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Gene Review

Fgf9  -  fibroblast growth factor 9

Mus musculus

Synonyms: Eks, FGF-9, Fgf-9, Fibroblast growth factor 9, GAF, ...
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Disease relevance of Fgf9

  • The observations provide evidence that targeted, in vivo activation of endogenous FGFR3 inhibits bone growth and demonstrate that signals derived from FGF9-FGFR3 interactions can physiologically block endochondral ossification to produce a phenotype characteristic of the achondroplasia group of human chondrodysplasias [1].
  • FGF9 was originally isolated from a culture medium of a human glioma cell line as a growth-promoting factor for glial cells [5] [2].
  • Retinoic acid induces gene expression of fibroblast growth factor-9 during induction of neuronal differentiation of mouse embryonal carcinoma P19 cells [2].
  • To begin to understand the developmental role of FGF-9/glial activating factor, we have cloned and sequenced the murine FGF-9 cDNA and expressed the protein in mammalian cells and in Escherichia coli [3].
  • In PDE2 binding of cGMP to the GAF domain causes an activation of the catalytic activity by a mechanism that apparently is shared even in the adenylyl cyclase of Anabaena, an organism separated from mouse by 2 billion years of evolution [4].

High impact information on Fgf9

  • Fgf9 appears to act downstream of Sry to stimulate mesenchymal proliferation, mesonephric cell migration, and Sertoli cell differentiation in the embryonic testis [5].
  • Reproductive system phenotypes range from testicular hypoplasia to complete sex reversal, with most Fgf9(-/-) XY reproductive systems appearing grossly female at birth [5].
  • Here we report male-to-female sex reversal in mice lacking Fibroblast growth factor 9 (Fgf9), demonstrating a novel role for FGF signaling in testicular embryogenesis [5].
  • In mice, loss of function of Fgf4 (refs 13,14), Fgf9 (D. Ornitz, pers. comm.) or Fgf17 (ref. 15) has no effect on limb formation [6].
  • However, we demonstrate that cGMP can directly activate PDE5 without phosphorylation in platelet cytosol, most likely via binding to the regulatory GAF domains [7].

Chemical compound and disease context of Fgf9


Biological context of Fgf9


Anatomical context of Fgf9

  • Fgf9(-/-) lungs exhibit reduced mesenchyme and decreased branching of airways, but show significant distal airspace formation and pneumocyte differentiation [16].
  • In embryonic lung, Fgf9 is detected in airway epithelium and visceral pleura at E10.5, but is restricted to the pleura by E12 [16].
  • Fgf9 null (Fgf9(-/-)) mouse embryos have agenesis of the embryonic cecum, lacking both mesenchymal expansion and an epithelial bud [17].
  • In the mouse, Fgf9 and Wnt4 are expressed in gonads of both sexes prior to sex determination [18].
  • FGF-9 may also be involved in differentiation of odontoblasts [19].

Associations of Fgf9 with chemical compounds

  • Moreover, receptor binding of FGF9 requires heparin in a manner specific to the receptor type [20].
  • The amino acid sequence of proteins purified from culture supernatant of the CHO cell line, which was cDNA transfected and selected as a high producer of FGF-9, showed that no peptides were cleaved from the N terminus except the initiation methionine [8].
  • Two cysteine residues and other consensus sequences in family members were also well conserved in the FGF-9 sequence [8].
  • However, treatment with IFN-gamma in the presence of protein tyrosine phosphatase inhibitor vanadate blocked the decrease in GAF activity [21].
  • The C3H/HeJ mice have been used, therefore, as assay animals to establish that peak levels of GAF appear in donor serum about 2 h after an injection of lipopolysaccharide, and it is produced intraperitoneally in C3H/HeJ mice given a mixture of endotoxin and peritoneal exudate cells derived from responder mice [22].

Regulatory relationships of Fgf9


Other interactions of Fgf9

  • The reduction in the amount of mesenchyme in Fgf9(-/-) lungs limits expression of mesenchymal Fgf10 [16].
  • Fgf-8 and Fgf-9 mRNAs were present in the oral epithelium of the first branchial arch at E10 and 1 day later expression became more restricted to the area of presumptive dental epithelium and persisted there until the start of epithelial budding [19].
  • Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads [18].
  • FGF9 is found to bind with high affinity (kd: 0.25 nM) to FGFR3, for which a specific ligand has not yet been identified [20].
  • We identify FGF-9 as a particularly potent Sox9 agonist [24].

