Alternative titles; symbols
HGNC Approved Gene Symbol: FGF7
Cytogenetic location: 15q21.2 Genomic coordinates (GRCh38): 15:49,423,242-49,488,775 (from NCBI)
Rubin et al. (1989) identified a growth factor specific for epithelial cells in conditioned medium of a human embryonic lung fibroblast cell line. Because of its predominant activity in keratinocytes, it was referred to as keratinocyte growth factor. KGF was found to consist of a single polypeptide chain of about 28 kD. In an addendum, Rubin et al. (1989) noted that by use of all the nucleotide probes based on the N-terminal sequence reported in their paper, they had isolated clones encoding KGF and had found significant structural homology between KGF and 5 known members of the fibroblast growth factor (FGF) family.
Rubin et al. (1989) found that KGF was a potent mitogen for epithelial cells but lacked mitogenic activity on either fibroblasts or endothelial cells. The release of this growth factor by human embryonic fibroblasts raised the possibility that KGF may play a role in mesenchymal stimulation of normal epithelial cell proliferation.
Werner et al. (1994) assessed the function of KGF in normal and wounded skin by expression of a dominant-negative KGF receptor (FGFR2; 176943) in basal keratinocytes. The skin of transgenic mice was characterized by epidermal atrophy, abnormalities in the hair follicles, and dermal hyperthickening. Upon skin injury, inhibition of KGF receptor signaling reduced the proliferation rate of epidermal keratinocytes at the wound edge, resulting in substantially delayed reepithelialization of the wound.
Oxidant-induced injury to the lung is associated with extensive damage to the lung epithelium. Instillation of KGF into the lungs of animals protects animals from oxidant-induced injury. An inherent problem in studying KGF function in vivo is that constitutive overexpression of KGF in the lung causes embryonic lethality with extensive pulmonary malformation. Ray et al. (2003) reported the development of a stringently regulated, tetracycline-inducible, lung-specific transgene system that allows regulated expression of KGF in the lung without causing developmental abnormalities from leaky KGF expression. Using this system, they showed that exposure of KGF-expressing mice to hyperoxia protects the lung epithelium but not the endothelium from cell death in accordance with the selective expression of KGF receptor on epithelial and not on endothelial cells. Investigations of KGF-induced cell survival pathways revealed KGF-induced activation of the multifunctional prosurvival Akt (AKT1; 164730) signaling axis both in vitro and in vivo. Inhibition of KGF-induced Akt activation by a dominant-negative mutant of Akt blocked the KGF-mediated protection of epithelial cells exposed to hyperoxia. KGF-induced Akt activation may play an important role in inhibiting lung alveolar cell death, thereby preserving the lung architecture and function during oxidative stress.
Using clustering of synaptic vesicles in cultured neurons as an assay, Umemori et al. (2004) purified putative target-derived presynaptic organizing molecules from mouse brain and identified Fgf22 (605831) as a major active species. Fgf7 and Fgf10 (602115), the closest relatives of Fgf22, shared this activity; other Fgfs had distinct effects. Neutralization of Fgf7, Fgf10, and Fgf22 inhibited presynaptic differentiation of mossy fibers at sites of contact with granule cells in vivo. Inactivation of Fgfr2 had similar effects. These results indicated that FGF22 and its relatives are presynaptic organizing molecules in the mammalian brain.
Terauchi et al. (2010) demonstrated that 2 members of the fibroblast growth factor family, FGF22 and FGF7, promote the organization of excitatory and inhibitory presynaptic terminals, respectively, as target-derived presynaptic organizers. In situ hybridization showed that Fgf22 and Fgf7 are expressed by CA3 pyramidal neurons in the mouse hippocampus. The differentiation of excitatory or inhibitory nerve terminals on dendrites of CA3 pyramidal neurons was specifically impaired in mutants lacking Fgf22 or Fgf7. Their presynaptic defects were rescued by postsynaptic expression of the appropriate FGF. Fgf22-deficient mice are resistant to epileptic seizures, and Fgf7-deficient mice are prone to them, as expected from the alterations in excitatory/inhibitory balance. Terauchi et al. (2010) demonstrated that differential effects of Fgf22 and Fgf7 involve both their distinct synaptic localizations and their use of different signaling pathways. Terauchi et al. (2010) concluded that specific FGFs act as target-derived presynaptic organizers and help to organize specific presynaptic terminals in the mammalian brain.
