Alternative titles; symbols
HGNC Approved Gene Symbol: FGF4
Cytogenetic location: 11q13.3 Genomic coordinates (GRCh38): 11:69,771,022-69,775,341 (from NCBI)
Sakamoto et al. (1986) tested the capacity for malignant transformation of DNA from 21 stomach cancers, 16 stomach cancers metastatic to lymph nodes, and 21 specimens of apparently noncancerous stomach mucosa from a total of 26 patients with stomach cancer. The DNA was transferred to NIH 3T3 cells by the calcium precipitation technique. Transforming ability was shown by 3 samples: a primary cancer, a metastatic cancer, and a presumably normal gastric mucosa. The transforming gene from the primary cancer was cloned. It bore no homology with previously reported transforming sequences. Taira et al. (1987) isolated an HST cDNA clone that had an efficient transforming activity in a focus-forming assay when it was inserted into an expression vector. Characterization of this clone allowed Taira et al. (1987) to predict that a 206-amino acid protein product was responsible for this transforming activity. In an addendum, Taira et al. (1987) indicated that 42.3% homology existed between the amino acid residues of 1 ORF (open reading frame) of HST and part of bovine basic fibroblast growth factor. They suggested that further studies would elucidate the role of the HST gene in the development of stomach cancer which, they stated, has the highest incidence of all known cancers.
Both HST and INT2 (164950) are in the fibroblast growth factor family of oncogenes. Yoshida et al. (1988) reported expression of HST1 in a human teratoma cell line and in 5 of 9 surgically resected human testicular germ cell tumors including seminomas and embryonal carcinomas. HST1, for which the designation HSTF1 was proposed for human gene nomenclature, is a heparin-binding growth factor with significant homology to human fibroblast growth factors and the mouse Int-2 protein. Huebner et al. (1988) isolated the same oncogene by transfection of Kaposi sarcoma DNA and demonstrated its significant homology to both basic and acidic FGFs ( see 134920 and 131220). Because of its origin from Kaposi sarcoma and because of its similarity to FGFs, they designated the oncogene 'K-FGF.'
Huebner et al. (1988) found that sequences adjacent to the 3-prime end of the K-FGF coding sequence in transfectants probably derived from the part of the genome lying between 12p12 and 12q13. Whether the juxtaposition of the chromosome 11-linked K-FGF gene to the chromosome 12-linked sequences within the original transfectants was pure accident remained to be determined. (It had earlier been demonstrated that sequences from the FMS oncogene on chromosome 5 were included in the transfectant.)
By in situ hybridization, Adelaide et al. (1988) mapped the HST gene to chromosome 11q13. This is also the location of the INT2 gene. Furthermore, Adelaide et al. (1988) found the 2 genes to be coamplified in a human melanoma.
Huebner et al. (1988) mapped the K-FGF oncogene to 11q11-q23 by hybridization studies using DNA from rodent-human somatic cell hybrids and then localized it more precisely to 11q13 by in situ hybridization. The 11q13 region is also the site of the BCL1 gene (168461), which is involved in the 11;14 translocation characteristic of some B-cell tumors; see 151400. The oncogene SEA (165110) has also been mapped to 11q13. By pulsed-field gel electrophoresis and by analysis of overlapping cosmid clones, Wada et al. (1988) concluded that HST1 is located about 35 kb downstream of INT2 in the same transcriptional orientation.
For a review of the role of this gene in limb development, see Johnson and Tabin (1997).
Zuniga et al. (1999) reported that the secreted bone morphogenetic protein (BMP) antagonist gremlin (GREM1; 603054) relays the Sonic hedgehog (SHH; 600725) signal from the polarizing region to the apical ectodermal ridge. Mesenchymal gremlin expression is lost in limb buds of mouse embryos homozygous for the 'limb deformity' (ld) mutation, which disrupts establishment of the Snhh/Fgf4 feedback loop. Grafting gremlin-expressing cells into ld mutant limb buds rescued Fgf4 expression and restored the Shh/Fgf4 feedback loop. Analysis of Shh-null mutant embryos revealed that Shh signaling is required for maintenance of gremlin and formin (FMN1; 136535), the gene disrupted by the ld mutations. In contrast, formin, gremlin, and Fgf4 activation were independent of Shh signaling. Zuniga et al. (1999) concluded that the study uncovered the cascade by which the SHH signal is relayed from the posterior mesenchyme to the apical ectodermal ridge and established that formin-dependent activation of the BMP antagonist gremlin is sufficient to induce FGF4 and establish the SHH/FGF4 feedback loop.
