Genomes and Genes
Gene Symbol: Fgf4
Description: fibroblast growth factor 4
Alias: Fgf-4, Fgfk, HBGF-4, Hst1, Hstf-1, KS3, hst, hst-1, kFGF, fibroblast growth factor 4, K-fibroblast growth factor, heparin-binding growth factor 4
- Niswander L, Martin G. Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse. Development. 1992;114:755-68 pubmed..Taken together, the data suggest that individual members of the gene family are expressed sequentially in developmental pathways such as mesoderm formation and myogenesis, and play a role in specific epithelial-mesenchymal interactions. ..
- Feldman B, Poueymirou W, Papaioannou V, DeChiara T, Goldfarb M. Requirement of FGF-4 for postimplantation mouse development. Science. 1995;267:246-9 pubmed..a means of elucidating embryonic functions of FGF-4, gene targeting was used to generate mice harboring a disrupted Fgf4 gene...
- te Welscher P, Zuniga A, Kuijper S, Drenth T, Goedemans H, Meijlink F, et al. Progression of vertebrate limb development through SHH-mediated counteraction of GLI3. Science. 2002;298:827-30 pubmed..Our genetic analysis indicates that SHH signaling counteracts GLI3-mediated repression of key regulator genes, cell survival, and distal progression of limb bud development. ..
- Miyagawa S, Moon A, Haraguchi R, Inoue C, Harada M, Nakahara C, et al. Dosage-dependent hedgehog signals integrated with Wnt/beta-catenin signaling regulate external genitalia formation as an appendicular program. Development. 2009;136:3969-78 pubmed publisher..Fgf8 induces phosphorylation of Erk1/2 and cell proliferation in the GT mesenchyme in vitro, yet Fgf4/8 compound-mutant phenotypes indicate dispensable functions of Fgf4/8 and the possibility of redundancy among ..
- Avilion A, Nicolis S, Pevny L, Perez L, Vivian N, Lovell Badge R. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 2003;17:126-40 pubmed..and at transient high levels for extraembryonic endoderm, but also indirectly through its role in regulating Fgf4 expression, for the establishment and proliferation of extraembryonic ectoderm from polar trophectoderm...
- Verheyden J, Sun X. An Fgf/Gremlin inhibitory feedback loop triggers termination of limb bud outgrowth. Nature. 2008;454:638-41 pubmed publisher..Our 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. ..
- Wang X, Suomalainen M, Jorgez C, Matzuk M, Wankell M, Werner S, et al. Modulation of activin/bone morphogenetic protein signaling by follistatin is required for the morphogenesis of mouse molar teeth. Dev Dyn. 2004;231:98-108 pubmed..We propose that finely tuned antagonistic effects between follistatin and TGF beta superfamily signals are critical for enamel knot formation and function, as well as for patterning of tooth cusps. ..
- Sagai T, Hosoya M, Mizushina Y, Tamura M, Shiroishi T. Elimination of a long-range cis-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb. Development. 2005;132:797-803 pubmed..These results suggest that the conserved intronic sequence evolved in a common ancestor of fishes and tetrapods to control fin and limb development. ..
- Lewandoski M, Sun X, Martin G. Fgf8 signalling from the AER is essential for normal limb development. Nat Genet. 2000;26:460-3 pubmed..Of the four mouse Fgf genes (Fgf4 , Fgf8, Fgf9, Fgf17) known to display AER-specific expression domains within the limb bud (AER-Fgfs), only Fgf8 is ..
- Sheth R, Bastida M, Ros M. Hoxd and Gli3 interactions modulate digit number in the amniote limb. Dev Biol. 2007;310:430-41 pubmed..Our results also support the notion that an adequate balance between positive and negative effects of different Hoxd genes is required for pentadactyly. ..
- Wilder P, Kelly D, Brigman K, Peterson C, Nowling T, Gao Q, et al. Inactivation of the FGF-4 gene in embryonic stem cells alters the growth and/or the survival of their early differentiated progeny. Dev Biol. 1997;192:614-29 pubmed..Thus, ES cells with both FGF-4 alleles inactivated should shed light on the important roles of FGF-4 during the early stages of mammalian development and help determine why FGF-4-/- embryos die shortly after implantation. ..
- Krawchuk D, Honma Yamanaka N, Anani S, Yamanaka Y. FGF4 is a limiting factor controlling the proportions of primitive endoderm and epiblast in the ICM of the mouse blastocyst. Dev Biol. 2013;384:65-71 pubmed publisher..To test this model, we reduced the amount of FGF4, the major FGF in the preimplantation embryo, using various genotypes of Fgf4 mutants...
