fibroblast growth factor 4


Summary: A HEPARIN binding fibroblast growth factor that may play a role in LIMB BUDS development.

Top Publications

  1. Dessimoz J, Opoka R, Kordich J, Grapin Botton A, Wells J. FGF signaling is necessary for establishing gut tube domains along the anterior-posterior axis in vivo. Mech Dev. 2006;123:42-55 pubmed
    ..These data show that FGF signaling is critical for patterning the gut tube by promoting posterior and inhibiting anterior endoderm cell fate. ..
  2. Guzman Ayala M, Ben Haim N, Beck S, Constam D. Nodal protein processing and fibroblast growth factor 4 synergize to maintain a trophoblast stem cell microenvironment. Proc Natl Acad Sci U S A. 2004;101:15656-60 pubmed
    ..Their proliferation depends on diffusible signals from neighboring cells in the epiblast, including fibroblast growth factor 4 (Fgf4)...
  3. 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
    ..Instead, depending on concentration, we noted no effect or conversion of all ICM cells to GATA6-positive PrE. We propose that heterogeneities in the availability of FGF produce the salt-and-pepper distribution of lineage-biased cells...
  4. Feldman B, Poueymirou W, Papaioannou V, DeChiara T, Goldfarb M. Requirement of FGF-4 for postimplantation mouse development. Science. 1995;267:246-9 pubmed
  5. Fernandes T, Kwon S, Bale S, Lee M, Diogo M, Clark D, et al. Three-dimensional cell culture microarray for high-throughput studies of stem cell fate. Biotechnol Bioeng. 2010;106:106-18 pubmed publisher
  6. Miller K, Rizzino A. Constitutive expression of fibroblast growth factor-4 does not alter the growth or the differentiation of embryonal carcinoma cells. Cell Growth Differ. 1996;7:203-11 pubmed
  7. Roth D, McKirnan M, Canestrelli I, Gao M, Dalton N, Lai N, et al. Intracoronary delivery of an adenovirus encoding fibroblast growth factor-4 in myocardial ischemia: effect of serum antibodies and previous exposure to adenovirus. Hum Gene Ther. 2006;17:230-8 pubmed
    ..FGF4, delivered by intracoronary injection, from normalizing regional myocardial function. ..
  8. Abell A, Granger D, Johnson N, Vincent Jordan N, Dibble C, Johnson G. Trophoblast stem cell maintenance by fibroblast growth factor 4 requires MEKK4 activation of Jun N-terminal kinase. Mol Cell Biol. 2009;29:2748-61 pubmed publisher
    ..stem (TS) cells cultured under undifferentiating, self-renewing conditions in the presence of fibroblast growth factor 4 (FGF4) display increased expression of Slug, Twist, and matrix metalloproteinase 2 (MMP2), loss of E-..
  9. Yang W, Klaman L, Chen B, Araki T, Harada H, Thomas S, et al. An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. Dev Cell. 2006;10:317-27 pubmed
    ..Bim depletion substantially blocks apoptosis and significantly restores Shp2 null TS cell proliferation, thereby establishing a key mechanism by which FGF4 controls stem cell survival. ..

More Information


  1. Kapur N, Rade J. Fibroblast growth factor 4 gene therapy for chronic ischemic heart disease. Trends Cardiovasc Med. 2008;18:133-41 pubmed publisher
    ..clinical trials have been conducted to determine the safety and efficacy of local delivery of fibroblast growth factor 4 with the use of adenovirus-vector-mediated gene transfer to induce myocardial angio-/arteriogenesis in ..
  2. Wells J, Melton D. Early mouse endoderm is patterned by soluble factors from adjacent germ layers. Development. 2000;127:1563-72 pubmed
    ..We conclude that the differentiation of gastrulation-stage endoderm is directed by adjacent mesoderm and ectoderm, one of the earliest reported patterning events in formation of the vertebrate gut tube. ..
  3. Gao M, Lai N, McKirnan M, Roth D, Rubanyi G, Dalton N, et al. Increased regional function and perfusion after intracoronary delivery of adenovirus encoding fibroblast growth factor 4: report of preclinical data. Hum Gene Ther. 2004;15:574-87 pubmed
    ..trials of intracoronary delivery of a replication-incompetent human adenovirus-5 vector encoding human fibroblast growth factor 4 (Ad5FGF4)...