Kratochwil et al. (2002) concluded that FGF4 is a direct target of LEF1 (153245) and Wnt signaling during tooth development in mice. Kratochwil et al. (2002) showed that beads soaked with recombinant FGF4 protein could fully overcome the developmental arrest of tooth germs seen in Lef1-deficient mice. The FGF4 beads also induced delayed expression of Shh (600725) in the epithelium. Using a chemical inhibitor of FGF signaling, Kratochwil et al. (2002) was able to mimic the arrest of tooth development seen in Lef1-deficient mice. The authors hypothesized that the sole function of LEF1 in odontogenesis may be to activate Fgf4 and to connect the Wnt and FGF signaling pathways at a specific developmental step.
Vertebrate limb outgrowth is driven by a positive feedback loop involving SHH, gremlin, and FGF4. By overexpressing individual components of the loop at a time after these genes are normally downregulated in chicken embryos, Scherz et al. (2004) found that Shh no longer maintains gremlin in the posterior limb. Shh-expressing cells and their descendants cannot express gremlin. The proliferation of these descendants forms a barrier separating the Shh signal from gremlin-expressing cells, which breaks down the Shh-Fgf4 loop and thereby affects limb size and provides a mechanism explaining regulative properties of the limb bud.
Mariani et al. (2008) demonstrated that mouse limbs lacking Fgf4, Fgf9 (600921), and Fgf17 (603725) have normal skeletal pattern, indicating that Fgf8 (600483) is sufficient among apical ectodermal ridge fibroblast growth factors (AER-FGF) to sustain normal limb formation. Inactivation of Fgf8 alone causes a mild skeletal phenotype; however, when Mariani et al. (2008) also removed different combinations of the other AER-FGF genes, they obtained unexpected skeletal phenotypes of increasing severity, reflecting the contribution that each FGF can make to the total AER-FGF signal. Analysis of the compound mutant limb buds revealed that, in addition to sustaining cell survival, AER-FGFs regulate proximal-distal patterning gene expression during early limb bud development, providing genetic evidence that AER-FGFs function to specify a distal domain and challenging the longstanding hypothesis that AER-FGF signaling is permissive rather than instructive for limb patterning. Mariani et al. (2008) also developed a 2-signal model for proximal-distal patterning to explain early specification.
Spence et al. (2011) established a robust and efficient process to direct the differentiation of human pluripotent stem cells into intestinal tissue in vitro using a temporal series of growth factor manipulations to mimic embryonic intestinal development. Using this culture system as a model to study human intestinal development, Spence et al. (2011) identified that the combined activity of WNT3A (606359) and FGF4 is required for hindgut specification, whereas FGF4 alone is sufficient to promote hindgut morphogenesis. Spence et al. (2011) concluded that human intestinal stem cells form de novo during development. Spence et al. (2011) also determined that NEUROG3 (604882) is both necessary and sufficient for human enteroendocrine cell development in vitro.
Feldman et al. (1995) demonstrated that Fgf4 -/- embryos die on embryonic day 5.0. To circumvent this early lethality and assess Fgf4 function in limb development, Sun et al. (2000) used the Cre/loxP system and found that Shh expression is maintained and limb formation is normal when Fgf4 is inactivated in mouse limbs, contradicting another model which suggested that Fgf4 expression is not maintained in Shh -/- mouse limbs. Sun et al. (2000) also found that maintenance of Fgf9 (600921) and Fgf17 (603725) expression is dependent on Shh, whereas Fgf8 (600483) expression is not. Sun et al. (2000) developed a model in which no individual Fgf expressed in the apical ectodermal ridge is solely necessary to maintain Shh expression, but instead the combined activity of 2 or more apical ectodermal ridge Fgfs function in a positive feedback loop with Shh to control limb development.
To determine the role of fibroblast growth factor signaling from the apical ectodermal ridge, Sun et al. (2002) inactivated Fgf4 and Fgf8 (600483) in apical ectodermal ridge cells or their precursors at different stages of mouse limb development. Sun et al. (2002) showed that Fgf4 and Fgf8 regulate cell number in the nascent limb bud and are required for survival of cells located far from the apical ectodermal ridge. On the basis of the skeletal phenotypes observed, Sun et al. (2002) concluded that these functions are essential to ensure that sufficient progenitor cells are available to form the normal complement of skeletal elements, and perhaps other limb tissues. In the absence of both Fgf4 and Fgf8 activities, limb development fails. None of 23 newborn double knockout mice examined had hindlimbs. In contrast, forelimbs contained elements of all 3 limb segments but were shorter and thinner than normal. Sun et al. (2002) found that in double homozygotes, forelimb proximal elements were invariably missing or severely hypoplastic when distal elements were present. They suggested that these observations argue against the progress zone model, which had been the prevailing model of limb proximal-distal patterning. Sun et al. (2002) hypothesized that limb skeletal patterning is achieved as a function of basic cellular processes including cell division, cell survival, and stereotypic behaviors of chondrocyte progenitors such as aggregate formation.
