Fibroblast growth factor 8

The protein encoded by this gene belongs to the fibroblast growth factor (FGF) family. FGF proteins are multifunctional signaling molecules with broad mitogenic and cell survival activity, playing critical roles in embryonic development, cell proliferation, morphogenesis, tissue repair, and tumor progression.{{cite journal | vauthors = White RA, Dowler LL, Angeloni SV, Pasztor LM, MacArthur CA | title = Assignment of FGF8 to human chromosome 10q25-q26: mutations in FGF8 may be responsible for some types of acrocephalosyndactyly linked to this region | journal = Genomics | volume = 30 | issue = 1 | pages = 109–111 | date = November 1995 | pmid = 8595889 | doi = 10.1006/geno.1995.0020 }} FGF8 signals primarily through fibroblast growth factor receptor 1 (FGFR1) to trigger downstream pathways involved in neural and limb development.{{cite journal | vauthors = Chung WC, Moyle SS, Tsai PS | title = Fibroblast growth factor 8 signaling through fibroblast growth factor receptor 1 is required for the emergence of gonadotropin-releasing hormone neurons | journal = Endocrinology | volume = 149 | issue = 10 | pages = 4997–5003 | date = October 2008 | pmid = 18566132 | doi = 10.1210/en.2007-1634 | pmc = 2582917 }}

FGF8 is essential for establishing the midbrain–hindbrain boundary (mesencephalon/metencephalon), a key signaling center during brain development. This region is defined by cross-repression between Otx2 and Gbx2, which helps maintain FGF8 expression. FGF8 then induces the expression of transcription factors, forming feedback loops that guide the development of the midbrain and hindbrain.{{cite book |vauthors=Harris WA, Sanes DH, Reh TA | title = Development of the Nervous System, Third Edition | publisher = Academic Press | location = Boston | year = 2011 | pages = 33–34 | isbn = 978-0-12-374539-2 }}{{cite journal | vauthors = Crossley PH, Martin GR | title = The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo | journal = Development | volume = 121 | issue = 2 | pages = 439–451 | date = February 1995 | pmid = 7768185 | doi = 10.1242/dev.121.2.439 }}

In the forebrain, FGF8 helps define cortical areas by regulating transcription factors such as Emx2, Pax6, COUP-TF1, and COUP-TF2. These factors are expressed in opposing gradients and interact to establish the anterior–posterior patterning of the cerebral cortex.{{cite journal | vauthors = Grove EA, Fukuchi-Shimogori T | title = Generating the cerebral cortical area map | journal = Annual Review of Neuroscience | volume = 26 | pages = 355–380 | year = 2003 | pmid = 14527269 | doi = 10.1146/annurev.neuro.26.041002.131137 }}{{cite journal | vauthors = Rebsam A, Seif I, Gaspar P | title = Refinement of thalamocortical arbors and emergence of barrel domains in the primary somatosensory cortex: a study of normal and monoamine oxidase a knock-out mice | journal = The Journal of Neuroscience | volume = 22 | issue = 19 | pages = 8541–8552 | date = October 2002 | pmid = 12351728 | pmc = 6757778 | doi = 10.1523/JNEUROSCI.22-19-08541.2002 | doi-access = free }}

FGF8 plays a pivotal role in early embryonic patterning, influencing the development of all three germ layers. In the mesoderm, FGF8 helps regulate somite formation through the Clock and wavefront model, promoting segmentation and the establishment of anterior–posterior identity.{{cite journal | vauthors = Dubrulle J, McGrew MJ, Pourquié O | title = FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation | journal = Cell | volume = 106 | issue = 2 | pages = 219–232 | date = July 2001 | pmid = 11511349 | doi = 10.1016/s0092-8674(01)00437-8 | hdl = 20.500.11820/9ca3df26-206e-47a6-b822-c6160724075e | hdl-access = free }}{{cite journal | vauthors = Moon AM, Capecchi MR | title = Fgf8 is required for outgrowth and patterning of the limbs | journal = Nature Genetics | volume = 26 | issue = 4 | pages = 455–459 | date = December 2000 | pmid = 11101845 | doi = 10.1038/82601 | pmc = 2001274 }}

In the endoderm, FGF8 acts in coordination with retinoic acid (RA) to direct organ specification. Low levels of FGF8 promote the formation of anterior endodermal derivatives such as the liver and pancreas,{{cite journal | vauthors = Calmont A, Wandzioch E, Tremblay KD, Minowada G, Kaestner KH, Martin GR, Zaret KS | title = An FGF response pathway that mediates hepatic gene induction in embryonic endoderm cells | journal = Developmental Cell | volume = 11 | issue = 3 | pages = 339–348 | date = September 2006 | pmid = 16950125 | doi = 10.1016/j.devcel.2006.06.015 | doi-access = free }} while higher levels specify posterior structures such as the hindgut.{{cite journal | vauthors = Park EJ, Ogden LA, Talbot A, Evans S, Cai CL, Black BL, Frank DU, Moon AM | title = Required, tissue-specific roles for Fgf8 in outflow tract formation and remodeling | journal = Development | volume = 133 | issue = 12 | pages = 2419–2433 | date = June 2006 | pmid = 16720879 | doi = 10.1242/dev.02367 | pmc = 1780034 }}

