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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''Glia-activating factor''' is a [[protein]] that in humans is encoded by the ''FGF9'' [[gene]].<ref name="pmid8321227">{{cite journal | vauthors = Miyamoto M, Naruo K, Seko C, Matsumoto S, Kondo T, Kurokawa T | title = Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property | journal = Molecular and Cellular Biology | volume = 13 | issue = 7 | pages = 4251–9 | date = July 1993 | pmid = 8321227 | pmc = 359975 | doi =  }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: FGF9 fibroblast growth factor 9 (glia-activating factor)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2254| accessdate = }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image = PBB_Protein_FGF9_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1g82.
| PDB = {{PDB2|1g82}}, {{PDB2|1ihk}}
| Name = Fibroblast growth factor 9 (glia-activating factor)
| HGNCid = 3687
| Symbol = FGF9
| AltSymbols =; GAF; HBFG-9; MGC119914; MGC119915
| OMIM = 600921
| ECnumber = 
| Homologene = 1523
| MGIid = 104723
| GeneAtlas_image1 = PBB_GE_FGF9_206404_at_tn.png
| Function = {{GNF_GO|id=GO:0008083 |text = growth factor activity}} {{GNF_GO|id=GO:0008201 |text = heparin binding}}
| Component = {{GNF_GO|id=GO:0005615 |text = extracellular space}}
| Process = {{GNF_GO|id=GO:0000074 |text = regulation of progression through cell cycle}} {{GNF_GO|id=GO:0001525 |text = angiogenesis}} {{GNF_GO|id=GO:0002053 |text = positive regulation of mesenchymal cell proliferation}} {{GNF_GO|id=GO:0006606 |text = protein import into nucleus}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}} {{GNF_GO|id=GO:0008543 |text = fibroblast growth factor receptor signaling pathway}} {{GNF_GO|id=GO:0008584 |text = male gonad development}} {{GNF_GO|id=GO:0030154 |text = cell differentiation}} {{GNF_GO|id=GO:0030324 |text = lung development}} {{GNF_GO|id=GO:0042472 |text = inner ear morphogenesis}} {{GNF_GO|id=GO:0045880 |text = positive regulation of smoothened signaling pathway}} {{GNF_GO|id=GO:0050679 |text = positive regulation of epithelial cell proliferation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2254
    | Hs_Ensembl = ENSG00000102678
    | Hs_RefseqProtein = NP_002001
    | Hs_RefseqmRNA = NM_002010
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 13
    | Hs_GenLoc_start = 21143170
    | Hs_GenLoc_end = 21176637
    | Hs_Uniprot = P31371
    | Mm_EntrezGene = 14180
    | Mm_Ensembl = ENSMUSG00000021974
    | Mm_RefseqmRNA = NM_013518
    | Mm_RefseqProtein = NP_038546
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 14
    | Mm_GenLoc_start = 57027028
    | Mm_GenLoc_end = 57066447
    | Mm_Uniprot = Q3TPG0
  }}
}}
'''Fibroblast growth factor 9 (glia-activating factor)''', also known as '''FGF9''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: FGF9 fibroblast growth factor 9 (glia-activating factor)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2254| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
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 cell]]s. 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.<ref name="entrez" /> This gene is involved in the patterning of sex determination, lung development, and skeletal development.
{{PBB_Summary
| section_title =
| summary_text = 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.<ref name="entrez">{{cite web | title = Entrez Gene: FGF9 fibroblast growth factor 9 (glia-activating factor)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2254| accessdate = }}</ref>
}}