  4. Rissanen T, Markkanen J, Arve K, Rutanen J, Kettunen M, Vajanto I, et al. Fibroblast growth factor 4 induces vascular permeability, angiogenesis and arteriogenesis in a rabbit hindlimb ischemia model. FASEB J. 2003;17:100-2 pubmed
    ..This study demonstrates for the first time that FGF-4 induces vascular permeability, therapeutic angiogenesis, and arteriogenesis comparable to that of VEGF and could be useful for the treatment of peripheral vascular disease. ..
  5. 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...
  6. Mayshar Y, Rom E, Chumakov I, Kronman A, Yayon A, Benvenisty N. Fibroblast growth factor 4 and its novel splice isoform have opposing effects on the maintenance of human embryonic stem cell self-renewal. Stem Cells. 2008;26:767-74 pubmed publisher
    ..Microarray analysis identified fibroblast growth factor 4 (FGF4) as a prime candidate for autocrine signaling...
  7. Wray J, Kalkan T, Smith A. The ground state of pluripotency. Biochem Soc Trans. 2010;38:1027-32 pubmed publisher
    ..The stability of this state is reflected in the homogeneity of ES cell populations cultured in the presence of small-molecule inhibitors of MEK (mitogen-activated protein kinase/ERK kinase) and GSK3. ..
  8. 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. ..
  9. Choi S, Kim S, Choi J, Park C, Shim W, Lim D. Fibroblast growth factor-2 and -4 promote the proliferation of bone marrow mesenchymal stem cells by the activation of the PI3K-Akt and ERK1/2 signaling pathways. Stem Cells Dev. 2008;17:725-36 pubmed publisher
    ..Taken together, these data suggest that FGF-2 and -4 promote the proliferation of Sca-1(+) BMMSCs by activation of the ERK1/2 and PI3K-Akt signaling pathways. ..
  10. Bobick B, Thornhill T, Kulyk W. Fibroblast growth factors 2, 4, and 8 exert both negative and positive effects on limb, frontonasal, and mandibular chondrogenesis via MEK-ERK activation. J Cell Physiol. 2007;211:233-43 pubmed
    ..Interestingly, the effects of FGF on late-stage frontonasal cells appear to be relayed by an ERK-independent system. ..
  11. 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. ..
  12. Kosaka N, Sakamoto H, Terada M, Ochiya T. Pleiotropic function of FGF-4: its role in development and stem cells. Dev Dyn. 2009;238:265-76 pubmed publisher
    ..In this review, we focus on the diverse biological functions of FGF-4 in the developmental process and also discuss its putative roles in stem cell biology. ..
  13. 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 pubmed
    b>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...
  14. Kosaka N, Kodama M, Sasaki H, Yamamoto Y, Takeshita F, Takahama Y, et al. FGF-4 regulates neural progenitor cell proliferation and neuronal differentiation. FASEB J. 2006;20:1484-5 pubmed
    The FGF-4 (fibroblast growth factor 4, known as HST-1) protein is an important mitogen for a variety of cell types...
  15. 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. ..
  16. Dailey L, Yuan H, Basilico C. Interaction between a novel F9-specific factor and octamer-binding proteins is required for cell-type-restricted activity of the fibroblast growth factor 4 enhancer. Mol Cell Biol. 1994;14:7758-69 pubmed
    ..One example is provided by the fibroblast growth factor 4 (FGF-4) gene, whose expression is restricted to specific embryonic tissues during development and to ..
  17. Frankenberg S, Gerbe F, Bessonnard S, Belville C, Pouchin P, Bardot O, et al. Primitive endoderm differentiates via a three-step mechanism involving Nanog and RTK signaling. Dev Cell. 2011;21:1005-13 pubmed publisher
    ..Thus, our results reveal three distinct phases in the PrE differentiation program. ..
  18. Hughes M, Dobric N, Scott I, Su L, Starovic M, St Pierre B, et al. The Hand1, Stra13 and Gcm1 transcription factors override FGF signaling to promote terminal differentiation of trophoblast stem cells. Dev Biol. 2004;271:26-37 pubmed
    ..By contrast, Hand1 and Stra13 promote cell cycle exit and restrict cells towards the TG fate, whereas Gcm1 promotes cell cycle exit and restriction towards the SynT fate. ..
