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Gene Review

Fgf4  -  fibroblast growth factor 4

Mus musculus

Synonyms: FGF-4, Fgf-4, Fgfk, Fibroblast growth factor 4, HBGF-4, ...
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Disease relevance of Fgf4


High impact information on Fgf4

  • We report here that inactivating Fgf8 in early limb ectoderm causes a substantial reduction in limb-bud size, a delay in Shh expression, misregulation of Fgf4 expression, and hypoplasia or aplasia of specific skeletal elements [6].
  • Experiments in chicks suggested that SHH expression in the ZPA is maintained by FGF4 expression in the AER, and vice versa, providing a molecular mechanism for coordinating the activities of these two signalling centres [7].
  • 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].
  • Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development [7].
  • Expansion of trophoblast precursors is restored, however, by an Oct4 target gene product, fibroblast growth factor-4 [8].

Chemical compound and disease context of Fgf4


Biological context of Fgf4

  • We have analyzed the phenotype of Fgf8(-/-) embryos and discovered that they fail to express Fgf4 in the streak [11].
  • Downregulation or ectopic anterior expression of Fgf4 is also seen [12].
  • This conditional mutation was designed so that concomitant with inactivation of the Fgf4 gene by excision of all Fgf4-coding sequences, a reporter gene was activated in Fgf4-expressing cells, allowing assessment of the site-specific recombination reaction [13].
  • We show by mutational analysis that a conserved E box located in the Fgf4 myotome enhancer is required for Fgf4-lacZ expression in the myotomes [14].
  • Distinct regulatory elements govern Fgf4 gene expression in the mouse blastocyst, myotomes, and developing limb [15].

Anatomical context of Fgf4


Associations of Fgf4 with chemical compounds


Physical interactions of Fgf4

  • These results demonstrate that in these cells bFGF transforms cells by interacting with its receptor and that bFGF and hst/K-fgf may use the same receptor [24].
  • Sox-2 and Oct-3 bind to the enhancer and are required for the activation of the FGF-4 gene [25].
  • In this study, we demonstrate that both the oxidizing agent diamide and the alkylating agent N-ethylmaleimide inhibit the ability of Oct-1, Oct-3, Sp1, and several Sp1-related nuclear proteins to bind important cis-regulatory elements located in the FGF-4 gene [26].

