FGF5

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Research comparing dogs with different coat lengths has demonstrated FGF5 as a major contributing factor [11][12][21]
Research comparing different breeds of dogs has demonstrated FGF5 as a major contributing factor in coat length. [11][12][24]

Fibroblast growth factor 5[edit]

Fibroblast growth factor 5 is a protein that in humans is encoded by the FGF5 gene.

The majority of FGF family members are glycosaminoglycan binding proteins which 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. FGF proteins interact with a family of specific tyrosine kinase receptors, a process often regulated by proteoglycans or extracellular binding protein cofactors. A number of intracellular signalling cascades are known to be activated after FGF-FGFR interaction including PI3K-AKT, PLCγ, RAS-MAPK and STAT pathways.[1]

FGF5 and its receptor[edit]

FGF5 is a 268 amino acid, 29.1 kDa protein, which also naturally occurs as a 123 amino acid isoform splice variant (FGF5s) [2],.[3] FGF5 is produced in the outer root sheath of the hair follicle as well as perifollicular macrophages, with maximum expression occurring in the late anagen phase of the hair cycle,.[4][5] The receptor for FGF5, FGFR1, is largely expressed in the dermal papilla cells of the hair follicle.,.[4][5] The alternatively spliced isoform FGF5s, has been identified as an antagonist of FGF5 in a number of studies.[2],,[3][6]

FGF5 and hair growth[edit]

The only described function of FGF5 in adults is in the regulation of the hair cycle. FGF5 performs a critical role in the hair cycle, where it acts as the key signalling molecule in initiating the transition from the anagen (growth) phase to the catagen (regression) phase.,,[7][8] Evidence of this activity was initially gathered via targeted disruption of the homolog of the FGF5 gene in mice, which resulted in a phenotype with abnormally long hair.[8]

In numerous genetic studies of long haired phenotypes of animals it has been shown that small changes in the FGF5 gene can disrupt its expression, leading to an increase in the length of the anagen phase of the hair cycle, resulting in phenotypes with extremely long hair. This has been demonstrated in many species, including cats [9],,[10] dogs [11], [12] mice,[8] rabbits,[13] donkeys,[14] sheep and goats,[15] where it is often referred to as the angora mutation. Recently, CRISPR modification of goats to artificially knock out the FGF5 gene, was shown to result in higher wool yield, without any fertility or other negative effects on the goats.[16]

It has been hypothesised that, in an alternate type of mutation, positive selection for increased expression of the FGF5 protein was one of the contributing factors in the evolutionary loss of hair in cetaceans as they transitioned from the terrestrial to the aquatic environment.[17]

FGF5 also affects the hair cycle in humans. Individuals with mutations in FGF5 exhibit familial trichomegaly, a condition that involves a significant increase in the portion of anagen phase hair as well as extremely long eyelashes. .[7] FGF5 has also been identified as a potentially important factor in androgenetic alopecia. In 2017, a large genome wide association study of men with early onset androgenetic alopecia identified polymorphisms in FGF5 as having a strong association with male pattern hair loss.[18]

Blocking FGF5 in the human scalp extends the hair cycle, resulting in less hair fall, faster hair growth rate and increased hair growth.,[19][20] In vitro methods using engineered cell lines and FGFR1 expressing dermal papilla cells have identified a number of naturally derived botanical isolates including Sanguisorba officnalis [19] and single molecule members of the monoterpenoid [20] as inhibitors (blockers) of FGF5. Clinical studies have shown that topical application of formulations containing these natural extracts and molecules are beneficial in men and women experiencing hair loss.,[19][20]

The Australian company Advangen [21] manufactures FGF5 inhibiting hair loss products and markets these in a number of countries including: Japan [22] under the trade names Jo-Ju and Lexilis; Australia under the names evolis and evolis professional; and the USA [23] as évolis professional.