  19. Rappolee D, Basilico C, Patel Y, Werb Z. Expression and function of FGF-4 in peri-implantation development in mouse embryos. Development. 1994;120:2259-69 pubmed
    ..These findings indicate that FGF-4 produced by undifferentiated ICM cells acts in the peri-implantation period of embryogenesis to influence the production and behavior of endoderm cells derived from them. ..
  20. 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. ..
  21. 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. ..
  22. Hirai K, Sasaki H, Yamamoto H, Sakamoto H, Kubota Y, Kakizoe T, et al. HST-1/FGF-4 protects male germ cells from apoptosis under heat-stress condition. Exp Cell Res. 2004;294:77-85 pubmed
    ..These results suggest that HST-1/FGF-4 can act as an important physiological anti-apoptotic factor for male germ cells in stimulating lactate production of Sertoli cells upon heat stress, thereby promoting germ cell survival. ..
  23. Akkarawongsa R, Cullinan A, Zinkel A, Clarin J, Brandt C. Corneal toxicity of cell-penetrating peptides that inhibit Herpes simplex virus entry. J Ocul Pharmacol Ther. 2006;22:279-89 pubmed
    ..Some slight epithelial cell sloughing was seen with the bKLA peptide in vivo. These results suggest that these CPPs-and EB in particular-have a favorable toxicity profile, and that further development is warranted. ..
  24. Erlebacher A, Price K, Glimcher L. Maintenance of mouse trophoblast stem cell proliferation by TGF-beta/activin. Dev Biol. 2004;275:158-69 pubmed
  25. Westerman B, Braat A, Taub N, Potman M, Vissers J, Blom M, et al. A genome-wide RNAi screen in mouse embryonic stem cells identifies Mp1 as a key mediator of differentiation. J Exp Med. 2011;208:2675-89 pubmed publisher
    ..b>Fibroblast growth factor 4 (FGF4) signaling is required for initial fate commitment of ES cells...
  26. Niswander L, Jeffrey S, Martin G, Tickle C. A positive feedback loop coordinates growth and patterning in the vertebrate limb. Nature. 1994;371:609-12 pubmed
    ..Moreover, Shh expression in mesenchyme can be activated by FGF4 in combination with retinoic acid. Once induced, Shh expression can be maintained by FGF4 alone, thus establishing a positive feedback loop between ZPA and ridge. ..
  27. Libri V, Onori A, Fanciulli M, Passananti C, Corbi N. The artificial zinc finger protein 'Blues' binds the enhancer of the fibroblast growth factor 4 and represses transcription. FEBS Lett. 2004;560:75-80 pubmed
    ..finger-based transcription factor, named Blues, able to bind and possibly to modify the expression of fibroblast growth factor 4 (FGF-4, K-fgf), originally identified as an oncogene...
  28. 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
    ..We conclude that the amount of FGF4 is limited and regulates PE/EPI proportions in the mouse embryo...
  29. Chan D, Wynshaw Boris A, Leder P. Formin isoforms are differentially expressed in the mouse embryo and are required for normal expression of fgf-4 and shh in the limb bud. Development. 1995;121:3151-62 pubmed
    ..although the AERs of ld limb buds express several AER markers, they do not express detectable levels of fibroblast growth factor 4 (fgf-4), which has been proposed to be the AER signal to the mesoderm...
  30. Filby C, Williamson R, van Kooy P, Pebay A, Dottori M, Elwood N, et al. Stimulation of Activin A/Nodal signaling is insufficient to induce definitive endoderm formation of cord blood-derived unrestricted somatic stem cells. Stem Cell Res Ther. 2011;2:16 pubmed publisher
    ..Stimulation of the Nodal signaling pathway with Activin A or IDE1/2 is insufficient to induce definitive endoderm formation from USSC, indicating that USSC differ in their stem cell potential from hESC. ..
  31. Pasi C, Dereli Öz A, Negrini S, Friedli M, Fragola G, Lombardo A, et al. Genomic instability in induced stem cells. Cell Death Differ. 2011;18:745-53 pubmed publisher
    ..The genomic aberrations were to a significant degree dependent on c-Myc expression and their presence could explain why p53 inactivation facilitates stem cell reprogramming. ..
