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Gene Review

Fgf3  -  fibroblast growth factor 3

Mus musculus

Synonyms: FGF-3, Fgf-3, Fibroblast growth factor 3, HBGF-3, Heparin-binding growth factor 3, ...
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Disease relevance of Fgf3


High impact information on Fgf3

  • In mouse, mesodermal Fgf10 acting redundantly with neural Fgf3 is required for induction of the placode [6].
  • In one tumor, the amplified region of chromosome 7 had an ectopically expressed int-2/FGF3 proto-oncogene, a gene known to cooperate with Wnt-1 in the production of mammary tumors [7].
  • METHODS: Using in situ hybridization with 35S-labeled RNA antisense probes that specifically detect mRNA coding for the Int-2 protein, we determined the cell-specific localization of int-2 mRNA expression in the mammary gland of transgenic FVB/N mice overexpressing int-2 mRNA [8].
  • CONCLUSION: Given the limitations of our experimental system and the limited information available to date on the secretion of Int-2 protein, these results suggest that, although the Int-2 protein contains a putative signal peptide, it may act primarily as an autocrine or as an ultra-short-range paracrine growth factor in mammary epithelium [8].
  • PURPOSE: Assuming that the Int-2 protein is secreted from mammary epithelial cells in a basolateral direction so that it is available to affect adjacent cells, we investigated whether it acts in a paracrine manner, exerting its effect externally on adjacent cells, or in an autocrine manner, exerting its effect internally within the same cell [8].

Biological context of Fgf3

  • Shh expression in mutant enamel knots was not rescued by FGFs in vitro, indicating that in addition to Fgf3, Runx2 regulates other mesenchymal genes required for early tooth morphogenesis [9].
  • These findings provide further evidence that fibroblast growth factors Int-2 and Hst can cooperate with Wnt-1, another secreted factor, in mammary tumorigenesis, and they illustrate the capacity of this system to identify cooperating oncogenes [10].
  • Expression analysis of FGF10 during mouse embryogenesis reveals a highly dynamic pattern of expression in the developing hindbrain, partially overlapping with FGF3 expression and coinciding with formation of the inner ear [11].
  • These data strengthen the link between Fgf-3 and a pregnancy-dependent phenotype and suggest that, in the strains analyzed, the frequency of Int-gene activation was influenced more by the hormonal status than by the genetic background [12].
  • Down-regulation of Fgf-3 and Fgf-10 expression in postmitotic odontoblasts correlated with the terminal differentiation of the odontoblasts and the neighboring ameloblasts [13].

Anatomical context of Fgf3

  • Moreover, dental epithelium as well as beads soaked in FGF1, FGF2 or FGF8 induce Fgf3 expression in dental mesenchyme in an Msx1-dependent manner [14].
  • Fgf3 has long been implicated in otic placode induction and early development of the otocyst; however, the results of experiments in mouse and chick embryos to determine its function have proved to be conflicting [15].
  • A comparison of two mammary epithelial cell lines showed a marked difference of potency and dependence upon heparin in their response to mouse Fgf3, suggesting a complex interaction between the ligand and its low and high affinity receptors [5].
  • Our results show that this in vivo model of multistep tumorigenesis reveals significant differences in the activation rates of Fgf3 and Fgf8 depending upon the status of Wnt1 expression in the mammary gland [16].
  • The expression of Fgf3 was downregulated in the mesenchyme of Runx2 mutant teeth [9].

Associations of Fgf3 with chemical compounds

  • In the mouse, insertion of a neomycin resistance gene into the Fgf3 gene via homologous recombination results in severe developmental defects during differentiation of the otic vesicle [11].
  • Heparin or heparan sulfate displaces FGF3 from binding sites on the cell surface inhibiting the growth of DMI cells and reverts the transformed phenotype () [17].
  • Because NIH3T3 cells do not express the high affinity tyrosine kinase FGF receptors for FGF3, these findings suggest that FGF3 attached to GPI-linked heparan sulfate-proteoglycan may have a broader biological activity as when bound to transmembrane or soluble heparan sulfate-proteoglycan [17].
  • The manifestations elicited by FGF-3 could be reversed by RU486 withdrawal [18].
  • In addition, synergism between the stimulus from estrogen and FGF-3 mitogenic pathways was evident and likely contributes to the pregnancy-dependent tumorigenesis of FGF-3 [18].