References[edit]

  1. ^ D. M. Ornitz and N. Itoh. (2015) “The fibroblast growth factor signaling pathway,” Wiley Interdiscip. Rev. Dev. Biol., vol. 4, no. 3, pp. 215–266,. PMID 25772309 PMC 4393358 doi:10.1002/wdev.176
  2. ^ a b S. Suzuki, T. Kato, H. Takimoto, et al., (1998) “Localization of Rat FGF-5 Protein in Skin Macrophage-like Cells and FGF-5S Protein in Hair Follicle: Possible Involvement of two Fgf-5 gene products in hair growth cycle regulation,” Growth (Lakeland), vol. 111, no. 6, pp. 963–972. PMID 9856803 doi:10.1046/j.1523-1747.1998.00427.x
  3. ^ a b S. Suzuki, Y. Ota, K. Ozawa, and T. Imamura. (2000) “Dual-mode regulation of hair growth cycle by two Fgf-5 gene products,” J. Invest. Dermatol., vol. 114, no. 3, pp. 456–463. PMID 10692103 doi:10.1046/j.1523-1747.2000.00912.x
  4. ^ a b T. A. Rosenquist and G. R. Martin. (1996) “Fibroblast growth factor signalling in the hair growth cycle: expression of the fibroblast growth factor receptor and ligand genes in the murine hair follicle.,” Dev. Dyn., vol. 205, no. 4, pp. 379–86. PMID 8901049 doi:10.1002/(SICI)1097-0177(199604)205:4<379::AID-AJA2>3.0.CO;2-F
  5. ^ a b Y. Ota, Y. Saitoh, S. Suzuki, et al., (2002) “Fibroblast growth factor 5 inhibits hair growth by blocking dermal papilla cell activation.,” Biochem. Biophys. Res. Commun., vol. 290, no. 1, pp. 169–176. PMID 11779149 doi:10.1006/bbrc.2001.6140
  6. ^ X. He, Y. Chao, G. Zhou, and Y. Chen. (2016) “Fibroblast growth factor 5-short (FGF5s) inhibits the activity of FGF5 in primary and secondary hair follicle dermal papilla cells of cashmere goats.,” Gene, vol. 575, no. 2 Pt 2, pp. 393–398. PMID 26390813 doi:10.1016/j.gene.2015.09.034
  7. ^ a b C. Higgins, L. Petukhova, S. Harel, et al., (2014) “FGF5 is a crucial regulator of hair length in humans,” Proc. Natl. Acad. Sci. U. S. A., vol. 111, no. 29, pp. 3–8. PMID 24989505 PMC 4115575 doi:10.1073/pnas.1402862111
  8. ^ a b c J. M. Hebert, T. Rosenquist, J. Gotz, and G. R. Martin. (1994) “FGF5 as a regulator of the hair growth cycle: Evidence from targeted and spontaneous mutations,” Cell, vol. 78, no. 6, pp. 1017–1025. PMID 7923352
  9. ^ C. Drögemüller, S. Rüfenacht, B. Wichert, and T. Leeb. (2007) “Mutations within the FGF5 gene are associated with hair length in cats,” Anim. Genet., vol. 38, no. 3, pp. 218–221. PMID 17433015 doi:10.1111/j.1365-2052.2007.01590.x
  10. ^ J. S. Kehler, V. A. David, A. A. Schaffer, et al., (2007) “Four independent mutations in the feline Fibroblast Growth Factor 5 gene determine the long-haired phenotype in domestic cats,” J. Hered., vol. 98, no. 6, pp. 555–566. PMID 17767004 PMC 3756544 doi:10.1093/jhered/esm072