==References==
=== Sex determination ===
{{reflist|2}}
 
==Further reading==
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.<ref name=biomedcentral>{{cite journal | vauthors = Sánchez L, Chaouiya C | title = Primary sex determination of placental mammals: a modelling study uncovers dynamical developmental constraints in the formation of Sertoli and granulosa cells | journal = BMC Systems Biology | volume = 10 | issue = 1 | pages = 37 | date = May 2016 | pmid = 27229461 | doi = 10.1186/s12918-016-0282-3 }}</ref> 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.<ref name=biomedcentral/> The absence of Fgf9 causes an individual, even an individual with X and Y [[chromosome]]s, to develop into a female, as it is needed to carry out important masculinizing developmental functions such as the multiplication of [[Sertoli cell]]s and creation of the [[testis cords]].<ref name="pmid16700629">{{cite journal | vauthors = Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier MC, Poulat F, Behringer RR, Lovell-Badge R, Capel B | title = Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination | journal = PLoS Biology | volume = 4 | issue = 6 | pages = e187 | date = June 2006 | pmid = 16700629 | pmc = 1463023 | doi = 10.1371/journal.pbio.0040187 }}</ref>
{{refbegin | 2}}
 
{{PBB_Further_reading
=== Lung development ===
| citations =  
 
*{{cite journal  | author=Miyamoto M, Naruo K, Seko C, ''et al.'' |title=Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property. |journal=Mol. Cell. Biol. |volume=13 |issue= 7 |pages= 4251-9 |year= 1993 |pmid= 8321227 |doi= }}
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.<ref name=lung>{{cite journal | vauthors = Yin Y, Wang F, Ornitz DM | title = Mesothelial- and epithelial-derived FGF9 have distinct functions in the regulation of lung development | journal = Development | volume = 138 | issue = 15 | pages = 3169–77 | date = August 2011 | pmid = 21750028 | doi = 10.1242/dev.065110 }}</ref> By the end of gestation, the lungs that are developed cannot sustain life and will result in a prenatal death.<ref name=lung/>
*{{cite journal  | author=Naruo K, Seko C, Kuroshima K, ''et al.'' |title=Novel secretory heparin-binding factors from human glioma cells (glia-activating factors) involved in glial cell growth. Purification and biological properties. |journal=J. Biol. Chem. |volume=268 |issue= 4 |pages= 2857-64 |year= 1993 |pmid= 8428960 |doi= }}
 
*{{cite journal  | author=Mattei MG, Penault-Llorca F, Coulier F, Birnbaum D |title=The human FGF9 gene maps to chromosomal region 13q11-q12. |journal=Genomics |volume=29 |issue= 3 |pages= 811-2 |year= 1996 |pmid= 8575785 |doi= 10.1006/geno.1995.9926 }}
=== Skeletal development ===
*{{cite journal | author=Santos-Ocampo S, Colvin JS, Chellaiah A, Ornitz DM |title=Expression and biological activity of mouse fibroblast growth factor-9. |journal=J. Biol. Chem. |volume=271 |issue= 3 |pages= 1726-31 |year= 1996 |pmid= 8576175 |doi= }}
 