- Chiang C, Litingtung Y, Harris M, Simandl B, Li Y, Beachy P, et al. Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev Biol. 2001;236:421-35 pubmed..According to this model, the limb bud signaling centers, including the zone of polarizing activity (ZPA) acting through Shh, are required to elaborate upon the axial information provided by the native limb field prepattern. ..
- Zuniga A, Haramis A, McMahon A, Zeller R. Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Nature. 1999;401:598-602 pubmed..fibroblast growth factor (FGF)4 signalling by the posterior AER, which in turn maintains the polarizing region (SHH/FGF4 feedback loop)...
- Nishioka N, Yamamoto S, Kiyonari H, Sato H, Sawada A, Ota M, et al. Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos. Mech Dev. 2008;125:270-83 pubmed
- Buscher D, Bosse B, Heymer J, Ruther U. Evidence for genetic control of Sonic hedgehog by Gli3 in mouse limb development. Mech Dev. 1997;62:175-82 pubmed..This data suggest that Gli3 is a regulator of Shh expression in mouse limb development. ..
- Jernvall J, Aberg T, Kettunen P, Keranen S, Thesleff I. The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot. Development. 1998;125:161-9 pubmed..These results show that the life history of the enamel knot is intimately linked to the initiation of tooth shape development and support the role of the enamel knot as an embryonic signaling center. ..
- Parr B, McMahon A. Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb. Nature. 1995;374:350-3 pubmed..Many mutant mice also lack posterior digits, demonstrating that Wnt-7a is also required for anterior-posterior patterning. We propose that normal limb development requires interactions between the signalling systems for these two axes. ..
- Kang M, Piliszek A, Artus J, Hadjantonakis A. FGF4 is required for lineage restriction and salt-and-pepper distribution of primitive endoderm factors but not their initial expression in the mouse. Development. 2013;140:267-79 pubmed publisher..Here, we investigated the phenotype resulting from zygotic and maternal/zygotic inactivation of Fgf4. Fgf4 heterozygous blastocysts exhibited increased numbers of NANOG-positive EPI cells and reduced numbers of GATA6-..
- Harfe B, Scherz P, Nissim S, Tian H, McMahon A, Tabin C. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell. 2004;118:517-28 pubmed..Genetic studies of the effects of limiting accessibility of Shh within the limb support this model, in which the effect of the Shh morphogen is dictated by a temporal as well as a spatial gradient. ..
- Kratochwil K, Galceran J, Tontsch S, Roth W, Grosschedl R. FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Genes Dev. 2002;16:3173-85 pubmed..function and find that the epithelium of the developmentally arrested Lef1(-/-) tooth rudiments fails to express Fgf4, Shh, and Bmp4, but not Wnt10a...
- Litingtung Y, Dahn R, Li Y, Fallon J, Chiang C. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature. 2002;418:979-83 pubmed
- te Welscher P, Fernandez Teran M, Ros M, Zeller R. Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling. Genes Dev. 2002;16:421-6 pubmed..These interactions polarize the nascent limb bud mesenchyme prior to SHH signaling. ..
- Sun X, Meyers E, Lewandoski M, Martin G. Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev. 1999;13:1834-46 pubmedFgf8 and Fgf4 encode FGF family members that are coexpressed in the primitive streak of the gastrulating mouse embryo. We have analyzed the phenotype of Fgf8(-/-) embryos and discovered that they fail to express Fgf4 in the streak...
- Heymer J, Ruther U. Syndactyly of Ft/+ mice correlates with an imbalance in bmp4 and fgf8 expression. Mech Dev. 1999;88:173-81 pubmed..The data suggest a negative effect of Bmp4 on Fgf8 expression and a positive influence on the induction of bone elements. ..
- Yang Y, Guillot P, Boyd Y, Lyon M, McMahon A. Evidence that preaxial polydactyly in the Doublefoot mutant is due to ectopic Indian Hedgehog signaling. Development. 1998;125:3123-32 pubmed..in the ectopic activation of several genes associated with anterior-posterior and proximal-distal patterning (Fgf4, Hoxd13, Bmp2)...
- Michos O, Panman L, Vintersten K, Beier K, Zeller R, Zuniga A. Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development. 2004;131:3401-10 pubmed..As a consequence, the metanephric mesenchyme is eliminated by apoptosis, in the same way as the core mesenchymal cells of the limb bud. ..
- Zuniga A, Zeller R. Gli3 (Xt) and formin (ld) participate in the positioning of the polarising region and control of posterior limb-bud identity. Development. 1999;126:13-21 pubmed..Concurrently, Gli3 functions independently of formin during initial posterior nesting of 5'HoxD domains, whereas their subsequent distal restriction and anterior expansion depends on genetic interaction of Gli3 and formin. ..