  32. Lejard V, Blais F, Guerquin M, Bonnet A, Bonnin M, Havis E, et al. EGR1 and EGR2 involvement in vertebrate tendon differentiation. J Biol Chem. 2011;286:5855-67 pubmed publisher
    ..These results identify EGRs as novel DNA-binding proteins involved in vertebrate tendon differentiation by regulating type I collagen production...
  33. Francis West P, Robertson K, Ede D, Rodriguez C, Izpisua Belmonte J, Houston B, et al. Expression of genes encoding bone morphogenetic proteins and sonic hedgehog in talpid (ta3) limb buds: their relationships in the signalling cascade involved in limb patterning. Dev Dyn. 1995;203:187-97 pubmed
    ..In addition, the dissociation between the expression of shh and Bmps suggests distinct roles for the encoded molecules in signalling and response in a-p patterning of limb buds. ..
  34. Lincoln J, Alfieri C, Yutzey K. BMP and FGF regulatory pathways control cell lineage diversification of heart valve precursor cells. Dev Biol. 2006;292:292-302 pubmed
    ..Together, these studies define regulatory pathways of AV valve progenitor cell diversification into leaflets and chordae tendineae that share inductive interactions and differentiation phenotypes with cartilage and tendon cell lineages. ..
  35. Sugawara S, Ito T, Sato S, Yokoo M, Mori Y, Kasuga K, et al. Production of bioactive bovine fibroblast growth factor 4 in E. coli based on the common nucleotide sequence of its structural gene in three breeds. Anim Sci J. 2013;84:275-80 pubmed publisher
    b>Fibroblast growth factor 4 (FGF4) is considered a crucial gene in the proper development of bovine embryos...
  36. Maurice S, Nussinovitch A, Jaffe N, Shoseyov O, Gertler A. Oral immunization of Carassius auratus with modified recombinant A-layer proteins entrapped in alginate beads. Vaccine. 2004;23:450-9 pubmed
    ..In spite of the presence of an increased titer to A-protein, vaccinated fish did not demonstrate resistance to infection with atypical A. salmonicida. ..
  37. Rodriguez Pallares J, Parga J, Rey P, Guerra M, Labandeira Garcia J. Expanded mesencephalic precursors develop into grafts of densely packed dopaminergic neurons that reinnervate the surrounding striatum and induce functional responses in the striatal neurons. Synapse. 2005;58:13-22 pubmed
    ..In the present study, we grafted cell aggregates treated with antibodies against fibroblast growth factor 4 into dopaminergic-denervated striata in rats...
  38. Ogawa Y, Fawaz F, Reyes C, Lai J, Pungor E. Development of parallel line analysis criteria for recombinant adenovirus potency assay and definition of a unit of potency. PDA J Pharm Sci Technol. 2007;61:183-93 pubmed
  39. Bayha E, Jørgensen M, Serup P, Grapin Botton A. Retinoic acid signaling organizes endodermal organ specification along the entire antero-posterior axis. PLoS ONE. 2009;4:e5845 pubmed publisher
  40. Weeks O, Bhullar B, Abzhanov A. Molecular characterization of dental development in a toothed archosaur, the American alligator Alligator mississippiensis. Evol Dev. 2013;15:393-405 pubmed publisher
    ..We propose that such modularity may have been a crucial for adaptive evolution within Amniota, allowing for the progressive modifications to tooth replacement, number, and shape. ..
  41. Tanaka M, Cohn M, Ashby P, Davey M, Martin P, Tickle C. Distribution of polarizing activity and potential for limb formation in mouse and chick embryos and possible relationships to polydactyly. Development. 2000;127:4011-21 pubmed
    ..Furthermore, when we apply simultaneously a polarizing signal and a limb induction signal to early chick flank, this leads to limb duplications. ..
  42. Galvin Burgess K, Travis E, Pierson K, Vivian J. TGF-?-superfamily signaling regulates embryonic stem cell heterogeneity: self-renewal as a dynamic and regulated equilibrium. Stem Cells. 2013;31:48-58 pubmed publisher
    ..Several pathways, including BMP, Nodal, and FGF signaling, have important regulatory function in defining the steady-state distribution of heterogeneity of stem cells. ..