*{{cite journal | author=Ornitz DM, Xu J, Colvin JS, ''et al.'' |title=Receptor specificity of the fibroblast growth factor family. |journal=J. Biol. Chem. |volume=271 |issue= 25 |pages= 15292-7 |year= 1996 |pmid= 8663044 |doi= }}
Another biological role presented by this gene is its involvement in skeletal development and repair. FGF9 and [[FGF18]] both stimulate chondrocyte proliferation.<ref name=bone>{{cite journal | vauthors = Sivaraj KK, Adams RH | title = Blood vessel formation and function in bone | journal = Development | volume = 143 | issue = 15 | pages = 2706–15 | date = August 2016 | pmid = 27486231 | doi = 10.1242/dev.136861 }}</ref> FGF9 heterozygous mutant mice had a compromised bone repair after an injury with less expression of [[VEGF]] and [[VEGFR2]] and lower [[osteoclast]] recruitment.<ref name=bone/> 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.<ref>{{cite web | title = Multiple Synostoses Syndrome | url = http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=3237&lng=EN | website = Orphanet | accessdate = 16 April 2017 }}</ref> A missense mutation in the second exon of the FGF9 gene, the S99N mutation, seems to be the third cause of SYNS.<ref name=SYNS>{{cite journal | vauthors = Wu XL, Gu MM, Huang L, Liu XS, Zhang HX, Ding XY, Xu JQ, Cui B, Wang L, Lu SY, Chen XY, Zhang HG, Huang W, Yuan WT, Yang JM, Gu Q, Fei J, Chen Z, Yuan ZM, Wang ZG | display-authors = 6 | title = Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene | journal = American Journal of Human Genetics | volume = 85 | issue = 1 | pages = 53–63 | date = July 2009 | pmid = 19589401 | pmc = 2706969 | doi = 10.1016/j.ajhg.2009.06.007 }}</ref> A mutation in [[Noggin (protein)|Noggin]] (NOG) and the Growth Differentiation Factor 5 ([[GDF5]]) are the other two causes of SYNS.<ref name=SYNS/> The S99N mutation results in cell signaling irregularities that interfere with [[chondrogenesis]] and [[osteogenesis]] causing the fusion of the joints during development.<ref name=SYNS/>
*{{cite journal  | author=Nakamura S, Todo T, Haga S, ''et al.'' |title=Motor neurons in human and rat spinal cord synthesize fibroblast growth factor-9. |journal=Neurosci. Lett. |volume=221 |issue= 2-3 |pages= 181-4 |year= 1997 |pmid= 9121694 |doi= }}
 
*{{cite journal  | author=Todo T, Kondo T, Nakamura S, ''et al.'' |title=Neuronal localization of fibroblast growth factor-9 immunoreactivity in human and rat brain. |journal=Brain Res. |volume=783 |issue= 2 |pages= 179-87 |year= 1998 |pmid= 9507114 |doi=  }}
== Interactions ==
*{{cite journal  | author=Giri D, Ropiquet F, Ittmann M |title=FGF9 is an autocrine and paracrine prostatic growth factor expressed by prostatic stromal cells. |journal=J. Cell. Physiol. |volume=180 |issue= 1 |pages= 53-60 |year= 1999 |pmid= 10362017 |doi= 10.1002/(SICI)1097-4652(199907)180:1<53::AID-JCP6>3.0.CO;2-P }}
 
*{{cite journal  | author=Klein RD, Maliner-Jongewaard MS, Udayakumar TS, ''et al.'' |title=Promatrilysin expression is induced by fibroblast growth factors in the prostatic carcinoma cell line LNCaP but not in normal primary prostate epithelial cells. |journal=Prostate |volume=41 |issue= 4 |pages= 215-23 |year= 1999 |pmid= 10544294 |doi=  }}
FGF9 has been shown to [[Protein-protein interaction|interact]] with [[Fibroblast growth factor receptor 3]].<ref name="pmid8576175">{{cite journal | vauthors = Santos-Ocampo S, Colvin JS, Chellaiah A, Ornitz DM | title = Expression and biological activity of mouse fibroblast growth factor-9 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 3 | pages = 1726–31 | date = January 1996 | pmid = 8576175 | doi = 10.1074/jbc.271.3.1726 }}</ref><ref name="pmid10574949">{{cite journal | vauthors = Chellaiah A, Yuan W, Chellaiah M, Ornitz DM | title = Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity | journal = The Journal of Biological Chemistry | volume = 274 | issue = 49 | pages = 34785–94 | date = December 1999 | pmid = 10574949 | doi = 10.1074/jbc.274.49.34785 }}</ref>
*{{cite journal | author=Chellaiah A, Yuan W, Chellaiah M, Ornitz DM |title=Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity. |journal=J. Biol. Chem. |volume=274 |issue= 49 |pages= 34785-94 |year= 2000 |pmid= 10574949 |doi= }}
{{Clear}}
*{{cite journal | author=Plotnikov AN, Eliseenkova AV, Ibrahimi OA, ''et al.'' |title=Crystal structure of fibroblast growth factor 9 reveals regions implicated in dimerization and autoinhibition. |journal=J. Biol. Chem. |volume=276 |issue= 6 |pages= 4322-9 |year= 2001 |pmid= 11060292 |doi= 10.1074/jbc.M006502200 }}
 
