Fibroblast growth factor 8 explained

Fibroblast growth factor 8 (FGF-8) is a protein that in humans is encoded by the FGF8 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.^[2]

FGF-8 is important and necessary for setting up and maintaining the midbrain/hindbrain border (or mesencephalon/metencephalon border) which plays the vital role of “organizer” in development, like the Spemann organizer” of the gastrulating embryo. FGF-8 is expressed in the region where Otx2 and Gbx2 cross inhibit each other and is maintained expression by this interaction. Once expressed, the Fgf8 induces other transcription factors to form cross-regulatory loops between cells, thus the border is established. Through development, the Fgf8 goes to regulate the growth and differentiation of progenitor cells in this region to produce ultimate structure of midbrain and hindbrain.^[3] Crossely’s experiment proves that the FGF-8 is sufficient to induce the repatterning of midbrain and hindbrain structure.^[4]

In the development of forebrain, cortical patterning centers are the boundaries or poles of cortical primordium, where multiple BMP and WNT genes are expressed. Besides, at the anterior pole several FGF family including Fgf3, 8,17 and 18 overlap in expression.^[5] The similarity in cortical gene expression in Emx2 mutants and mice in which the anterior FGF8 source is augmented suggests that FGF8 controls the graded expression (low anterior, high posterior) of Emx2 in the cortical primordium. Emx2 is one of the protomap molecular determinants that prove to be closely interacted with Pax6. Emx2 and Pax6 are expressed in opposing gradients along the A/P axis of the cortical primordium and cooperate to set up area pattern. Fgf8 and Emx2 antagonize each other to create the development map. FGF-8 promotes the development of anterior part and suppresses posterior fate, while the Emx2 does the reverse. What's more, FGF8 manipulations suggest FGF8 controls the cortical graded expression of COUP-TF1.^[6] Moreover, the sharpness of both COUPTF1 and COUP-TF2 expression borders would be expected of genes involved in boundary specification. Thus, the interaction between them regulates the A/P axis of cortical primordium and directs the development map of cortical area.

FGF8 signaling from the apical ectodermal ridge (AER), which borders the distal end of the limb bud,^[7] is necessary for forming normal limbs. In the absence of FGF8, limb buds can be reduced in size, hypoplasia or aplasia of bones or digits within the three limb segments may occur, as well as delays in subsequent expressions of other genes (Shh or FGF4). FGF8 is responsible for cell proliferation and survival, as well. Loss of function or decreased expression could result in the malformation or absence of essential limb components. Studies have shown that the forelimbs tend to be more affected by the loss of FGF8 signaling than the hindlimbs^[7] and the loss tends to affect the proximal components more heavily than the distal components.^[8] FGF8 not only aids in the formation of the limb bud and skeletal components of the limb, but the tendons within the limb are affected by it near the portions closest to the muscle extremities.^[9] This diffusible polypeptide is responsible for inducing the limb bud, then inducing and maintaining sonic hedgehog expression in the established limb bud promoting outgrowth of the limb. Evidence for this comes from a study done by Crossley and his colleagues, in which FGF8 soaked beads were surgically used to replace AER areas with the beads.^[10] These studies showed that ectopic limbs formed either fully functional or mostly functional limbs near the normal limbs or limb areas. FGF8 has also been recorded to regulate craniofacial structure formation, including the teeth, palate, mandible, and salivary glands.^[11] Decreased expression can result in the absence of molar teeth, failure to close the palate, or decreased mandible size.

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^[11] 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.^[11] 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.

