FGF5

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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

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

Research comparing dogs with different coat lengths has demonstrated FGF5 as a major contributing factor
Research comparing different breeds of dogs has demonstrated FGF5 as a major contributing factor in coat length.

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]

References

  1. ↑ Ornitz DM, Itoh N. "The Fibroblast Growth Factor signaling pathway". Wiley Interdisciplinary Reviews: Developmental Biology. 4 (3): 215–66. doi:10.1002/wdev.176. PMC 4393358. PMID 25772309.
  2. ↑ 2.0 2.1 Suzuki S, Kato T, Takimoto H, Masui S, Oshima H, Ozawa K, Suzuki S, Imamura T (December 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". The Journal of Investigative Dermatology. 111 (6): 963–72. doi:10.1046/j.1523-1747.1998.00427.x. PMID 9856803.
  3. ↑ 3.0 3.1 Suzuki S, Ota Y, Ozawa K, Imamura T (March 2000). "Dual-mode regulation of hair growth cycle by two Fgf-5 gene products". The Journal of Investigative Dermatology. 114 (3): 456–63. doi:10.1046/j.1523-1747.2000.00912.x. PMID 10692103.
  4. ↑ 4.0 4.1 Rosenquist TA, Martin GR (April 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". Developmental Dynamics. 205 (4): 379–86. doi:10.1002/(SICI)1097-0177(199604)205:4<379::AID-AJA2>3.0.CO;2-F. PMID 8901049.
  5. ↑ 5.0 5.1 Ota Y, Saitoh Y, Suzuki S, Ozawa K, Kawano M, Imamura T (January 2002). "Fibroblast growth factor 5 inhibits hair growth by blocking dermal papilla cell activation". Biochemical and Biophysical Research Communications. 290 (1): 169–76. doi:10.1006/bbrc.2001.6140. PMID 11779149.
  6. ↑ He X, Chao Y, Zhou G, Chen Y (January 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. 575 (2 Pt 2): 393–398. doi:10.1016/j.gene.2015.09.034. PMID 26390813.
  7. ↑ 7.0 7.1 Higgins CA, Petukhova L, Harel S, Ho YY, Drill E, Shapiro L, Wajid M, Christiano AM (July 2014). "FGF5 is a crucial regulator of hair length in humans". Proceedings of the National Academy of Sciences of the United States of America. 111 (29): 10648–53. doi:10.1073/pnas.1402862111. PMC 4115575. PMID 24989505.
  8. ↑ 8.0 8.1 8.2 Hébert JM, Rosenquist T, Götz J, Martin GR (September 1994). "FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations". Cell. 78 (6): 1017–25. PMID 7923352.
  9. ↑ Drögemüller C, Rüfenacht S, Wichert B, Leeb T (June 2007). "Mutations within the FGF5 gene are associated with hair length in cats". Animal Genetics. 38 (3): 218–21. doi:10.1111/j.1365-2052.2007.01590.x. PMID 17433015.
  10. ↑ Kehler JS, David VA, Schäffer AA, Bajema K, Eizirik E, Ryugo DK, Hannah SS, O'Brien SJ, Menotti-Raymond M. "Four independent mutations in the feline fibroblast growth factor 5 gene determine the long-haired phenotype in domestic cats". The Journal of Heredity. 98 (6): 555–66. doi:10.1093/jhered/esm072. PMC 3756544. PMID 17767004.
  11. ↑ Dierks C, Mömke S, Philipp U, Distl O (August 2013). "Allelic heterogeneity of FGF5 mutations causes the long-hair phenotype in dogs". Animal Genetics. 44 (4): 425–31. doi:10.1111/age.12010. PMID 23384345.
  12. ↑ Housley DJ, Venta PJ (August 2006). "The long and the short of it: evidence that FGF5 is a major determinant of canine 'hair'-itability". Animal Genetics. 37 (4): 309–15. doi:10.1111/j.1365-2052.2006.01448.x. PMID 16879338.
  13. ↑ Li CX, Jiang MS, Chen SY, Lai SJ (July 2008). "[Correlation analysis between single nucleotide polymorphism of FGF5 gene and wool yield in rabbits]". Yi Chuan = Hereditas. 30 (7): 893–9. PMID 18779133.
  14. ↑ Legrand R, Tiret L, Abitbol M (September 2014). "Two recessive mutations in FGF5 are associated with the long-hair phenotype in donkeys". Genetics, Selection, Evolution. 46: 65. doi:10.1186/s12711-014-0065-5. PMC 4175617. PMID 25927731.
  15. ↑ Liu HY, Yang GQ, Zhang W, Zhu XP, Jia ZH (February 2009). "[Effects of FGF5 gene on fibre traits on Inner Mongolian cashmere goats]". Yi Chuan = Hereditas. 31 (2): 175–9. PMID 19273426.
  16. ↑ Wang X, Cai B, Zhou J, Zhu H, Niu Y, Ma B, Yu H, Lei A, Yan H, Shen Q, Shi L, Zhao X, Hua J, Huang X, Qu L, Chen Y. "Disruption of FGF5 in Cashmere Goats Using CRISPR/Cas9 Results in More Secondary Hair Follicles and Longer Fibers". PLOS One. 11 (10): e0164640. doi:10.1371/journal.pone.0164640. PMC 5068700. PMID 27755602.
  17. ↑ Chen Z, Wang Z, Xu S, Zhou K, Yang G (February 2013). "Characterization of hairless (Hr) and FGF5 genes provides insights into the molecular basis of hair loss in cetaceans". BMC Evolutionary Biology. 13: 34. doi:10.1186/1471-2148-13-34. PMC 3608953. PMID 23394579.
  18. ↑ Heilmann-Heimbach S, Herold C, Hochfeld LM, Hillmer AM, Nyholt DR, Hecker J, et al. (March 2017). "Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness". Nature Communications. 8: 14694. doi:10.1038/ncomms14694. PMC 5344973. PMID 28272467.
  19. ↑ 19.0 19.1 19.2 Maeda T, Yamamoto T, Isikawa Y, 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. 69 (1): 81–86. doi:10.2336/nishinihonhifu.69.81.
  20. ↑ 20.0 20.1 20.2 Burg D, Yamamoto M, Namekata M, Haklani J, Koike K, Halasz M. "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". Clinical, Cosmetic and Investigational Dermatology. 10: 71–85. doi:10.2147/CCID.S123401. PMC 5338843. PMID 28280377.