  11. ^ C. Dierks, S. Momke, U. Philipp, and O. Distl. (2007) “Allelic heterogeneity of FGF5 mutations causes the long-hair phenotype in dogs.,” Anim. Genet., vol. 44, no. 4, pp. 425–431. PMID 23384345 doi:10.1111/age.12010
  12. ^ D. J. E. Housley and P. J. Venta. (2006) “The long and the short of it: Evidence that FGF5 is a major determinant of canine ‘hair’-itability,” Anim. Genet., vol. 37, no. 4, pp. 309–315. PMID 16879338 doi:10.1111/j.1365-2052.2006.01448.x
  13. ^ C.-X. Li, M.-S. Jiang, S.-Y. Chen, and S.-J. Lai. (2008) “Correlation analysis between single nucleotide polymorphism of FGF5 gene and wool yield in rabbits.,” Yi chuan = Hered., vol. 30, no. 7, pp. 893–899. PMID 18779133
  14. ^ R. Legrand, L. Tiret, and M. Abitbol. (2014) “Two recessive mutations in FGF5 are associated with the long-hair phenotype in donkeys,” Genet. Sel. Evol., vol. 46, pp. 1–7. PMID 25927731 PMC 4175617 doi:10.1186/s12711-014-0065-5
  15. ^ H.-Y. Liu, G.-Q. Yang, W. Zhang, et al., (2009) “Effects of FGF5 gene on fibre traits on Inner Mongolian cashmere goats.” Yi chuan = Hered., vol. 31, no. 2, pp. 175–179. PMID 19273426
  16. ^ X. Wang, B. Cai, J. Zhou, et al., (2016) “Disruption of FGF5 in Cashmere Goats Using CRISPR/Cas9 Results in More Secondary Hair Follicles and Longer Fibers,” PLoS One, vol. 11, no. 10, p. e0164640, 2016. PMID 27755602 PMC 5068700 doi:10.1371/journal.pone.0164640
  17. ^ Z. Chen, Z. Wang, S. Xu, et al., (2013) “Characterization of hairless (Hr) and FGF5 genes provides insights into the molecular basis of hair loss in cetaceans.,” BMC Evol. Biol., vol. 13, no. 1, p. 34. PMID 23394579 PMC 3608953 doi:10.1186/1471-2148-13-34
  18. ^ S. Heilmann-Heimbach, C. Herold, L. M. Hochfeld, et al.,. (2017) “Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness.,” Nat. Commun., vol. 8, p. 14694. PMID 28272467 PMC 5344973 doi:10.1038/ncomms14694
  19. ^ a b c T. Maeda, T. Yamamoto, Y. Isikawa, et al., (2007) “Sanguisorba Officinalis Root Extract Has FGF-5 Inhibitory Activity and Reduces Hair Loss by Causing Prolongation of the Anagen Period,” Nishinihon J. Dermatology, vol. 69, no. 1, pp. 81–86. doi:10.2336/nishinihonhifu.69.81
  20. ^ a b c D. Burg, M. Yamamoto, M. Namekata, et al., (2017) “Promotion of anagen, increased hair density and reduction of hair fall in a clinical setting following identification of FGF5-inhibiting compounds via a novel 2-stage process.,” Clin. Cosmet. Investig. Dermatol., vol. 10, pp. 71–85. PMID 28280377 PMC 5338843 doi:10.2147/CCID.S123401
  21. ^ Advangen International Pty. Ltd. (2016). What is FGF5 ? Available: https://www.evolisproducts.com.au/fgf-5-hair-loss
  22. ^ Advangen. Japan. Jo-Ju and Lexilis. Available: http://www.shop-advangen.com/
  23. ^ EvolisUSA, E. U. (2016). Evolis USA Professional Instagram. Retrieved from https://www.instagram.com/evolisusa/