Clinical significance

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.^[12] 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.^[2]

Further reading

• Powers CJ, McLeskey SW, Wellstein A . Fibroblast growth factors, their receptors and signaling . Endocrine-Related Cancer . 7 . 3 . 165–97 . September 2000 . 11021964 . 10.1677/erc.0.0070165 . 10.1.1.323.4337 .
• Mattila MM, Härkönen PL . Role of fibroblast growth factor 8 in growth and progression of hormonal cancer . Cytokine & Growth Factor Reviews . 18 . 3–4 . 257–66 . 2007 . 17512240 . 10.1016/j.cytogfr.2007.04.010 .
• Duester G . Retinoic acid regulation of the somitogenesis clock . Birth Defects Research. Part C, Embryo Today . 81 . 2 . 84–92 . June 2007 . 17600781 . 2235195 . 10.1002/bdrc.20092 .
• Tanaka A, Miyamoto K, Matsuo H, Matsumoto K, Yoshida H . Human androgen-induced growth factor in prostate and breast cancer cells: its molecular cloning and growth properties . FEBS Letters . 363 . 3 . 226–30 . April 1995 . 7737407 . 10.1016/0014-5793(95)00324-3 . 35818377 . free .
• Gemel J, Gorry M, Ehrlich GD, MacArthur CA . Structure and sequence of human FGF8 . Genomics . 35 . 1 . 253–7 . July 1996 . 8661131 . 10.1006/geno.1996.0349 .
• Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M . 6 . Receptor specificity of the fibroblast growth factor family . The Journal of Biological Chemistry . 271 . 25 . 15292–7 . June 1996 . 8663044 . 10.1074/jbc.271.25.15292 . free .
• Payson RA, Wu J, Liu Y, Chiu IM . The human FGF-8 gene localizes on chromosome 10q24 and is subjected to induction by androgen in breast cancer cells . Oncogene . 13 . 1 . 47–53 . July 1996 . 8700553 .
• Ghosh AK, Shankar DB, Shackleford GM, Wu K, T'Ang A, Miller GJ, Zheng J, Roy-Burman P . 6 . Molecular cloning and characterization of human FGF8 alternative messenger RNA forms . Cell Growth & Differentiation . 7 . 10 . 1425–34 . October 1996 . 8891346 .
• Yoshiura K, Leysens NJ, Chang J, Ward D, Murray JC, Muenke M . Genomic structure, sequence, and mapping of human FGF8 with no evidence for its role in craniosynostosis/limb defect syndromes . American Journal of Medical Genetics . 72 . 3 . 354–62 . October 1997 . 9332670 . 10.1002/(SICI)1096-8628(19971031)72:3<354::AID-AJMG21>3.0.CO;2-R .
• Chellaiah A, Yuan W, Chellaiah M, Ornitz DM . 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 . December 1999 . 10574949 . 10.1074/jbc.274.49.34785 . free .
• Loo BB, Darwish KK, Vainikka SS, Saarikettu JJ, Vihko PP, Hermonen JJ, Goldman AA, Alitalo KK, Jalkanen MM . 6 . Production and characterization of the extracellular domain of recombinant human fibroblast growth factor receptor 4 . The International Journal of Biochemistry & Cell Biology . 32 . 5 . 489–97 . May 2000 . 10736564 . 10.1016/S1357-2725(99)00145-4 .
• Xu J, Liu Z, Ornitz DM . Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures . Development . 127 . 9 . 1833–43 . May 2000 . 10.1242/dev.127.9.1833 . 10751172 .
• Tanaka S, Ueo H, Mafune K, Mori M, Wands JR, Sugimachi K . A novel isoform of human fibroblast growth factor 8 is induced by androgens and associated with progression of esophageal carcinoma . Digestive Diseases and Sciences . 46 . 5 . 1016–21 . May 2001 . 11341643 . 10.1023/A:1010753826788 . 30175286 .
• Ruohola JK, Viitanen TP, Valve EM, Seppänen JA, Loponen NT, Keskitalo JJ, Lakkakorpi PT, Härkönen PL . 6 . Enhanced invasion and tumor growth of fibroblast growth factor 8b-overexpressing MCF-7 human breast cancer cells . Cancer Research . 61 . 10 . 4229–37 . May 2001 . 11358849 .
• Mattila MM, Ruohola JK, Valve EM, Tasanen MJ, Seppänen JA, Härkönen PL . FGF-8b increases angiogenic capacity and tumor growth of androgen-regulated S115 breast cancer cells . Oncogene . 20 . 22 . 2791–804 . May 2001 . 11420691 . 10.1038/sj.onc.1204430 . 22624526 .
• Zammit C, Coope R, Gomm JJ, Shousha S, Johnston CL, Coombes RC . Fibroblast growth factor 8 is expressed at higher levels in lactating human breast and in breast cancer . British Journal of Cancer . 86 . 7 . 1097–103 . April 2002 . 11953856 . 2364190 . 10.1038/sj.bjc.6600213 .
• Brondani V, Klimkait T, Egly JM, Hamy F . Promoter of FGF8 reveals a unique regulation by unliganded RARalpha . Journal of Molecular Biology . 319 . 3 . 715–28 . June 2002 . 12054865 . 10.1016/S0022-2836(02)00376-5 .
• Gnanapragasam VJ, Robson CN, Neal DE, Leung HY . Regulation of FGF8 expression by the androgen receptor in human prostate cancer . Oncogene . 21 . 33 . 5069–80 . August 2002 . 12140757 . 10.1038/sj.onc.1205663 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Kallmann syndrome

