Affinage

FGF4

Fibroblast growth factor 4 · UniProt P08620

Length
206 aa
Mass
22.0 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGF4 is a secreted, heparan-sulfate-dependent fibroblast growth factor that functions as a paracrine and autocrine mitogen and differentiation signal across multiple developmental and metabolic contexts. Its transcription in pluripotent cells is driven by a Sox2/Oct-3 ternary complex on a downstream enhancer, with additional regulation by LEF1/Wnt signaling in dental epithelium and FXR in hepatocytes; epigenetic activation requires KDM7A-mediated removal of H3K9me2/H3K27me2, and Sox2 binding is promoted by ARTD1-dependent PARylation (PMID:7590241, PMID:12502739, PMID:20084082, PMID:23939864, PMID:39393353). FGF4 signals through FGFR2 and FGFR4 to activate PKCζ–MEK–ERK1/2 and AMPK–Caspase 6 cascades, and is the principal FGF controlling the ratio of primitive endoderm to epiblast in the inner cell mass, maintaining trophoblast stem cells, and — redundantly with FGF8 — sustaining limb bud mesenchyme survival and axial elongation (PMID:24063807, PMID:9851926, PMID:15328019, PMID:22954964, PMID:29249667, PMID:35152446). In postnatal tissues, hepatic FGF4 acts through an FGFR4–LRH-1 signaling node to repress bile acid synthesis genes Cyp7a1 and Cyp8b1 as a first-line intrahepatic checkpoint, protects hepatocytes from NAFLD-associated lipotoxicity and ferroptosis, and shields male germ cells from heat-stress apoptosis via MAPK activation (PMID:39393353, PMID:35152446, PMID:36702076, PMID:14980503).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1987 High

    Identification of FGF4 (hst) as an oncogene encoding a 206-aa protein sufficient for NIH3T3 transformation established the gene as a growth-promoting factor.

    Evidence cDNA cloning and expression-vector transfection transformation assay in NIH3T3 cells

    PMID:2953031

    Open questions at the time
    • No receptor or signaling pathway identified
    • Endogenous expression context unknown
  2. 1991 High

    Demonstrating that FGF4 transforming activity requires secretion and extracellular receptor engagement resolved whether FGF4 acts intracellularly or as a classical secreted ligand; concurrent identification of Oct4 binding at the FGF4 enhancer linked its expression to pluripotency.

    Evidence Signal-peptide deletion, KDEL-retention mutants, neutralizing antibodies, and suramin reversal in NIH3T3 assays; CAT reporter and EMSA in EC/ES cells

    PMID:1655808 PMID:1723621 PMID:1990270

    Open questions at the time
    • Specific FGF receptor identity not determined
    • Sox2 co-requirement not yet recognized
  3. 1992 High

    Establishing heparan sulfate proteoglycan dependence for FGF4 activity defined a co-receptor requirement essential for signaling competence.

    Evidence Chlorate inhibition of sulfation abolishes FGF4 activity on MM14 myoblasts; heparin rescue restores signaling

    PMID:1379245

    Open questions at the time
    • Specific HSPG species not identified
    • In vivo relevance of HSPG requirement untested
  4. 1994 Medium

    Multiple studies revealed FGF4's diverse paracrine roles — stimulating dental cell proliferation, promoting ICM parietal endoderm differentiation, driving angiogenesis, and increasing megakaryocyte/platelet production — extending its biology beyond simple oncogenic transformation.

    Evidence Recombinant FGF4 addition to dental tissues, isolated ICM, CAM/cornea angiogenesis assays, and adenoviral gene transfer in mice

    PMID:7520355 PMID:7809043 PMID:7848830 PMID:7925026

    Open questions at the time
    • Receptor specificity for each tissue context unknown
    • Dose-response relationships not established
    • In vivo genetic confirmation lacking for most contexts
  5. 1995 High

    The Sox2/Oct-3 ternary complex mechanism was defined, and Fgf4-knockout lethality proved FGF4 is an essential embryonic mitogen whose loss causes ICM proliferation failure rescuable by exogenous protein.