24. Cadieu E, Neff MW, Quignon P, Walsh K, Chase K, Parker HG, VonHoldt BM, Rhue A, Boyko A, Byers A, Wong A. Coat variation in the domestic dog is governed by variants in three genes. science. 2009 Oct 2;326(5949):150-3.

Further reading[edit]

  • Li K, Stewart DJ, Ward HJ (2001). "Technology evaluation: gene therapy (FGF-5), Vical". Curr. Opin. Mol. Ther. 1 (2): 260–5. PMID 11715949. 
  • Werner S, Roth WK, Bates B, et al. (1991). "Fibroblast growth factor 5 proto-oncogene is expressed in normal human fibroblasts and induced by serum growth factors". Oncogene. 6 (11): 2137–44. PMID 1658709. 
  • Haub O, Drucker B, Goldfarb M (1990). "Expression of the murine fibroblast growth factor 5 gene in the adult central nervous system". Proc. Natl. Acad. Sci. U.S.A. 87 (20): 8022–6. doi:10.1073/pnas.87.20.8022. PMC 54884Freely accessible. PMID 1700424. 
  • Bates B, Hardin J, Zhan X, et al. (1991). "Biosynthesis of human fibroblast growth factor-5". Mol. Cell. Biol. 11 (4): 1840–5. PMC 359856Freely accessible. PMID 2005884. 
  • Hébert JM, Rosenquist T, Götz J, Martin GR (1994). "FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations". Cell. 78 (6): 1017–25. doi:10.1016/0092-8674(94)90276-3. PMID 7923352. 
  • Li JJ, Huang YQ, Moscatelli D, et al. (1993). "Expression of fibroblast growth factors and their receptors in acquired immunodeficiency syndrome-associated Kaposi sarcoma tissue and derived cells". Cancer. 72 (7): 2253–9. doi:10.1002/1097-0142(19931001)72:7<2253::AID-CNCR2820720732>3.0.CO;2-4. PMID 8374885. 
  • Clements DA, Wang JK, Dionne CA, Goldfarb M (1993). "Activation of fibroblast growth factor (FGF) receptors by recombinant human FGF-5". Oncogene. 8 (5): 1311–6. PMID 8386828. 
  • Ornitz DM, Xu J, Colvin JS, et al. (1996). "Receptor specificity of the fibroblast growth factor family". J. Biol. Chem. 271 (25): 15292–7. doi:10.1074/jbc.271.25.15292. PMID 8663044. 
  • Kitaoka T, Morse LS, Schneeberger S, et al. (1997). "Expression of FGF5 in choroidal neovascular membranes associated with ARMD". Curr. Eye Res. 16 (4): 396–9. doi:10.1076/ceyr.16.4.396.10685. PMID 9134330. 
  • Schneeberger SA, Hjelmeland LM, Tucker RP, Morse LS (1997). "Vascular endothelial growth factor and fibroblast growth factor 5 are colocalized in vascular and avascular epiretinal membranes". Am. J. Ophthalmol. 124 (4): 447–54. doi:10.1016/s0002-9394(14)70861-x. PMID 9323936. 
  • Kornmann M, Ishiwata T, Beger HG, Korc M (1997). "Fibroblast growth factor-5 stimulates mitogenic signaling and is overexpressed in human pancreatic cancer: evidence for autocrine and paracrine actions". Oncogene. 15 (12): 1417–24. doi:10.1038/sj.onc.1201307. PMID 9333017. 
  • Ozawa K, Suzuki S, Asada M, et al. (1998). "An alternatively spliced fibroblast growth factor (FGF)-5 mRNA is abundant in brain and translates into a partial agonist/antagonist for FGF-5 neurotrophic activity". J. Biol. Chem. 273 (44): 29262–71. doi:10.1074/jbc.273.44.29262. PMID 9786939. 
  • de Vries CJ, van Achterberg TA, Horrevoets AJ, et al. (2000). "Differential display identification of 40 genes with altered expression in activated human smooth muscle cells. Local expression in atherosclerotic lesions of smags, smooth muscle activation-specific genes". J. Biol. Chem. 275 (31): 23939–47. doi:10.1074/jbc.M910099199. PMID 10823842. 
  • Hanada K, Perry-Lalley DM, Ohnmacht GA, et al. (2001). "Identification of fibroblast growth factor-5 as an overexpressed antigen in multiple human adenocarcinomas". Cancer Res. 61 (14): 5511–6. PMID 11454700. 
  • Kornmann M, Lopez ME, Beger HG, Korc M (2002). "Expression of the IIIc variant of FGF receptor-1 confers mitogenic responsiveness to heparin and FGF-5 in TAKA-1 pancreatic ductal cells". Int. J. Pancreatol. 29 (2): 85–92. doi:10.1385/IJGC:29:2:085. PMID 11876253. 
  • Sieuwerts AM, Martens JW, Dorssers LC, et al. (2003). "Differential effects of fibroblast growth factors on expression of genes of the plasminogen activator and insulin-like growth factor systems by human breast fibroblasts". Thromb. Haemost. 87 (4): 674–83. PMID 12008951. 
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241Freely accessible. PMID 12477932.