The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein was isolated as a secreted factor that exhibits a growth-stimulating effect on cultured glial cells. In nervous system, this protein is produced mainly by neurons and may be important for glial cell development. Expression of the mouse homolog of this gene was found to be dependent on Sonic hedgehog (Shh) signaling. Mice lacking the homolog gene displayed a male-to-female sex reversal phenotype, which suggested a role in testicular embryogenesis.[2] This gene is involved in the patterning of sex determination, lung development, and skeletal development.
Sex determination
FGF9 has also been shown to play a vital role in male sex development. FGF9’s role in sex determination begins with its expression in the bi-potent gonads for both females and males.[3] Once activated by SOX9, it is responsible for forming a feedforward loop with Sox9, increasing the levels of both genes. It forms a positive feedback loop upregulating SOX9, while simultaneously inactivating the female Wnt4 signaling pathway.[3] The absence of Fgf9 causes an individual, even an individual with X and Y chromosomes, to develop into a female, as it is needed to carry out important masculinizing developmental functions such as the multiplication of Sertoli cells and creation of the testis cords.[4]
Lung development
In lung development, FGF9 is expressed in the mesothelium and pulmonary epithelium, where its purpose is to retain lung mesenchymal proliferation. Inactivation of FGF9 results in diminished epithelial branching.[5] By the end of gestation, the lungs that are developed cannot sustain life and will result in a prenatal death.[5]
Skeletal development
Another biological role presented by this gene is its involvement in skeletal development and repair. FGF9 and FGF18 both stimulate chondrocyte proliferation.[6] FGF9 heterozygous mutant mice had a compromised bone repair after an injury with less expression of VEGF and VEGFR2 and lower osteoclast recruitment.[6] One disease associated with this gene is multiple synostoses syndrome (SYNS), a rare bone disease that has to do with the fusion of the fingers and toes.[7] A missense mutation in the second exon of the FGF9 gene, the S99N mutation, seems to be the third cause of SYNS.[8] A mutation in Noggin (NOG) and the Growth Differentiation Factor 5 (GDF5) are the other two causes of SYNS.[8] The S99N mutation results in cell signaling irregularities that interfere with chondrogenesis and osteogenesis causing the fusion of the joints during development.[8]
↑Santos-Ocampo S, Colvin JS, Chellaiah A, Ornitz DM (January 1996). "Expression and biological activity of mouse fibroblast growth factor-9". The Journal of Biological Chemistry. 271 (3): 1726–31. doi:10.1074/jbc.271.3.1726. PMID8576175.
↑Chellaiah A, Yuan W, Chellaiah M, Ornitz DM (December 1999). "Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity". The Journal of Biological Chemistry. 274 (49): 34785–94. doi:10.1074/jbc.274.49.34785. PMID10574949.
Further reading
Naruo K, Seko C, Kuroshima K, Matsutani E, Sasada R, Kondo T, Kurokawa T (February 1993). "Novel secretory heparin-binding factors from human glioma cells (glia-activating factors) involved in glial cell growth. Purification and biological properties". The Journal of Biological Chemistry. 268 (4): 2857–64. PMID8428960.
Mattei MG, Penault-Llorca F, Coulier F, Birnbaum D (October 1995). "The human FGF9 gene maps to chromosomal region 13q11-q12". Genomics. 29 (3): 811–2. doi:10.1006/geno.1995.9926. PMID8575785.
Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M (June 1996). "Receptor specificity of the fibroblast growth factor family". The Journal of Biological Chemistry. 271 (25): 15292–7. doi:10.1074/jbc.271.25.15292. PMID8663044.
Nakamura S, Todo T, Haga S, Aizawa T, Motoi Y, Ueki A, Kurokawa T, Ikeda K (January 1997). "Motor neurons in human and rat spinal cord synthesize fibroblast growth factor-9". Neuroscience Letters. 221 (2–3): 181–4. doi:10.1016/S0304-3940(96)13312-7. PMID9121694.
Todo T, Kondo T, Nakamura S, Kirino T, Kurokawa T, Ikeda K (February 1998). "Neuronal localization of fibroblast growth factor-9 immunoreactivity in human and rat brain". Brain Research. 783 (2): 179–87. doi:10.1016/S0006-8993(97)01340-1. PMID9507114.
Klein RD, Maliner-Jongewaard MS, Udayakumar TS, Boyd JL, Nagle RB, Bowden GT (December 1999). "Promatrilysin expression is induced by fibroblast growth factors in the prostatic carcinoma cell line LNCaP but not in normal primary prostate epithelial cells". The Prostate. 41 (4): 215–23. doi:10.1002/(SICI)1097-0045(19991201)41:4<215::AID-PROS1>3.0.CO;2-V. PMID10544294.
Plotnikov AN, Eliseenkova AV, Ibrahimi OA, Shriver Z, Sasisekharan R, Lemmon MA, Mohammadi M (February 2001). "Crystal structure of fibroblast growth factor 9 reveals regions implicated in dimerization and autoinhibition". The Journal of Biological Chemistry. 276 (6): 4322–9. doi:10.1074/jbc.M006502200. PMID11060292.
Hecht HJ, Adar R, Hofmann B, Bogin O, Weich H, Yayon A (March 2001). "Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces". Acta Crystallographica Section D. 57 (Pt 3): 378–84. doi:10.1107/S0907444900020813. PMID11223514.
Alizadeh M, Miyamura N, Handa JT, Hjelmeland LM (February 2003). "Human RPE cells express the FGFR2IIIc and FGFR3IIIc splice variants and FGF9 as a potential high affinity ligand". Experimental Eye Research. 76 (2): 249–56. doi:10.1016/S0014-4835(02)00252-X. PMID12565813.
Wing LY, Chuang PC, Wu MH, Chen HM, Tsai SJ (November 2003). "Expression and mitogenic effect of fibroblast growth factor-9 in human endometriotic implant is regulated by aberrant production of estrogen". The Journal of Clinical Endocrinology and Metabolism. 88 (11): 5547–54. doi:10.1210/jc.2003-030597. PMID14602803.
Popovici C, Conchonaud F, Birnbaum D, Roubin R (September 2004). "Functional phylogeny relates LET-756 to fibroblast growth factor 9". The Journal of Biological Chemistry. 279 (38): 40146–52. doi:10.1074/jbc.M405795200. PMID15199049.
Fakhry A, Ratisoontorn C, Vedhachalam C, Salhab I, Koyama E, Leboy P, Pacifici M, Kirschner RE, Nah HD (February 2005). "Effects of FGF-2/-9 in calvarial bone cell cultures: differentiation stage-dependent mitogenic effect, inverse regulation of BMP-2 and noggin, and enhancement of osteogenic potential". Bone. 36 (2): 254–66. doi:10.1016/j.bone.2004.10.003. PMID15780951.