FGF8 is secreted by the apical ectodermal ridge (AER) at the distal end of limb buds and is essential for limb initiation, patterning, and outgrowth.{{cite journal | vauthors = Lewandoski M, Sun X, Martin GR | title = Fgf8 signalling from the AER is essential for normal limb development | journal = Nature Genetics | volume = 26 | issue = 4 | pages = 460–463 | date = December 2000 | pmid = 11101846 | doi = 10.1038/82609 | s2cid = 28105181 }} Loss of FGF8 results in limb reduction or absence, with forelimbs and proximal segments being most affected.{{cite journal | vauthors = Moon AM, Capecchi MR | title = Fgf8 is required for outgrowth and patterning of the limbs | journal = Nature Genetics | volume = 26 | issue = 4 | pages = 455–459 | date = December 2000 | pmid = 11101845 | pmc = 2001274 | doi = 10.1038/82601 }} FGF8 also influences Sonic hedgehog (Shh) signaling and is involved in tendon and digit formation.{{cite journal | vauthors = Crossley PH, Minowada G, MacArthur CA, Martin GR | title = Roles for FGF8 in the induction, initiation, and maintenance of chick limb development | journal = Cell | volume = 84 | issue = 1 | pages = 127–136 | date = January 1996 | pmid = 8548816 | doi = 10.1016/s0092-8674(00)80999-x | s2cid = 14188382 | doi-access = free }}{{cite journal | vauthors = Edom-Vovard F, Bonnin M, Duprez D | title = Fgf8 transcripts are located in tendons during embryonic chick limb development | journal = Mechanisms of Development | volume = 108 | issue = 1–2 | pages = 203–206 | date = October 2001 | pmid = 11578876 | doi = 10.1016/s0925-4773(01)00483-x | s2cid = 16604609 | doi-access = free }}

FGF8 also contributes to craniofacial development, including the formation of the teeth, palate, mandible, and salivary glands. Altered expression can result in craniofacial abnormalities such as cleft palate, mandibular hypoplasia, or tooth agenesis.{{cite journal | vauthors = Hao Y, Tang S, Yuan Y, Liu R, Chen Q | title = Roles of FGF8 subfamily in embryogenesis and oral‑maxillofacial diseases (Review) | journal = International Journal of Oncology | volume = 54 | issue = 3 | pages = 797–806 | date = March 2019 | pmid = 30628659 | doi = 10.3892/ijo.2019.4677 | doi-access = free }} In conclusion, FGF8 expression has effects on a person’s facial appearance, brain, lungs,

heart, kidneys, and limbs. If there is not enough FGF8 or too much, there can be defects in all of

these systems like limb loss, cleft lip/ palate, kidney disease, and neurodevelopmental defects.

This protein is known to be a factor that supports androgen and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and angiogenesis. The adult expression of this gene was once thought to be restricted to testes and ovaries but has been described in several organ systems.{{cite journal | vauthors = Estienne A, Price CA | title = The fibroblast growth factor 8 family in the female reproductive tract | journal = Reproduction | volume = 155 | issue = 1 | pages = R53–R62 | date = January 2018 | pmid = 29269444 | doi = 10.1530/REP-17-0542 | doi-access = free }} Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs reveal roles in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination. The alternative splicing of this gene results in four transcript variants.{{cite web | title = Entrez Gene: FGF8 fibroblast growth factor 8 (androgen-induced)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2253}}

FGF8 has been documented to play a role in oralmaxillogacial diseases and CRISPR-cas9 gene targeting on FGF8 may be key in treating these diseases. Cleft lip and/or palate (CLP) genome wide gene analysis shows a D73H missense mutation in the FGF8 gene which reduces the binding affinity of FGF8. Loss of TBX1 and Tfap2 can result in proliferation and apoptosis in the palate cells increasing the risk of CLP. Overexpression of FGF8 due to misregulation of the Gli processing gene may result in cliliopathies. Agnathia, a malformation of the mandible, is often a lethal condition that comes from the absence of BMP4 regulators (noggin and chordin), resulting in high levels of BMP4 signaling, which in turn drastically reduces FGF8 signaling, increasing cell death during mandibular outgrowth. Lastly, the ability for FGF8 to regulate cell proliferation has caused interest in its effects on tumors or squamous cell carcinoma. CRISPR-cas9 gene targeting methods are currently being studied to determine if they are the key to solving FGF8 mutations associated with oral diseases.