*{{cite journal | author=Hecht  HJ, Adar  R, Hofmann  B, ''et al.'' |title=Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces. |journal=Acta Crystallogr. D Biol. Crystallogr. |volume=57 |issue= Pt 3 |pages= 378-84 |year= 2001 |pmid= 11223514 |doi= }}
== References ==
*{{cite journal | author=Tsai SJ, Wu MH, Chen HM, ''et al.'' |title=Fibroblast growth factor-9 is an endometrial stromal growth factor. |journal=Endocrinology |volume=143 |issue= 7 |pages= 2715-21 |year= 2002 |pmid= 12072406 |doi= }}
{{reflist|33em}}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
 
*{{cite journal | author=Alizadeh M, Miyamura N, Handa JT, Hjelmeland LM |title=Human RPE cells express the FGFR2IIIc and FGFR3IIIc splice variants and FGF9 as a potential high affinity ligand. |journal=Exp. Eye Res. |volume=76 |issue= 2 |pages= 249-56 |year= 2003 |pmid= 12565813 |doi= }}
== Further reading ==
*{{cite journal | author=Wing LY, Chuang PC, Wu MH, ''et al.'' |title=Expression and mitogenic effect of fibroblast growth factor-9 in human endometriotic implant is regulated by aberrant production of estrogen. |journal=J. Clin. Endocrinol. Metab. |volume=88 |issue= 11 |pages= 5547-54 |year= 2003 |pmid= 14602803 |doi= }}
{{refbegin|33em}}
*{{cite journal | author=Dunham A, Matthews LH, Burton J, ''et al.'' |title=The DNA sequence and analysis of human chromosome 13. |journal=Nature |volume=428 |issue= 6982 |pages= 522-8 |year= 2004 |pmid= 15057823 |doi= 10.1038/nature02379 }}
* {{cite journal | vauthors = Naruo K, Seko C, Kuroshima K, Matsutani E, Sasada R, Kondo T, Kurokawa T | title = Novel secretory heparin-binding factors from human glioma cells (glia-activating factors) involved in glial cell growth. Purification and biological properties | journal = The Journal of Biological Chemistry | volume = 268 | issue = 4 | pages = 2857–64 | date = February 1993 | pmid = 8428960 | doi =  }}
*{{cite journal | author=Popovici C, Conchonaud F, Birnbaum D, Roubin R |title=Functional phylogeny relates LET-756 to fibroblast growth factor 9. |journal=J. Biol. Chem. |volume=279 |issue= 38 |pages= 40146-52 |year= 2004 |pmid= 15199049 |doi= 10.1074/jbc.M405795200 }}
* {{cite journal | vauthors = Mattei MG, Penault-Llorca F, Coulier F, Birnbaum D | title = The human FGF9 gene maps to chromosomal region 13q11-q12 | journal = Genomics | volume = 29 | issue = 3 | pages = 811–2 | date = October 1995 | pmid = 8575785 | doi = 10.1006/geno.1995.9926 }}
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
* {{cite journal | vauthors = Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M | title = Receptor specificity of the fibroblast growth factor family | journal = The Journal of Biological Chemistry | volume = 271 | issue = 25 | pages = 15292–7 | date = June 1996 | pmid = 8663044 | doi = 10.1074/jbc.271.25.15292 }}
*{{cite journal  | author=Fakhry A, Ratisoontorn C, Vedhachalam C, ''et al.'' |title=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. |journal=Bone |volume=36 |issue= 2 |pages= 254-66 |year= 2005 |pmid= 15780951 |doi= 10.1016/j.bone.2004.10.003 }}
* {{cite journal | vauthors = Nakamura S, Todo T, Haga S, Aizawa T, Motoi Y, Ueki A, Kurokawa T, Ikeda K | title = Motor neurons in human and rat spinal cord synthesize fibroblast growth factor-9 | journal = Neuroscience Letters | volume = 221 | issue = 2-3 | pages = 181–4 | date = January 1997 | pmid = 9121694 | doi = 10.1016/S0304-3940(96)13312-7 }}
}}
