Fibroblast growth factor 4 is a protein that in humans is encoded by the FGF4gene.[5][6]
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 gene was identified by its oncogenic transforming activity. This gene and FGF3, another oncogenic growth factor, are located closely on chromosome 11. Co-amplification of both genes was found in various kinds of human tumors. Studies on the mouse homolog suggested a function in bone morphogenesis and limb development through the sonic hedgehog (SHH) signaling pathway.[6]
Function
During embryonic development, the 21-kD protein FGF4 acts as a signaling molecule critical for cell survival, proliferation, and patterning. It facilitates the survival and growth of the inner cell mass during the postimplantation phase by functioning as an autocrine or paracrine ligand.[7][8] In the apical ectodermal ridge (AER), FGF4 plays a key role in initiating and sustaining limb bud outgrowth for both forelimbs and hindlimbs.[9] It also regulates limb digit number and programmed cell death in the interdigital mesenchyme.[10] Altered levels or regulation of FGF4 can lead to limb abnormalities such as postaxial polydactyly and cutaneous syndactyly, collectively known as polysyndactyly. In the absence of Fgf8, FGF4 is able to compensate by rescuing skeletal defects, indicating overlapping functions of FGF4 and FGF8 in limb skeleton patterning.[10] In zebrafish, FGF4 is required for establishing the correct left-right patterning of visceral organs such as the liver, pancreas, and heart. In this context, FGF4 functions independently of FGF8, highlighting their distinct roles in visceral organ development.[11]
Fgf signaling pathway has also been demonstrated to drive hindgut identity during gastrointestinal development, and the up regulation of the Fgf4 in pluripotent stem cell has been used to direct their differentiation for the generation of intestinal Organoids and tissues in vitro.[12]
Clinical significance
In canines, FGF4 retrogene insertions on chromosomes 12 and 18 have important clinical implications, particularly in relation to skeletal morphology and intervertebral disc disease (IVDD). These insertions are associated with disproportionate dwarfism characterized by shortened limbs and abnormal vertebral development.[13][14]
The FGF4 retrogene on chromosome 12 is particularly associated with chondrodystrophy, a condition marked by shortened long bones, premature degeneration of intervertebral discs, and increased susceptibility to IVDD. These dogs often develop clinical symptoms such as spinal pain, limb weakness, and in severe cases, paralysis.[13][14]
Meanwhile, the insertion on chromosome 18 contributes to a similar short-limbed phenotype but with variable impact on disc health. Recognition of these genetic variants has practical implications for veterinary care and breeding strategies, especially in predisposed breeds like Dachshunds, Corgis, and Basset Hounds.[13]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Galland F, Stefanova M, Lafage M, Birnbaum D (Jul 1992). "Localization of the 5' end of the MCF2 oncogene to human chromosome 15q15----q23". Cytogenetics and Cell Genetics. 60 (2): 114–116. doi:10.1159/000133316. PMID1611909.
^Yamauchi H, Miyakawa N, Miyake A, Itoh N (August 2009). "Fgf4 is required for left-right patterning of visceral organs in zebrafish". Developmental Biology. 332 (1): 177–185. doi:10.1016/j.ydbio.2009.05.568. PMID19481538.
^Lancaster MA, Knoblich JA (July 2014). "Organogenesis in a dish: modeling development and disease using organoid technologies". Science. 345 (6194): 1247125. doi:10.1126/science.1247125. PMID25035496. S2CID16105729.
Wada A, Sakamoto H, Katoh O, Yoshida T, Yokota J, Little PF, et al. (December 1988). "Two homologous oncogenes, HST1 and INT2, are closely located in human genome". Biochemical and Biophysical Research Communications. 157 (2): 828–835. doi:10.1016/S0006-291X(88)80324-3. PMID2974287.
Huebner K, Ferrari AC, Delli Bovi P, Croce CM, Basilico C (1989). "The FGF-related oncogene, K-FGF, maps to human chromosome region 11q13, possibly near int-2". Oncogene Research. 3 (3): 263–270. PMID3060803.
Adelaide J, Mattei MG, Marics I, Raybaud F, Planche J, De Lapeyriere O, et al. (April 1988). "Chromosomal localization of the hst oncogene and its co-amplification with the int.2 oncogene in a human melanoma". Oncogene. 2 (4): 413–416. PMID3283658.
Helland R, Berglund GI, Otlewski J, Apostoluk W, Andersen OA, Willassen NP, et al. (January 1999). "High-resolution structures of three new trypsin-squash-inhibitor complexes: a detailed comparison with other trypsins and their complexes". Acta Crystallographica. Section D, Biological Crystallography. 55 (Pt 1): 139–148. Bibcode:1999AcCrD..55..139H. doi:10.1107/S090744499801052X. PMID10089404.
Britto JA, Evans RD, Hayward RD, Jones BM (December 2001). "From genotype to phenotype: the differential expression of FGF, FGFR, and TGFbeta genes characterizes human cranioskeletal development and reflects clinical presentation in FGFR syndromes". Plastic and Reconstructive Surgery. 108 (7): 2026–39, discussion 2040–6. doi:10.1097/00006534-200112000-00030. PMID11743396.
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): 674–683. doi:10.1055/s-0037-1613065. PMID12008951. S2CID13862591.
Koh KR, Ohta K, Nakamae H, Hino M, Yamane T, Takubo T, et al. (October 2002). "Differential effects of fibroblast growth factor-4, epidermal growth factor and transforming growth factor-beta1 on functional development of stromal layers in acute myeloid leukemia". Leukemia Research. 26 (10): 933–938. doi:10.1016/S0145-2126(02)00033-4. PMID12163055.
Lopez-Sanchez C, Climent V, Schoenwolf GC, Alvarez IS, Garcia-Martinez V (August 2002). "Induction of cardiogenesis by Hensen's node and fibroblast growth factors". Cell and Tissue Research. 309 (2): 237–249. doi:10.1007/s00441-002-0567-2. PMID12172783. S2CID11783465.