FGF-8 knockout models have led to lethality in gastrulating state embryos in mice models.{{cite journal | vauthors = Sun X, Meyers EN, Lewandoski M, Martin GR | title = Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo | journal = Genes & Development | volume = 13 | issue = 14 | pages = 1834–1846 | date = July 1999 | pmid = 10421635 | doi = 10.1101/gad.13.14.1834 | pmc = 316887 }} Research has demonstrated that decreased expression of FGF-8 can alter the cleft lip pathology in mice.{{cite journal | vauthors = Green RM, Feng W, Phang T, Fish JL, Li H, Spritz RA, Marcucio RS, Hooper J, Jamniczky H, Hallgrímsson B, Williams T | title = Tfap2a-dependent changes in mouse facial morphology result in clefting that can be ameliorated by a reduction in Fgf8 gene dosage | journal = Disease Models & Mechanisms | volume = 8 | issue = 1 | pages = 31–43 | date = January 2015 | pmid = 25381013 | doi = 10.1242/dmm.017616 | pmc = 4283648 }} However, due to the importance that FGF-8 has in the development and programming in multiple organ systems, full "knockout" models have led to embryonic death in multiple studies, limiting the ability to study the removal of the morphogen in adult models.{{cite journal | vauthors = Hao Y, Tang S, Yuan Y, Liu R, Chen Q | title = Roles of FGF8 subfamily in embryogenesis and oral‑maxillofacial diseases (Review) | journal = International Journal of Oncology | volume = 54 | issue = 3 | pages = 797–806 | date = March 2019 | pmid = 30628659 | doi = 10.3892/ijo.2019.4677 }} While knockout experiments have occurred with this gene, a lack of/mutation in FGF8 in the early stages of embryo development is lethal. Disruption of the gene in later developmental stages has caused several issues with limb formation and development. Researchers hope to determine a way to study the signaling molecule in the future to investigate how to prevent defects including Kallmann syndrome.