  43. Boulet A, Moon A, Arenkiel B, Capecchi M. The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Dev Biol. 2004;273:361-72 pubmed
    ..By using a CRE driver expressed in both forelimb and hindlimb ectoderm to inactivate Fgf4 and Fgf8, we have produced mice lacking all limbs, allowing a direct comparison of FGF requirements in the two locations. ..
  44. Jeong W, Lee J, Bazer F, Song G, Kim J. Fibroblast growth factor 4-induced migration of porcine trophectoderm cells is mediated via the AKT cell signaling pathway. Mol Cell Endocrinol. 2016;419:208-16 pubmed publisher
    ..This network is regulated by an astonishing number of molecules such as growth factors. Fibroblast growth factor 4 (FGF4) is a multipotent growth factor that elicits diverse biological actions on various types of cells ..
  45. Ambrosetti D, Scholer H, Dailey L, Basilico C. Modulation of the activity of multiple transcriptional activation domains by the DNA binding domains mediates the synergistic action of Sox2 and Oct-3 on the fibroblast growth factor-4 enhancer. J Biol Chem. 2000;275:23387-97 pubmed
    ..These findings define a mechanism that may also be utilized by other Sox x POU protein complexes in gene activation. ..
  46. Kawase E, Hashimoto K, Pedersen R. Autocrine and paracrine mechanisms regulating primordial germ cell proliferation. Mol Reprod Dev. 2004;68:5-16 pubmed
    ..We account for these findings in a model involving regulation of PGC proliferation, in which SCF modulates the response to FGFs. ..
  47. Harduf H, Halperin E, Reshef R, Ron D. Sef is synexpressed with FGFs during chick embryogenesis and its expression is differentially regulated by FGFs in the developing limb. Dev Dyn. 2005;233:301-12 pubmed
    ..The spatiotemporal pattern of cSef expression during limb development suggests a role for cSef in regulating limb outgrowth but not limb initiation. ..
  48. Trepel M, Stoneham C, Eleftherohorinou H, Mazarakis N, Pasqualini R, Arap W, et al. A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage-mediated, vascular-targeted suicide gene transfer. Mol Cancer Ther. 2009;8:2383-91 pubmed publisher
  49. Wei W, Sun H, Ting K, Zhang L, Lee H, Li G, et al. Inhibition of cardiomyocytes differentiation of mouse embryonic stem cells by CD38/cADPR/Ca2+ signaling pathway. J Biol Chem. 2012;287:35599-611 pubmed publisher
    ..Taken together, our data indicate that the CD38-cADPR-Ca(2+) signaling pathway antagonizes the CM differentiation of mouse ES cells. ..
  50. Hossain M, Fielding K, Trescher W, Ho T, Wilson M, Laterra J. Human FGF-1 gene delivery protects against quinolinate-induced striatal and hippocampal injury in neonatal rats. Eur J Neurosci. 1998;10:2490-9 pubmed
    ..Our results show that intracerebral FGF-1 gene expression within the developing brain can protect striatum and hippocampus from quinolinate-mediated injury. ..
  51. Lopez Sanchez C, Climent V, Schoenwolf G, Alvarez I, Garcia Martinez V. Induction of cardiogenesis by Hensen's node and fibroblast growth factors. Cell Tissue Res. 2002;309:237-49 pubmed
    ..Collectively, these data suggest that the organizer plays a crucial role in cardiac induction and morphogenesis, mediated in part by endogenous members of the FGF and TGFbeta families. ..
  52. Kook S, Jeon Y, Lim S, Jang M, Cho E, Lee S, et al. Fibroblast growth factor-4 enhances proliferation of mouse embryonic stem cells via activation of c-Jun signaling. PLoS ONE. 2013;8:e71641 pubmed publisher
    ..Collectively, it is suggested that FGF4 triggers proliferation of stem cells by activating MAPK-mediated signaling, while it affects differently osteogenic differentiation according to the origins of stem cells. ..
  53. Yada Y, Makino S, Chigusa Ishiwa S, Shiroishi T. The mouse polydactylous mutation, luxate (lx), causes anterior shift of the anteroposterior border in the developing hindlimb bud. Int J Dev Biol. 2002;46:975-82 pubmed
    ..Thus, ectopic Shh is not a primary defect of the lx mutation. Rather, our results indicate that the lx mutation affects the positioning of the anteroposterior border in developing hindlimb buds. ..