Analytical, diagnostic and therapeutic context of Fgf9


  1. Skeletal dysplasia and defective chondrocyte differentiation by targeted overexpression of fibroblast growth factor 9 in transgenic mice. Garofalo, S., Kliger-Spatz, M., Cooke, J.L., Wolstin, O., Lunstrum, G.P., Moshkovitz, S.M., Horton, W.A., Yayon, A. J. Bone Miner. Res. (1999) [Pubmed]
  2. Retinoic acid induces gene expression of fibroblast growth factor-9 during induction of neuronal differentiation of mouse embryonal carcinoma P19 cells. Seo, M., Noguchi, K. FEBS Lett. (1995) [Pubmed]
  3. Expression and biological activity of mouse fibroblast growth factor-9. Santos-Ocampo, S., Colvin, J.S., Chellaiah, A., Ornitz, D.M. J. Biol. Chem. (1996) [Pubmed]
  4. The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding. Martinez, S.E., Wu, A.Y., Glavas, N.A., Tang, X.B., Turley, S., Hol, W.G., Beavo, J.A. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  5. Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Colvin, J.S., Green, R.P., Schmahl, J., Capel, B., Ornitz, D.M. Cell (2001) [Pubmed]
  6. Fgf8 signalling from the AER is essential for normal limb development. Lewandoski, M., Sun, X., Martin, G.R. Nat. Genet. (2000) [Pubmed]
  7. Direct activation of PDE5 by cGMP: long-term effects within NO/cGMP signaling. Mullershausen, F., Friebe, A., Feil, R., Thompson, W.J., Hofmann, F., Koesling, D. J. Cell Biol. (2003) [Pubmed]
  8. Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property. Miyamoto, M., Naruo, K., Seko, C., Matsumoto, S., Kondo, T., Kurokawa, T. Mol. Cell. Biol. (1993) [Pubmed]
  9. The use of Reuber hepatoma cells for the study of a lipopolysaccharide-induced macrophage factor: glucocorticoid-antagonizing factor. Goodrum, K.J., Berry, L.J. Lab. Invest. (1979) [Pubmed]
  10. Purification and characteristics of glucocorticoid antagonizing factor in endotoxemia. Sakaguchi, S., Yokota, K. Microbiol. Immunol. (1987) [Pubmed]
  11. Fgf9 signaling regulates inner ear morphogenesis through epithelial-mesenchymal interactions. Pirvola, U., Zhang, X., Mantela, J., Ornitz, D.M., Ylikoski, J. Dev. Biol. (2004) [Pubmed]
  12. Genomic organization and embryonic expression of the mouse fibroblast growth factor 9 gene. Colvin, J.S., Feldman, B., Nadeau, J.H., Goldfarb, M., Ornitz, D.M. Dev. Dyn. (1999) [Pubmed]
  13. Sprouty2 is involved in male sex organogenesis by controlling fibroblast growth factor 9-induced mesonephric cell migration to the developing testis. Chi, L., Itäranta, P., Zhang, S., Vainio, S. Endocrinology (2006) [Pubmed]
  14. Molecular cloning and expression in gonad of Rana rugosa WT1 and Fgf9. Yamamura, Y., Aoyama, S., Oshima, Y., Kato, T., Osawa, N., Nakamura, M. Zool. Sci. (2005) [Pubmed]
  15. FGF9 promotes survival of germ cells in the fetal testis. Dinapoli, L., Batchvarov, J., Capel, B. Development (2006) [Pubmed]
  16. Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Colvin, J.S., White, A.C., Pratt, S.J., Ornitz, D.M. Development (2001) [Pubmed]
  17. Reciprocal epithelial-mesenchymal FGF signaling is required for cecal development. Zhang, X., Stappenbeck, T.S., White, A.C., Lavine, K.J., Gordon, J.I., Ornitz, D.M. Development (2006) [Pubmed]
  18. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. Kim, Y., Kobayashi, A., Sekido, R., DiNapoli, L., Brennan, J., Chaboissier, M.C., Poulat, F., Behringer, R.R., Lovell-Badge, R., Capel, B. PLoS Biol. (2006) [Pubmed]
  19. Expression and function of FGFs-4, -8, and -9 suggest functional redundancy and repetitive use as epithelial signals during tooth morphogenesis. Kettunen, P., Thesleff, I. Dev. Dyn. (1998) [Pubmed]
  20. Identification of fibroblast growth factor 9 (FGF9) as a high affinity, heparin dependent ligand for FGF receptors 3 and 2 but not for FGF receptors 1 and 4. Hecht, D., Zimmerman, N., Bedford, M., Avivi, A., Yayon, A. Growth Factors (1995) [Pubmed]
  21. The role of protein tyrosine phosphatase SHP-1 in the regulation of IFN-gamma signaling in neural cells. Massa, P.T., Wu, C. J. Immunol. (1996) [Pubmed]
  22. Elicitation of endotoxemic effects in C3H/HeJ mice with glucocorticoid antagonizing factor and partial characterization of the factor. Moore, R.N., Goodrum, K.J., Couch, R.E., Berry, L.J. Infect. Immun. (1978) [Pubmed]
  23. Tissue interactions pattern the mesenchyme of the embryonic mouse lung. Weaver, M., Batts, L., Hogan, B.L. Dev. Biol. (2003) [Pubmed]
  24. FGF signaling antagonizes cytokine-mediated repression of Sox9 in SW1353 chondrosarcoma cells. Schaefer, J.F., Millham, M.L., de Crombrugghe, B., Buckbinder, L. Osteoarthr. Cartil. (2003) [Pubmed]
  25. Overlapping effects of different members of the FGF family on lens fiber differentiation in transgenic mice. Lovicu, F.J., Overbeek, P.A. Development (1998) [Pubmed]
  26. FGF9 and SHH regulate mesenchymal Vegfa expression and development of the pulmonary capillary network. White, A.C., Lavine, K.J., Ornitz, D.M. Development (2007) [Pubmed]
  27. Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis. Barnard, J.C., Williams, A.J., Rabier, B., Chassande, O., Samarut, J., Cheng, S.Y., Bassett, J.H., Williams, G.R. Endocrinology (2005) [Pubmed]
  28. Generation of an Fgf9 conditional null allele. Lin, Y., Liu, G., Wang, F. Genesis (2006) [Pubmed]
  29. Expression patterns of fibroblast growth factors-18 and -20 in mouse embryos is suggestive of novel roles in calvarial and limb development. Hajihosseini, M.K., Heath, J.K. Mech. Dev. (2002) [Pubmed]
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