- Khokha M, Hsu D, Brunet L, Dionne M, Harland R. Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning. Nat Genet. 2003;34:303-7 pubmed..Although Bmps and their antagonists have multiple roles in limb development, these experiments show that gremlin is the principal BMP antagonist required for early limb outgrowth and patterning. ..
- Zhao X, Zhang Z, Song Y, Zhang X, Zhang Y, Hu Y, et al. Transgenically ectopic expression of Bmp4 to the Msx1 mutant dental mesenchyme restores downstream gene expression but represses Shh and Bmp2 in the enamel knot of wild type tooth germ. Mech Dev. 2000;99:29-38 pubmed..Expression of Shh and Bmp2 in the enamel knot may not represent critical signals for tooth patterning. ..
- Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe Nebenius D, Chambers I, et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998;95:379-91 pubmed..Expansion of trophoblast precursors is restored, however, by an Oct4 target gene product, fibroblast growth factor-4. Therefore, Oct4 also determines paracrine growth factor signaling from stem cells to the trophectoderm. ..
- Bénazet J, Bischofberger M, Tiecke E, Gonçalves A, Martin J, Zuniga A, et al. A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning. Science. 2009;323:1050-3 pubmed publisher..This self-regulatory signaling network results in robust regulation of distal limb development that is able to compensate for variations by interconnectivity among the three signaling pathways. ..
- Lu P, Minowada G, Martin G. Increasing Fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function. Development. 2006;133:33-42 pubmed..However, when both Fgf8 and Fgf4 are simultaneously inactivated in the AER, the limb does not develop...
- Sun X, Mariani F, Martin G. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature. 2002;418:501-8 pubmed..the role of fibroblast growth factor (FGF) signalling from the apical ectodermal ridge (AER), we inactivated Fgf4 and Fgf8 in AER cells or their precursors at different stages of mouse limb development...
- Yuan H, Corbi N, Basilico C, Dailey L. Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes Dev. 1995;9:2635-45 pubmedb>Fibroblast growth factor 4 (FGF-4) has been shown to be a signaling molecule whose expression is essential for postimplantation mouse development and, at later embryonic stages, for limb patterning and growth...
- Hayes C, Brown J, Lyon M, Morriss Kay G. Sonic hedgehog is not required for polarising activity in the Doublefoot mutant mouse limb bud. Development. 1998;125:351-7 pubmed..upregulation of the direct Shh target genes Ptc and Gli, and induction of the downstream target genes Bmp2, Fgf4 and Hoxd13...
- Seifert A, Yamaguchi T, Cohn M. Functional and phylogenetic analysis shows that Fgf8 is a marker of genital induction in mammals but is not required for external genital development. Development. 2009;136:2643-51 pubmed publisher..We propose that induction of external genitalia involves an epithelial-epithelial interaction at the cloacal membrane, and suggest that the cloacal ectoderm may be the source of the genital initiation signal...
- Haraguchi R, Suzuki K, Murakami R, Sakai M, Kamikawa M, Kengaku M, et al. Molecular analysis of external genitalia formation: the role of fibroblast growth factor (Fgf) genes during genital tubercle formation. Development. 2000;127:2471-9 pubmed..These results suggest that the FGF system is a key element in orchestrating GT development. ..
- Kunath T, Saba El Leil M, Almousailleakh M, Wray J, Meloche S, Smith A. FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development. 2007;134:2895-902 pubmed..Here, we delineate the role of autocrine production of fibroblast growth factor 4 (Fgf4) and associated activation of the Erk1/2 (Mapk3/1) signalling cascade...
- Barna M, Pandolfi P, Niswander L. Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. Nature. 2005;436:277-81 pubmed..The initial division of the vertebrate limb into two distinct molecular domains is consistent with fossil evidence indicating that the upper and lower extremities of the limb have different evolutionary origins. ..
- Mariani F, Ahn C, Martin G. Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning. Nature. 2008;453:401-5 pubmed publisher..Fibroblast growth factor (FGF) gene family members are key AER-derived signals, with Fgf4, Fgf8, Fgf9 and Fgf17 expressed specifically in the mouse AER...
- Zeng H, Hoover A, Liu A. PCP effector gene Inturned is an important regulator of cilia formation and embryonic development in mammals. Dev Biol. 2010;339:418-28 pubmed publisher..In conclusion, we show that PCP effector gene Intu is an important regulator of cilia formation, Hh signal transduction, and embryonic development in mammals. ..
- Scherz P, McGlinn E, Nissim S, Tabin C. Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb. Dev Biol. 2007;308:343-54 pubmed
- Azami T, Waku T, Matsumoto K, Jeon H, Muratani M, Kawashima A, et al. Klf5 maintains the balance of primitive endoderm versus epiblast specification during mouse embryonic development by suppression of Fgf4. Development. 2017;144:3706-3718 pubmed publisher..ERK) signalling is involved in segregation of the EPI and PrE lineages; however, the mechanism involved in Fgf4 regulation is poorly understood...