* {{cite journal | vauthors = Todo T, Kondo T, Nakamura S, Kirino T, Kurokawa T, Ikeda K | title = Neuronal localization of fibroblast growth factor-9 immunoreactivity in human and rat brain | journal = Brain Research | volume = 783 | issue = 2 | pages = 179–87 | date = February 1998 | pmid = 9507114 | doi = 10.1016/S0006-8993(97)01340-1 }}
* {{cite journal | vauthors = Giri D, Ropiquet F, Ittmann M | title = FGF9 is an autocrine and paracrine prostatic growth factor expressed by prostatic stromal cells | journal = Journal of Cellular Physiology | volume = 180 | issue = 1 | pages = 53–60 | date = July 1999 | pmid = 10362017 | doi = 10.1002/(SICI)1097-4652(199907)180:1<53::AID-JCP6>3.0.CO;2-P }}
* {{cite journal | vauthors = Klein RD, Maliner-Jongewaard MS, Udayakumar TS, Boyd JL, Nagle RB, Bowden GT | title = Promatrilysin expression is induced by fibroblast growth factors in the prostatic carcinoma cell line LNCaP but not in normal primary prostate epithelial cells | journal = The Prostate | volume = 41 | issue = 4 | pages = 215–23 | date = December 1999 | pmid = 10544294 | doi = 10.1002/(SICI)1097-0045(19991201)41:4<215::AID-PROS1>3.0.CO;2-V }}
* {{cite journal | vauthors = Plotnikov AN, Eliseenkova AV, Ibrahimi OA, Shriver Z, Sasisekharan R, Lemmon MA, Mohammadi M | title = Crystal structure of fibroblast growth factor 9 reveals regions implicated in dimerization and autoinhibition | journal = The Journal of Biological Chemistry | volume = 276 | issue = 6 | pages = 4322–9 | date = February 2001 | pmid = 11060292 | doi = 10.1074/jbc.M006502200 }}
* {{cite journal | vauthors = Hecht HJ, Adar R, Hofmann B, Bogin O, Weich H, Yayon A | title = Structure of fibroblast growth factor 9 shows a symmetric dimer with unique receptor- and heparin-binding interfaces | journal = Acta Crystallographica Section D | volume = 57 | issue = Pt 3 | pages = 378–84 | date = March 2001 | pmid = 11223514 | doi = 10.1107/S0907444900020813 }}
* {{cite journal | vauthors = Tsai SJ, Wu MH, Chen HM, Chuang PC, Wing LY | title = Fibroblast growth factor-9 is an endometrial stromal growth factor | journal = Endocrinology | volume = 143 | issue = 7 | pages = 2715–21 | date = July 2002 | pmid = 12072406 | doi = 10.1210/en.143.7.2715 }}
* {{cite journal | vauthors = Alizadeh M, Miyamura N, Handa JT, Hjelmeland LM | title = Human RPE cells express the FGFR2IIIc and FGFR3IIIc splice variants and FGF9 as a potential high affinity ligand | journal = Experimental Eye Research | volume = 76 | issue = 2 | pages = 249–56 | date = February 2003 | pmid = 12565813 | doi = 10.1016/S0014-4835(02)00252-X }}
* {{cite journal | vauthors = Wing LY, Chuang PC, Wu MH, Chen HM, Tsai SJ | title = Expression and mitogenic effect of fibroblast growth factor-9 in human endometriotic implant is regulated by aberrant production of estrogen | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 11 | pages = 5547–54 | date = November 2003 | pmid = 14602803 | doi = 10.1210/jc.2003-030597 }}
* {{cite journal | vauthors = Popovici C, Conchonaud F, Birnbaum D, Roubin R | title = Functional phylogeny relates LET-756 to fibroblast growth factor 9 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 38 | pages = 40146–52 | date = September 2004 | pmid = 15199049 | doi = 10.1074/jbc.M405795200 }}
* {{cite journal | vauthors = Fakhry A, Ratisoontorn C, Vedhachalam C, Salhab I, Koyama E, Leboy P, Pacifici M, Kirschner RE, Nah HD | title = 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 | journal = Bone | volume = 36 | issue = 2 | pages = 254–66 | date = February 2005 | pmid = 15780951 | doi = 10.1016/j.bone.2004.10.003 }}
{{refend}}
{{refend}}