Further reading

  • Li K, Stewart DJ, Ward HJ (April 1999). "Technology evaluation: gene therapy (FGF-5), Vical". Current Opinion in Molecular Therapeutics. 1 (2): 260–5. PMID 11715949.
  • Werner S, Roth WK, Bates B, Goldfarb M, Hofschneider PH (November 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 (October 1990). "Expression of the murine fibroblast growth factor 5 gene in the adult central nervous system". Proceedings of the National Academy of Sciences of the United States of America. 87 (20): 8022–6. doi:10.1073/pnas.87.20.8022. PMC 54884. PMID 1700424.
  • Bates B, Hardin J, Zhan X, Drickamer K, Goldfarb M (April 1991). "Biosynthesis of human fibroblast growth factor-5". Molecular and Cellular Biology. 11 (4): 1840–5. PMC 359856. PMID 2005884.
  • Hébert JM, Rosenquist T, Götz J, Martin GR (September 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, Nicolaides A, Zhang WC, Friedman-Kien AE (October 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 (May 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, 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.
  • Kitaoka T, Morse LS, Schneeberger S, Ishigooka H, Hjelmeland LM (April 1997). "Expression of FGF5 in choroidal neovascular membranes associated with ARMD". Current Eye Research. 16 (4): 396–9. doi:10.1076/ceyr.16.4.396.10685. PMID 9134330.
  • Schneeberger SA, Hjelmeland LM, Tucker RP, Morse LS (October 1997). "Vascular endothelial growth factor and fibroblast growth factor 5 are colocalized in vascular and avascular epiretinal membranes". American Journal of Ophthalmology. 124 (4): 447–54. doi:10.1016/s0002-9394(14)70861-x. PMID 9323936.
  • Kornmann M, Ishiwata T, Beger HG, Korc M (September 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, Tomooka Y, Li AJ, Yoneda A, Komi A, Imamura T (October 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". The Journal of Biological Chemistry. 273 (44): 29262–71. doi:10.1074/jbc.273.44.29262. PMID 9786939.
  • de Vries CJ, van Achterberg TA, Horrevoets AJ, ten Cate JW, Pannekoek H (August 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". The Journal of Biological Chemistry. 275 (31): 23939–47. doi:10.1074/jbc.M910099199. PMID 10823842.
  • Hanada K, Perry-Lalley DM, Ohnmacht GA, Bettinotti MP, Yang JC (July 2001). "Identification of fibroblast growth factor-5 as an overexpressed antigen in multiple human adenocarcinomas". Cancer Research. 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". International Journal of Pancreatology. 29 (2): 85–92. doi:10.1385/IJGC:29:2:085. PMID 11876253.
  • Sieuwerts AM, Martens JW, Dorssers LC, Klijn JG, Foekens JA (April 2002). "Differential effects of fibroblast growth factors on expression of genes of the plasminogen activator and insulin-like growth factor systems by human breast fibroblasts". Thrombosis and Haemostasis. 87 (4): 674–83. PMID 12008951.
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