Mattei et al. (1995) used isotopic in situ hybridization to map Fgf7 to region F-G of mouse chromosome 2. By analysis of DNA from human-rodent somatic cell hybrids with an exon 1 probe, Kelley et al. (1992) found that FGF7 is located on human chromosome 15. Mouse chromosome 2 presents a conserved region of synteny with 15q13-q22. Thus, the human mutation may reside at this site. Using the murine Fgf7 probe for in situ hybridization to human metaphase chromosomes, Mattei et al. (1995) found signals on chromosome 15. Kelley et al. (1992) found a portion of the KGF gene (composed of exons 2 and 3, the intron between them, and a 3-prime noncoding segment) that was amplified to approximately 16 copies in the human genome and distributed to multiple chromosomes.
Using a cosmid probe encoding KGF exon 1 for fluorescence in situ hybridization, Zimonjic et al. (1997) assigned the KGF7 gene to 15q15-q21.1. In addition, copies of KGF-like sequences hybridizing only with a cosmid probe encoding exons 2 and 3 were localized to dispersed sites on chromosome 2q21, 9p11, 9q12-q13, 18p11, 18q11, 21q11, and 21q21.1. The distribution of KGF-like sequences suggested a role for alphoid DNA in their amplification and dispersion. In chimpanzee, KGF-like sequences were observed at 5 chromosomal sites, which were each homologous to sites in human, while in gorilla a subset of 4 of these homologous sites was identified. In orangutan 2 sites were identified, while gibbon exhibited only a single site. The chromosomal localization of KGF sequences in human and great ape genomes indicated that amplification and dispersion occurred in multiple discrete steps, with initial KGF gene duplication and dispersion occurring in multiple discrete steps, with initial KGF gene duplication and dispersion taking place in gibbon and involving loci corresponding to human chromosomes 15 and 21. The findings of Zimonjic et al. (1997) supported the concept of a closer evolutionary relationship of human with chimpanzee and with primates and a possible selective pressure for KGF dispersion during the evolution of higher primates.
Kelley, M. J., Pech, M., Seuanez, H. N., Rubin, J. S., O'Brien, S. J., Aaronson, S. A. Emergence of the keratinocyte growth factor multigene family during the great ape radiation. Proc. Nat. Acad. Sci. 89: 9287-9291, 1992. [PubMed: 1409637] [Full Text: https://doi.org/10.1073/pnas.89.19.9287]
Mattei, M.-G., deLapeyriere, O., Bresnick, J., Dickson, C., Birnbaum, D., Mason, I. Mouse Fgf7 (fibroblast growth factor 7) and Fgf8 (fibroblast growth factor 8) genes map to chromosomes 2 and 19 respectively. Mammalian Genome 6: 196-197, 1995. [PubMed: 7749227] [Full Text: https://doi.org/10.1007/BF00293012]
Ray, P., Devaux, Y., Stolz, D. B., Yarlagadda, M., Watkins, S. C., Lu, Y., Chen, L., Yang, X., Ray, A. Inducible expression of keratinocyte growth factor (KGF) in mice inhibits lung epithelial cell death induced by hyperoxia. Proc. Nat. Acad. Sci. 100: 6098-6103, 2003. [PubMed: 12732722] [Full Text: https://doi.org/10.1073/pnas.1031851100]
Rubin, J. S., Osada, H., Finch, P. W., Taylor, W. G., Rudikoff, S., Aaronson, S. A. Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc. Nat. Acad. Sci. 86: 802-806, 1989. [PubMed: 2915979] [Full Text: https://doi.org/10.1073/pnas.86.3.802]
Terauchi, A., Johnson-Venkatesh, E. M., Toth, A. B., Javed, D., Sutton, M. A., Umemori, H. Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature 465: 783-787, 2010. [PubMed: 20505669] [Full Text: https://doi.org/10.1038/nature09041]
Umemori, H., Linhoff, M. W., Ornitz, D. M., Sanes, J. R. FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell 118: 257-270, 2004. [PubMed: 15260994] [Full Text: https://doi.org/10.1016/j.cell.2004.06.025]
Werner, S., Smola, H., Liao, X., Longaker, M. T., Krieg, T., Hofschneider, P. H., Williams, L. T. The function of KGF in morphogenesis of epithelium and reepithelialization of wounds. Science 266: 819-822, 1994. [PubMed: 7973639] [Full Text: https://doi.org/10.1126/science.7973639]
Zimonjic, D. B., Kelley, M. J., Rubin, J. S., Aaronson, S. A., Popescu, N. C. Fluorescence in situ hybridization analysis of keratinocyte growth factor gene amplification and dispersion in evolution of great apes and humans. Proc. Nat. Acad. Sci. 94: 11461-11465, 1997. [PubMed: 9326632] [Full Text: https://doi.org/10.1073/pnas.94.21.11461]