Disease relevance of Fgf3

• FGF-3, originally named int-2, was discovered as an oncogene frequently activated in mammary carcinomas resulting from the chromosomal integration of the mouse mammary tumor virus (MMTV) [1].
• In the absence of Shh signalling, Fgf3 reporter expression is lost in the ventral CNS, DRG, and superior cervical nerves, whereas activation of reporter expression in cranial ganglion cells is Shh independent [2].
• High levels of FGF-3 expression resulted in diffuse alveolar type II cell hyperplasia [3].
• Conversely, differentiated embryonal carcinoma cells in the endoderm lineage express FGF-3, but not FGF-4 mRNA [4].
• fgf3 has been implicated in the embryonic and fetal development of the mouse and as an oncogene in murine breast cancer [5].

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

• In situ hybridization analysis showed developmentally regulated expression during tooth formation for Fgf-3 and Fgf-10 that was mainly restricted to the dental papilla mesenchymal cells [13].
• Transplantation and pharmacological experiments show that Fgf8 and Fgf3 are required in the neural keel and cranial mesoderm during early somite stages to promote first pouch formation [25].
• Int-2, an autocrine and/or ultra-short-range effector in transgenic mammary tissue transplants [8].
• Gene mapping experiments show that Fis-1, a preferred integration region for Friend murine leukemia virus in hematopoietic neoplasms, is extremely closely linked to Int-2, a preferred integration region for mouse mammary tumor virus in mammary carcinomas [26].
• Fis-1 is distinct from three oncogenes on mouse chromosome 7, Ha-ras, fes, and Int-2, based on restriction enzyme analysis and blot hybridization [27].

References