Physical interactions of Fgf3

  • Using a receptor binding competition assay, Fgf3 was shown to bind with high affinity to the IIIb isoforms of Fgf receptor (FgfR) 1 and FgfR2 (ID50 = approximately 0.8 nM) and with a lower affinity to the IIIc variant of FgfR2 (ID50 = approximately 9 nM) [5].

Regulatory relationships of Fgf3

  • However, only Sox7 expression markedly activated the Fgf-3 promoter in these cells [19].
  • FGF-3 also up-regulated the production of plasminogen activators [20].
  • Interestingly, FGF-3 production greatly stimulated the synthesis of pro-MMP-9 (Matrix Metalloprotease-9) and, to a lesser extent, that of pro-MMP-2 [20].

Other interactions of Fgf3

  • Fgf8, Fgf3 and Fgf4 were found to be activated in 11%, 80% and 5%, respectively, of the tumors in the combined nontransgenic groups [16].
  • FGF3 to 5 and FGF7 RNA were not detected in fetal or postnatal lung [21].
  • In a study of formation of the stem-cell compartment, we focused on expression patterns of fibroblast growth factor (Fgf) 10 and Fgf3 in developing mice incisors [22].
  • The expression domains of Krox-20 and Fgf-3 are also displaced in a rostral direction and the intensity of Fgf-3 hybridization is greatly reduced [23].
  • This appears to result in a failure to establish an ectodermal signalling center expressing Fgf3 and Fgf15 [24].