Notes and References

1. White RA, Dowler LL, Angeloni SV, Pasztor LM, MacArthur CA . Assignment of FGF8 to human chromosome 10q25-q26: mutations in FGF8 may be responsible for some types of acrocephalosyndactyly linked to this region . Genomics . 30 . 1 . 109–11 . November 1995 . 8595889 . 10.1006/geno.1995.0020 .
2. Web site: Entrez Gene: FGF8 fibroblast growth factor 8 (androgen-induced).
3. Book: Harris WA, Sanes DH, Reh TA . Development of the Nervous System, Third Edition . Academic Press . Boston . 2011 . 33–34 . 978-0-12-374539-2 .
4. Crossley PH, Martin GR . The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo . Development . 121 . 2 . 439–51 . February 1995 . 10.1242/dev.121.2.439 . 7768185 .
5. Grove EA, Fukuchi-Shimogori T . Generating the cerebral cortical area map . Annual Review of Neuroscience . 26 . 355–80 . 2003 . 14527269 . 10.1146/annurev.neuro.26.041002.131137 .
6. Rebsam A, Seif I, Gaspar P . 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 . The Journal of Neuroscience . 22 . 19 . 8541–52 . October 2002 . 12351728 . 6757778 . 10.1523/JNEUROSCI.22-19-08541.2002 . free .
7. Lewandoski M, Sun X, Martin GR . Fgf8 signalling from the AER is essential for normal limb development . Nature Genetics . 26 . 4 . 460–3 . December 2000 . 11101846 . 10.1038/82609 . 28105181 .
8. Moon AM, Capecchi MR . Fgf8 is required for outgrowth and patterning of the limbs . Nature Genetics . 26 . 4 . 455–9 . December 2000 . 11101845 . 2001274 . 10.1038/82601 .
9. Edom-Vovard F, Bonnin M, Duprez D . Fgf8 transcripts are located in tendons during embryonic chick limb development . Mechanisms of Development . 108 . 1–2 . 203–6 . October 2001 . 11578876 . 10.1016/s0925-4773(01)00483-x . 16604609 . free .
10. Crossley PH, Minowada G, MacArthur CA, Martin GR . Roles for FGF8 in the induction, initiation, and maintenance of chick limb development . Cell . 84 . 1 . 127–36 . January 1996 . 8548816 . 10.1016/s0092-8674(00)80999-x . 14188382 . free .
11. Hao Y, Tang S, Yuan Y, Liu R, Chen Q . Roles of FGF8 subfamily in embryogenesis and oral‑maxillofacial diseases (Review) . International Journal of Oncology . 54 . 3 . 797–806 . March 2019 . 30628659 . 10.3892/ijo.2019.4677 . free .
12. Estienne A, Price CA . The fibroblast growth factor 8 family in the female reproductive tract . Reproduction . 155 . 1 . R53–R62 . January 2018 . 29269444 . 10.1530/REP-17-0542 . free .