{{reflist}}

{{refbegin|35em}}

• {{cite journal | vauthors = Powers CJ, McLeskey SW, Wellstein A | title = Fibroblast growth factors, their receptors and signaling | journal = Endocrine-Related Cancer | volume = 7 | issue = 3 | pages = 165–197 | date = September 2000 | pmid = 11021964 | doi = 10.1677/erc.0.0070165 | citeseerx = 10.1.1.323.4337 }}
• {{cite journal | vauthors = Mattila MM, Härkönen PL | title = Role of fibroblast growth factor 8 in growth and progression of hormonal cancer | journal = Cytokine & Growth Factor Reviews | volume = 18 | issue = 3–4 | pages = 257–266 | year = 2007 | pmid = 17512240 | doi = 10.1016/j.cytogfr.2007.04.010 }}
• {{cite journal | vauthors = Duester G | title = Retinoic acid regulation of the somitogenesis clock | journal = Birth Defects Research. Part C, Embryo Today | volume = 81 | issue = 2 | pages = 84–92 | date = June 2007 | pmid = 17600781 | pmc = 2235195 | doi = 10.1002/bdrc.20092 }}
• {{cite journal | vauthors = Tanaka A, Miyamoto K, Matsuo H, Matsumoto K, Yoshida H | title = Human androgen-induced growth factor in prostate and breast cancer cells: its molecular cloning and growth properties | journal = FEBS Letters | volume = 363 | issue = 3 | pages = 226–230 | date = April 1995 | pmid = 7737407 | doi = 10.1016/0014-5793(95)00324-3 | s2cid = 35818377 | doi-access = free }}
• {{cite journal | vauthors = Gemel J, Gorry M, Ehrlich GD, MacArthur CA | title = Structure and sequence of human FGF8 | journal = Genomics | volume = 35 | issue = 1 | pages = 253–257 | date = July 1996 | pmid = 8661131 | doi = 10.1006/geno.1996.0349 }}
• {{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 = 15292–15297 | date = June 1996 | pmid = 8663044 | doi = 10.1074/jbc.271.25.15292 | doi-access = free }}
• {{cite journal | vauthors = Payson RA, Wu J, Liu Y, Chiu IM | title = The human FGF-8 gene localizes on chromosome 10q24 and is subjected to induction by androgen in breast cancer cells | journal = Oncogene | volume = 13 | issue = 1 | pages = 47–53 | date = July 1996 | pmid = 8700553 }}
• {{cite journal | vauthors = Ghosh AK, Shankar DB, Shackleford GM, Wu K, T'Ang A, Miller GJ, Zheng J, Roy-Burman P | title = Molecular cloning and characterization of human FGF8 alternative messenger RNA forms | journal = Cell Growth & Differentiation | volume = 7 | issue = 10 | pages = 1425–1434 | date = October 1996 | pmid = 8891346 }}
• {{cite journal | vauthors = Yoshiura K, Leysens NJ, Chang J, Ward D, Murray JC, Muenke M | title = Genomic structure, sequence, and mapping of human FGF8 with no evidence for its role in craniosynostosis/limb defect syndromes | journal = American Journal of Medical Genetics | volume = 72 | issue = 3 | pages = 354–362 | date = October 1997 | pmid = 9332670 | doi = 10.1002/(SICI)1096-8628(19971031)72:3<354::AID-AJMG21>3.0.CO;2-R }}
• {{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 = 34785–34794 | date = December 1999 | pmid = 10574949 | doi = 10.1074/jbc.274.49.34785 | doi-access = free }}
• {{cite journal | vauthors = Loo BB, Darwish KK, Vainikka SS, Saarikettu JJ, Vihko PP, Hermonen JJ, Goldman AA, Alitalo KK, Jalkanen MM | title = Production and characterization of the extracellular domain of recombinant human fibroblast growth factor receptor 4 | journal = The International Journal of Biochemistry & Cell Biology | volume = 32 | issue = 5 | pages = 489–497 | date = May 2000 | pmid = 10736564 | doi = 10.1016/S1357-2725(99)00145-4 }}
• {{cite journal | vauthors = Xu J, Liu Z, Ornitz DM | title = Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures | journal = Development | volume = 127 | issue = 9 | pages = 1833–1843 | date = May 2000 | pmid = 10751172 | doi = 10.1242/dev.127.9.1833 }}
• {{cite journal | vauthors = Tanaka S, Ueo H, Mafune K, Mori M, Wands JR, Sugimachi K | title = A novel isoform of human fibroblast growth factor 8 is induced by androgens and associated with progression of esophageal carcinoma | journal = Digestive Diseases and Sciences | volume = 46 | issue = 5 | pages = 1016–1021 | date = May 2001 | pmid = 11341643 | doi = 10.1023/A:1010753826788 | s2cid = 30175286 }}
• {{cite journal | vauthors = Ruohola JK, Viitanen TP, Valve EM, Seppänen JA, Loponen NT, Keskitalo JJ, Lakkakorpi PT, Härkönen PL | title = Enhanced invasion and tumor growth of fibroblast growth factor 8b-overexpressing MCF-7 human breast cancer cells | journal = Cancer Research | volume = 61 | issue = 10 | pages = 4229–4237 | date = May 2001 | pmid = 11358849 }}
• {{cite journal | vauthors = Mattila MM, Ruohola JK, Valve EM, Tasanen MJ, Seppänen JA, Härkönen PL | title = FGF-8b increases angiogenic capacity and tumor growth of androgen-regulated S115 breast cancer cells | journal = Oncogene | volume = 20 | issue = 22 | pages = 2791–2804 | date = May 2001 | pmid = 11420691 | doi = 10.1038/sj.onc.1204430 | s2cid = 22624526 | doi-access = }}
• {{cite journal | vauthors = Zammit C, Coope R, Gomm JJ, Shousha S, Johnston CL, Coombes RC | title = Fibroblast growth factor 8 is expressed at higher levels in lactating human breast and in breast cancer | journal = British Journal of Cancer | volume = 86 | issue = 7 | pages = 1097–1103 | date = April 2002 | pmid = 11953856 | pmc = 2364190 | doi = 10.1038/sj.bjc.6600213 }}
• {{cite journal | vauthors = Brondani V, Klimkait T, Egly JM, Hamy F | title = Promoter of FGF8 reveals a unique regulation by unliganded RARalpha | journal = Journal of Molecular Biology | volume = 319 | issue = 3 | pages = 715–728 | date = June 2002 | pmid = 12054865 | doi = 10.1016/S0022-2836(02)00376-5 }}
• {{cite journal | vauthors = Gnanapragasam VJ, Robson CN, Neal DE, Leung HY | title = Regulation of FGF8 expression by the androgen receptor in human prostate cancer | journal = Oncogene | volume = 21 | issue = 33 | pages = 5069–5080 | date = August 2002 | pmid = 12140757 | doi = 10.1038/sj.onc.1205663 | doi-access = free }}

{{refend}}

• [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=kms GeneReviews/NCBI/NIH/UW entry on Kallmann syndrome]
• {{UCSC genome browser|FGF8}}
• {{UCSC gene details|FGF8}}

{{PDB Gallery|geneid=2253}}

{{Growth factors}}

{{Intercellular signaling peptides and proteins}}

{{Growth factor receptor modulators}}