In a series of experiments involving removal of the apical ectodermal ridge from chick limb buds, Dudley et al. (2002) demonstrated that the various limb bud segments are specified early in limb development as distinct domains, with subsequent development involving expansion of progenitor populations before differentiation. Dudley et al. (2002) also found that the distal limb mesenchyme becomes progressively determined, that is, irreversibly fixed, to a progressively limited range of potential proximodistal fates. Their observations, coupled with those of Sun et al. (2002), refuted the progress zone model of vertebrate limb development.
Limb bud outgrowth is driven by signals in a positive feedback loop involving fibroblast growth factor genes, Sonic hedgehog (SHH; 600725), and gremlin-1 (GREM1; 603054). Precise termination of these signals is essential to restrict limb bud size. That the sequence in mouse limb buds is different from that in chick limb buds drove Verheyden and Sun (2008) to explore alternative mechanisms. By analyzing compound mouse mutants defective in genes comprising the positive loop, Verheyden and Sun (2008) provided genetic evidence that Fgf signaling can repress Grem1 expression, revealing a novel Fgf/Grem1 inhibitory loop. The repression occurs in both mouse and chick limb buds and is dependent on high Fgf activity. These data supported a mechanism where the positive Fgf/Shh loop drives outgrowth and an increase in Fgf signaling, which triggers the Fgf/Grem1 inhibitory loop. The inhibitory loop then operates to terminate outgrowth signals in the order observed in either mouse or chick limb buds. Verheyden and Sun (2008) concluded that their study unveils the concept of a self-promoting and self-terminating circuit that may be used to attain proper tissue size in a broad spectrum of developmental and regenerative settings. Verheyden and Sun (2008) demonstrated that Fgf8 repression of Fgf4 expression is dependent on Grem1 but not Sonic hedgehog.
Parker et al. (2009) used a multibreed association analysis in the domestic dog to demonstrate that expression of a recently acquired retrogene encoding Fgf4 is strongly associated with chondrodysplasia, a short-legged phenotype that defines at least 19 dog breeds including dachshund, corgi, and basset hound. Parker et al. (2009) identified an approximately 5-kb insert in affected dogs that contained a conserved Fgfr retrogene. Neither the introns nor the upstream promoters of the gene were present in the insert; however, all exons were present, with no alterations in the coding sequence, as well as the 3-prime untranslated region (UTR) and polyadenylate tail characteristic of retrotransposition of processed mRNA. Parker et al. (2009) then showed that the Fgfr retrogene is expressed. The retrogene is inserted in the middle of a long interspersed nuclear element (LINE) with both LINEs and SINEs upstream.
Naiche et al. (2011) showed that deletion of both Fgf4 and Fgf8 in presomitic mesoderm (PSM) of mouse embryos resulted in loss of expression of most PSM genes, including cycling genes, Wnt pathway genes, and markers of undifferentiated PSM. In contrast, markers of nascent somite cell fate expanded throughout the PSM. Restoration of Wnt signaling only partially restored PSM markers, and premature PSM differentiation continued. Naiche et al. (2011) concluded that FGF signaling operates independently of Wnt signaling to maintain the wavefront signal that controls somatogenesis and that FGF4 and FGF8 are the sole signaling mediators of this wavefront activity.
Boulet and Capecchi (2012) reported that loss of expression of both Fgf4 and Fgf8 in mice during late gastrulation resulted in thoracic vertebrae and ribs with abnormal morphology, malformed or absent lumbar and sacral vertebrae, and no tail vertebrae. Expression of Wnt3a in tail and transcription factor T (601397) in nascent mesoderm was severely reduced. Expression of genes in the Notch (see 190198) signaling pathway involved in segmentation were also severely affected. After production of 15 to 20 somites, somite formation ceased. The defects appeared to result from a failure to produce sufficient paraxial mesoderm. Boulet and Capecchi (2012) proposed that FGF4 and FGF8 are required to maintain a population of progenitor cells in the epiblast that generates mesoderm and contributes to the stem-cell population that is incorporated in the tailbud and required for axial elongation of the mouse embryo after gastrulation.
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