- Mason I, Fuller Pace F, Smith R, Dickson C. FGF-7 (keratinocyte growth factor) expression during mouse development suggests roles in myogenesis, forebrain regionalisation and epithelial-mesenchymal interactions. Mech Dev. 1994;45:15-30 pubmed..Our results suggest that FGF-7 is likely to have diverse roles during development. ..
- Hardcastle Z, Mo R, Hui C, Sharpe P. The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Development. 1998;125:2803-11 pubmed..These results show an essential role for Shh signalling in tooth development that involves functional redundancy of downstream Gli genes...
- Cai C, Liang X, Shi Y, Chu P, Pfaff S, Chen J, et al. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 2003;5:877-89 pubmed..Our results have implications for the development of specific cardiac lineages, left-right asymmetry, cardiac evolution, and isolation of cardiac progenitor cells. ..
- Pispa J, Jung H, Jernvall J, Kettunen P, Mustonen T, Tabata M, et al. Cusp patterning defect in Tabby mouse teeth and its partial rescue by FGF. Dev Biol. 1999;216:521-34 pubmed..Instead FGF-10 partially restored morphogenesis and stimulated the development of additional tooth cusps in cultured Tabby molars. ..
- Simmons D, Cross J. Determinants of trophoblast lineage and cell subtype specification in the mouse placenta. Dev Biol. 2005;284:12-24 pubmed..Here, we review recent insights into the molecular pathways regulating trophoblast lineage segregation, stem cell maintenance, and subtype differentiation. ..
- Kitajima S, Takagi A, Inoue T, Saga Y. MesP1 and MesP2 are essential for the development of cardiac mesoderm. Development. 2000;127:3215-26 pubmed..These results strongly indicate that the defect in the cranial-cardiac mesoderm is cell-autonomous, whereas the defect in the paraxial mesoderm is a non-cell-autonomous secondary consequence. ..
- Boer B, Bernadt C, Desler M, Wilder P, Kopp J, Rizzino A. Differential activity of the FGF-4 enhancer in F9 and P19 embryonal carcinoma cells. J Cell Physiol. 2006;208:97-108 pubmed
- Fraidenraich D, Iwahori A, Rudnicki M, Basilico C. Activation of fgf4 gene expression in the myotomes is regulated by myogenic bHLH factors and by sonic hedgehog. Dev Biol. 2000;225:392-406 pubmedThe Fgf4 gene encodes an important signaling molecule which is expressed in specific developmental stages, including the inner cell mass of the blastocyst, the myotomes, and the limb bud apical ectodermal ridge (AER)...
- Nightingale S, Western P, Hutson J. The migrating gubernaculum grows like a "limb bud". J Pediatr Surg. 2008;43:387-90 pubmed publisher..Hox genes and Fgfs may be fruitful areas of research to unravel the molecular control of gubernacular migration during testicular descent. ..
- Naiche L, Holder N, Lewandoski M. FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis. Proc Natl Acad Sci U S A. 2011;108:4018-23 pubmed publisher..Here we show that when both Fgf4 and Fgf8 are deleted in the PSM, expression of most PSM genes is absent, including cycling genes, WNT pathway genes,..
- Ma Y, Rosfjord E, Huebert C, Wilder P, Tiesman J, Kelly D, et al. Transcriptional regulation of the murine k-FGF gene in embryonic cell lines. Dev Biol. 1992;154:45-54 pubmed..Last, this study has identified regions upstream of the transcription start site that appear to regulate the expression of the murine k-FGF gene in EC cells and in ES cells. ..
- Yamaguchi T, Bradley A, McMahon A, Jones S. A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development. 1999;126:1211-23 pubmed..The reduced number of proliferating cells in both the progress zone and the primitive streak mesoderm suggests that one function of Wnt5a is to regulate the proliferation of progenitor cells. ..
- Nowling T, Bernadt C, Johnson L, Desler M, Rizzino A. The co-activator p300 associates physically with and can mediate the action of the distal enhancer of the FGF-4 gene. J Biol Chem. 2003;278:13696-705 pubmed..Our results also suggest that intragenic distal enhancers may use mechanisms that differ from extragenic distal enhancers. ..
- Huang C, Xiang Y, Wang Y, Li X, Xu L, Zhu Z, et al. Dual-specificity histone demethylase KIAA1718 (KDM7A) regulates neural differentiation through FGF4. Cell Res. 2010;20:154-65 pubmed publisher..that the pro-neural differentiation effect of KDM7A is mediated through direct transcriptional activation of FGF4, a signal molecule implicated in neural differentiation...