGFR3 in vivo during endochondral ossification.
The first aim will explore the expression of FGFR3 in the growth plates of normal mice using a transgenic mouse in which the LacZ gene is under control of the FGFR3 promoter and by immunohistochemistry.
The second aim explores whether ligand affinity is altered by the Ach and TD mutation and whether chondrocyte gene activity is altered in culture.
The third aim will ascertain by RT-PCR which FGFs are present in the adult growth plate. In the fourth aim it is proposed to complete a catalog of the expression of FGF9 by organ system ISH, RNAse protection assay, immunolocalization, FGF9-LacZ transgenic and the FGF9 gene structure will be completed.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Javois, Lorette Claire
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Washington University
Other Basic Sciences
Schools of Medicine
Saint Louis
United States
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Wang, Q; Green, R P; Zhao, G et al. (2001) Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains. Development 128:3867-76
Ornitz, D M; Itoh, N (2001) Fibroblast growth factors. Genome Biol 2:REVIEWS3005
Colvin, J S; Green, R P; Schmahl, J et al. (2001) Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104:875-89
Ibrahimi, O A; Eliseenkova, A V; Plotnikov, A N et al. (2001) Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome. Proc Natl Acad Sci U S A 98:7182-7
Ornitz, D M (2001) Regulation of chondrocyte growth and differentiation by fibroblast growth factor receptor 3. Novartis Found Symp 232:63-76; discussion 76-80, 272-82
Henderson, J E; Naski, M C; Aarts, M M et al. (2000) Expression of FGFR3 with the G380R achondroplasia mutation inhibits proliferation and maturation of CFK2 chondrocytic cells. J Bone Miner Res 15:155-65
Ornitz, D M (2000) FGFs, heparan sulfate and FGFRs: complex interactions essential for development. Bioessays 22:108-12
Yu, K; Herr, A B; Waksman, G et al. (2000) Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome. Proc Natl Acad Sci U S A 97:14536-41
McEwen, D G; Green, R P; Naski, M C et al. (1999) Fibroblast growth factor receptor 3 gene transcription is suppressed by cyclic adenosine 3',5'-monophosphate. Identification of a chondrocytic regulatory element. J Biol Chem 274:30934-42
Chellaiah, A; Yuan, W; Chellaiah, M et al. (1999) Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity. J Biol Chem 274:34785-94

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