Analytical, diagnostic and therapeutic context of Fgf3


  1. Disregulation of ocular morphogenesis by lens-specific expression of FGF-3/int-2 in transgenic mice. Robinson, M.L., Ohtaka-Maruyama, C., Chan, C.C., Jamieson, S., Dickson, C., Overbeek, P.A., Chepelinsky, A.B. Dev. Biol. (1998) [Pubmed]
  2. Regulatory analysis of the mouse Fgf3 gene: control of embryonic expression patterns and dependence upon sonic hedgehog (Shh) signalling. Powles, N., Marshall, H., Economou, A., Chiang, C., Murakami, A., Dickson, C., Krumlauf, R., Maconochie, M. Dev. Dyn. (2004) [Pubmed]
  3. Phenotypic consequences of lung-specific inducible expression of FGF-3. Zhao, B., Chua, S.S., Burcin, M.M., Reynolds, S.D., Stripp, B.R., Edwards, R.A., Finegold, M.J., Tsai, S.Y., DeMayo, F.J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  4. Expression and function of FGF-4 in peri-implantation development in mouse embryos. Rappolee, D.A., Basilico, C., Patel, Y., Werb, Z. Development (1994) [Pubmed]
  5. Receptor binding and mitogenic properties of mouse fibroblast growth factor 3. Modulation of response by heparin. Mathieu, M., Chatelain, E., Ornitz, D., Bresnick, J., Mason, I., Kiefer, P., Dickson, C. J. Biol. Chem. (1995) [Pubmed]
  6. FGF8 initiates inner ear induction in chick and mouse. Ladher, R.K., Wright, T.J., Moon, A.M., Mansour, S.L., Schoenwolf, G.C. Genes Dev. (2005) [Pubmed]
  7. Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability. Donehower, L.A., Godley, L.A., Aldaz, C.M., Pyle, R., Shi, Y.P., Pinkel, D., Gray, J., Bradley, A., Medina, D., Varmus, H.E. Genes Dev. (1995) [Pubmed]
  8. Int-2, an autocrine and/or ultra-short-range effector in transgenic mammary tissue transplants. Ornitz, D.M., Cardiff, R.D., Kuo, A., Leder, P. J. Natl. Cancer Inst. (1992) [Pubmed]
  9. Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis. Aberg, T., Wang, X.P., Kim, J.H., Yamashiro, T., Bei, M., Rice, R., Ryoo, H.M., Thesleff, I. Dev. Biol. (2004) [Pubmed]
  10. Mouse mammary tumor virus infection accelerates mammary carcinogenesis in Wnt-1 transgenic mice by insertional activation of int-2/Fgf-3 and hst/Fgf-4. Shackleford, G.M., MacArthur, C.A., Kwan, H.C., Varmus, H.E. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  11. Requirements for FGF3 and FGF10 during inner ear formation. Alvarez, Y., Alonso, M.T., Vendrell, V., Zelarayan, L.C., Chamero, P., Theil, T., Bösl, M.R., Kato, S., Maconochie, M., Riethmacher, D., Schimmang, T. Development (2003) [Pubmed]
  12. Mouse mammary-tumor virus activates Fgf-3/Int-2 less frequently in tumors from virgin than from parous mice. Clausse, N., Smith, R., Calberg-Bacq, C.M., Peters, G., Dickson, C. Int. J. Cancer (1993) [Pubmed]
  13. Associations of FGF-3 and FGF-10 with signaling networks regulating tooth morphogenesis. Kettunen, P., Laurikkala, J., Itäranta, P., Vainio, S., Itoh, N., Thesleff, I. Dev. Dyn. (2000) [Pubmed]
  14. FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development. Bei, M., Maas, R. Development (1998) [Pubmed]
  15. Fgf3 and Fgf8 are required together for formation of the otic placode and vesicle. Maroon, H., Walshe, J., Mahmood, R., Kiefer, P., Dickson, C., Mason, I. Development (2002) [Pubmed]
  16. Preferential activation of Fgf8 by proviral insertion in mammary tumors of Wnt1 transgenic mice. Kapoun, A.M., Shackleford, G.M. Oncogene (1997) [Pubmed]
  17. FGF3 attached to a phosholipid membrane anchor gains a high transforming capacity. Implications of microdomains for FGF3 cell transformation. Köhl, R., Antoine, M., Reimers, K., Kiefer, P. J. Biol. Chem. (2002) [Pubmed]
  18. Inducible expression of FGF-3 in mouse mammary gland. Ngan, E.S., Ma, Z.Q., Chua, S.S., DeMayo, F.J., Tsai, S.Y. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  19. SOX7 and GATA-4 are competitive activators of Fgf-3 transcription. Murakami, A., Shen, H., Ishida, S., Dickson, C. J. Biol. Chem. (2004) [Pubmed]
  20. FGF-3 and FGF-4 elicit distinct oncogenic properties in mouse mammary myoepithelial cells. Hajitou, A., Baramova, E.N., Bajou, K., Noë, V., Bruyneel, E., Mareel, M., Collette, J., Foidart, J.M., Calberg-Bacq, C.M. Oncogene (1998) [Pubmed]
  21. Differential expression of fibroblast growth factor receptors 1 to 4 and ligand genes in late fetal and early postnatal rat lung. Powell, P.P., Wang, C.C., Horinouchi, H., Shepherd, K., Jacobson, M., Lipson, M., Jones, R. Am. J. Respir. Cell Mol. Biol. (1998) [Pubmed]
  22. FGF10 maintains stem cell population during mouse incisor development. Harada, H., Toyono, T., Toyoshima, K., Ohuchi, H. Connect. Tissue Res. (2002) [Pubmed]
  23. Altered rhombomere-specific gene expression and hyoid bone differentiation in the mouse segmentation mutant, kreisler (kr). Frohman, M.A., Martin, G.R., Cordes, S.P., Halamek, L.P., Barsh, G.S. Development (1993) [Pubmed]
  24. Fibroblast growth factor signalling and regional specification of the pharyngeal ectoderm. Trokovic, N., Trokovic, R., Partanen, J. Int. J. Dev. Biol. (2005) [Pubmed]
  25. An essential role for Fgfs in endodermal pouch formation influences later craniofacial skeletal patterning. Crump, J.G., Maves, L., Lawson, N.D., Weinstein, B.M., Kimmel, C.B. Development (2004) [Pubmed]
  26. A preferred region for integration of Friend murine leukemia virus in hematopoietic neoplasms is closely linked to the Int-2 oncogene. Silver, J., Buckler, C.E. J. Virol. (1986) [Pubmed]
  27. Common proviral integration region on mouse chromosome 7 in lymphomas and myelogenous leukemias induced by Friend murine leukemia virus. Silver, J., Kozak, C. J. Virol. (1986) [Pubmed]
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