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Revision as of 01:09, 11 November 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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View/Edit Human

Glia-activating factor is a protein that in humans is encoded by the FGF9 gene.[1][2]

Function

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]

Interactions

FGF9 has been shown to interact with Fibroblast growth factor receptor 3.[9][10]

References

  1. ↑ Miyamoto M, Naruo K, Seko C, Matsumoto S, Kondo T, Kurokawa T (July 1993). "Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property". Molecular and Cellular Biology. 13 (7): 4251–9. PMC 359975. PMID 8321227.
  2. ↑ 2.0 2.1 "Entrez Gene: FGF9 fibroblast growth factor 9 (glia-activating factor)".
  3. ↑ 3.0 3.1 Sánchez L, Chaouiya C (May 2016). "Primary sex determination of placental mammals: a modelling study uncovers dynamical developmental constraints in the formation of Sertoli and granulosa cells". BMC Systems Biology. 10 (1): 37. doi:10.1186/s12918-016-0282-3. PMID 27229461.
  4. ↑ Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier MC, Poulat F, Behringer RR, Lovell-Badge R, Capel B (June 2006). "Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination". PLoS Biology. 4 (6): e187. doi:10.1371/journal.pbio.0040187. PMC 1463023. PMID 16700629.
  5. ↑ 5.0 5.1 Yin Y, Wang F, Ornitz DM (August 2011). "Mesothelial- and epithelial-derived FGF9 have distinct functions in the regulation of lung development". Development. 138 (15): 3169–77. doi:10.1242/dev.065110. PMID 21750028.
  6. ↑ 6.0 6.1 Sivaraj KK, Adams RH (August 2016). "Blood vessel formation and function in bone". Development. 143 (15): 2706–15. doi:10.1242/dev.136861. PMID 27486231.
  7. ↑ "Multiple Synostoses Syndrome". Orphanet. Retrieved 16 April 2017.
  8. ↑ 8.0 8.1 8.2 Wu XL, Gu MM, Huang L, Liu XS, Zhang HX, Ding XY, et al. (July 2009). "Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene". American Journal of Human Genetics. 85 (1): 53–63. doi:10.1016/j.ajhg.2009.06.007. PMC 2706969. PMID 19589401.
  9. ↑ 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. PMID 8576175.
  10. ↑ 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. PMID 10574949.

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. PMID 8428960.
  • 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. PMID 8575785.
  • 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. PMID 8663044.
  • 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. PMID 9121694.
  • 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. PMID 9507114.
  • Giri D, Ropiquet F, Ittmann M (July 1999). "FGF9 is an autocrine and paracrine prostatic growth factor expressed by prostatic stromal cells". Journal of Cellular Physiology. 180 (1): 53–60. doi:10.1002/(SICI)1097-4652(199907)180:1<53::AID-JCP6>3.0.CO;2-P. PMID 10362017.
  • 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. PMID 10544294.
  • 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. PMID 11060292.
  • 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. PMID 11223514.
  • Tsai SJ, Wu MH, Chen HM, Chuang PC, Wing LY (July 2002). "Fibroblast growth factor-9 is an endometrial stromal growth factor". Endocrinology. 143 (7): 2715–21. doi:10.1210/en.143.7.2715. PMID 12072406.
  • 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. PMID 12565813.
  • 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. PMID 14602803.
  • 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. PMID 15199049.
  • 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. PMID 15780951.
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