Regulatory relationships of Fgf4


Other interactions of Fgf4


Analytical, diagnostic and therapeutic context of Fgf4


  1. Increasing Fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function. Lu, P., Minowada, G., Martin, G.R. Development (2006) [Pubmed]
  2. Isolation of cDNAs encoding four mouse FGF family members and characterization of their expression patterns during embryogenesis. Hébert, J.M., Basilico, C., Goldfarb, M., Haub, O., Martin, G.R. Dev. Biol. (1990) [Pubmed]
  3. Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Yuan, H., Corbi, N., Basilico, C., Dailey, L. Genes Dev. (1995) [Pubmed]
  4. Molecular biology of the hst-1 gene. Sugimura, T., Yoshida, T., Sakamoto, H., Katoh, O., Hattori, Y., Terada, M. Ciba Found. Symp. (1990) [Pubmed]
  5. The mouse homolog of the hst/k-FGF gene is adjacent to int-2 and is activated by proviral insertion in some virally induced mammary tumors. Peters, G., Brookes, S., Smith, R., Placzek, M., Dickson, C. Proc. Natl. Acad. Sci. U.S.A. (1989) [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. Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development. Sun, X., Lewandoski, M., Meyers, E.N., Liu, Y.H., Maxson, R.E., Martin, G.R. Nat. Genet. (2000) [Pubmed]
  8. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Nichols, J., Zevnik, B., Anastassiadis, K., Niwa, H., Klewe-Nebenius, D., Chambers, I., Schöler, H., Smith, A. Cell (1998) [Pubmed]
  9. All-trans-retinoic acid and hexamethylene bisacetamide (HMBA) regulate TGF-alpha and Hst-1/kFGF expression in differentiation sensitive but not in resistant human teratocarcinomas. Miller, W.H., Maerz, W.J., Kurie, J., Moy, D., Baselga, J., Lucas, D.A., Grippo, J.F., Masui, H., Dmitrovsky, E. Differentiation (1994) [Pubmed]
  10. Quantitative demonstration of spontaneous metastasis by MCF-7 human breast cancer cells cotransfected with fibroblast growth factor 4 and LacZ. Kurebayashi, J., McLeskey, S.W., Johnson, M.D., Lippman, M.E., Dickson, R.B., Kern, F.G. Cancer Res. (1993) [Pubmed]
  11. Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Sun, X., Meyers, E.N., Lewandoski, M., Martin, G.R. Genes Dev. (1999) [Pubmed]
  12. Embryonic retinoic acid synthesis is required for forelimb growth and anteroposterior patterning in the mouse. Niederreither, K., Vermot, J., Schuhbaur, B., Chambon, P., Dollé, P. Development (2002) [Pubmed]
  13. Normal limb development in conditional mutants of Fgf4. Moon, A.M., Boulet, A.M., Capecchi, M.R. Development (2000) [Pubmed]
  14. Activation of fgf4 gene expression in the myotomes is regulated by myogenic bHLH factors and by sonic hedgehog. Fraidenraich, D., Iwahori, A., Rudnicki, M., Basilico, C. Dev. Biol. (2000) [Pubmed]
  15. Distinct regulatory elements govern Fgf4 gene expression in the mouse blastocyst, myotomes, and developing limb. Fraidenraich, D., Lang, R., Basilico, C. Dev. Biol. (1998) [Pubmed]
  16. Multipotent cell lineages in early mouse development depend on SOX2 function. Avilion, A.A., Nicolis, S.K., Pevny, L.H., Perez, L., Vivian, N., Lovell-Badge, R. Genes Dev. (2003) [Pubmed]
  17. The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Boulet, A.M., Moon, A.M., Arenkiel, B.R., Capecchi, M.R. Dev. Biol. (2004) [Pubmed]
  18. Paracrine and autocrine effects of fibroblast growth factor-4 in endothelial cells. Dell'Era, P., Belleri, M., Stabile, H., Massardi, M.L., Ribatti, D., Presta, M. Oncogene (2001) [Pubmed]
  19. 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]
  20. Retinoic acid specifically downregulates Fgf4 and inhibits posterior cell proliferation in the developing mouse autopod. Hayes, C., Morriss-Kay, G.M. J. Anat. (2001) [Pubmed]
  21. Inhibition of DNA binding of Sox2 by the SUMO conjugation. Tsuruzoe, S., Ishihara, K., Uchimura, Y., Watanabe, S., Sekita, Y., Aoto, T., Saitoh, H., Yuasa, Y., Niwa, H., Kawasuji, M., Baba, H., Nakao, M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  22. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Ye, W., Shimamura, K., Rubenstein, J.L., Hynes, M.A., Rosenthal, A. Cell (1998) [Pubmed]
  23. Cell transformation by kFGF requires secretion but not glycosylation. Fuller-Pace, F., Peters, G., Dickson, C. J. Cell Biol. (1991) [Pubmed]
  24. Transformation of NIH 3T3 cells with basic fibroblast growth factor or the hst/K-fgf oncogene causes downregulation of the fibroblast growth factor receptor: reversal of morphological transformation and restoration of receptor number by suramin. Moscatelli, D., Quarto, N. J. Cell Biol. (1989) [Pubmed]
  25. The co-activator p300 associates physically with and can mediate the action of the distal enhancer of the FGF-4 gene. Nowling, T., Bernadt, C., Johnson, L., Desler, M., Rizzino, A. J. Biol. Chem. (2003) [Pubmed]
  26. Effects of oxidation and reduction on the binding of transcription factors to cis-regulatory elements located in the FGF-4 gene. Lickteig, K., Lamb, K., Brigman, K., Rizzino, A. Mol. Reprod. Dev. (1996) [Pubmed]
  27. Nodal protein processing and fibroblast growth factor 4 synergize to maintain a trophoblast stem cell microenvironment. Guzman-Ayala, M., Ben-Haim, N., Beck, S., Constam, D.B. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  28. Formin isoforms are differentially expressed in the mouse embryo and are required for normal expression of fgf-4 and shh in the limb bud. Chan, D.C., Wynshaw-Boris, A., Leder, P. Development (1995) [Pubmed]
  29. FGF-4 regulates expression of Evx-1 in the developing mouse limb. Niswander, L., Martin, G.R. Development (1993) [Pubmed]
  30. Fibroblast growth factor receptors 1 and 2 are differentially regulated in murine embryonal carcinoma cells and in response to fibroblast growth factor-4. Ali, J., Mansukhani, A., Basilico, C. J. Cell. Physiol. (1995) [Pubmed]
  31. 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]
  32. Interaction between the signaling molecules WNT7a and SHH during vertebrate limb development: dorsal signals regulate anteroposterior patterning. Yang, Y., Niswander, L. Cell (1995) [Pubmed]
  33. FGF-4 and BMP-2 have opposite effects on limb growth. Niswander, L., Martin, G.R. Nature (1993) [Pubmed]
  34. FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Kratochwil, K., Galceran, J., Tontsch, S., Roth, W., Grosschedl, R. Genes Dev. (2002) [Pubmed]
  35. Preferential activation of Fgf8 by proviral insertion in mammary tumors of Wnt1 transgenic mice. Kapoun, A.M., Shackleford, G.M. Oncogene (1997) [Pubmed]
  36. The suppression of fibroblast growth factor 2/fibroblast growth factor 4-dependent tumour angiogenesis and growth by the anti-growth factor activity of dextran derivative (CMDB7). Bagheri-Yarmand, R., Kourbali, Y., Mabilat, C., Morère, J.F., Martin, A., Lu, H., Soria, C., Jozefonvicz, J., Crépin, M. Br. J. Cancer (1998) [Pubmed]
  37. A conserved enhancer element that drives FGF4 gene expression in the embryonic myotomes is synergistically activated by GATA and bHLH proteins. Iwahori, A., Fraidenraich, D., Basilico, C. Dev. Biol. (2004) [Pubmed]
  38. Requirement of FGF-4 for postimplantation mouse development. Feldman, B., Poueymirou, W., Papaioannou, V.E., DeChiara, T.M., Goldfarb, M. Science (1995) [Pubmed]
  39. Differentially expressed fibroblast growth factors regulate skeletal muscle development through autocrine and paracrine mechanisms. Hannon, K., Kudla, A.J., McAvoy, M.J., Clase, K.L., Olwin, B.B. J. Cell Biol. (1996) [Pubmed]
  40. Hst-1 (FGF-4) antisense oligonucleotides block murine limb development. Ochiya, T., Sakamoto, H., Tsukamoto, M., Sugimura, T., Terada, M. J. Cell Biol. (1995) [Pubmed]
  41. An upstream NF-Y-binding site is required for transcriptional activation from the hst promoter in F9 embryonal carcinoma cells. Hasan, S., Koda, T., Kakinuma, M. J. Biol. Chem. (1994) [Pubmed]
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