    Evidence Ternary complex reconstitution on Fgf4 enhancer DNA with EMSA/reporter assays; homozygous Fgf4 gene targeting with embryo culture and FGF4 protein rescue

    PMID:7590241 PMID:7809630

    Open questions at the time
    • Downstream signaling pathway from FGFR in ICM not characterized
    • Relative contributions of mitogenic vs. differentiation functions not separated
  6. 1998 High

    FGF4 was shown to be necessary and sufficient for trophoblast stem cell self-renewal, and to antagonize BMP-induced apoptosis in limb mesenchyme, establishing it as a key survival and stemness factor.

    Evidence TS cell derivation/maintenance with FGF4 addition/withdrawal and in vivo chimera analysis; FGF4 bead implantation in chick limb buds blocking BMP4-induced apoptosis

    PMID:9507096 PMID:9851926

    Open questions at the time
    • Identity of downstream FGF receptor in trophoblast stem cells not defined
    • Mechanism of BMP antagonism (convergent signaling vs. transcriptional) not resolved
  7. 2000 High

    Conditional AER-specific Fgf4 knockout yielded normal limbs, overturning the assumed essential role of FGF4 alone in limb patterning and revealing functional redundancy among AER-FGFs.

    Evidence Cre/loxP conditional knockout in two independent studies with limb morphology and in situ hybridization analysis

    PMID:10662638 PMID:10802662

    Open questions at the time
    • Which AER-FGF combination is minimally sufficient not yet tested
    • Quantitative contribution of FGF4 vs. FGF8 undetermined
  8. 2002 High

    FGF4 was identified as a direct transcriptional target of LEF1/Wnt signaling that mediates epithelial-mesenchymal cross-talk in tooth morphogenesis, broadening the upstream regulatory landscape beyond Oct4/Sox2.

    Evidence ChIP/reporter for LEF1 on Fgf4 promoter; FGF4-bead rescue of Lef1-null tooth arrest

    PMID:12502739

    Open questions at the time
    • Whether Wnt-dependent Fgf4 regulation operates in non-dental tissues unknown
    • Mechanism of FGF4-induced Shh in mesenchyme not characterized
  9. 2004 High

    Double Fgf4/Fgf8 conditional knockout proved that FGF4 and FGF8 are functionally redundant in sustaining limb mesenchyme survival and Shh expression, resolving why single Fgf4 loss had no limb phenotype.

    Evidence Double conditional knockout with apoptosis analysis and in situ hybridization for Shh and Fgf10

    PMID:15328019

    Open questions at the time
    • Whether FGF4/FGF8 redundancy extends to signaling pathway level or is purely quantitative not resolved
  10. 2005 High

    Allele-swap experiments demonstrated full functional interchangeability of FGF4 and FGF8 in limb skeletal development, establishing molecular equivalence at the receptor-activation level.

    Evidence Conditional Fgf4 gain-of-function allele activated simultaneously with Fgf8 inactivation via Cre; skeletal preparation analysis

    PMID:16308330

    Open questions at the time
    • Whether FGF4 and FGF8 activate identical downstream intracellular cascades not tested biochemically
  11. 2010 High

    KDM7A was shown to directly activate FGF4 transcription by removing repressive H3K9me2/H3K27me2 marks, linking chromatin state to FGF4 expression and neural differentiation.

    Evidence KDM7A knockdown in mouse ESCs with ChIP at Fgf4 locus; rescue with wild-type but not catalytic-dead KDM7A

    PMID:20084082

    Open questions at the time
    • Whether KDM7A acts at the Fgf4 enhancer or promoter specifically not mapped at nucleosome resolution
    • Interaction with Sox2/Oct4 complex not tested
  12. 2012 High

    Double Fgf4/Fgf8 loss during late gastrulation revealed that these FGFs maintain paraxial mesoderm progenitors and are required for axial elongation beyond ~15–20 somites.

    Evidence Double conditional knockout with skeletal preparation and in situ hybridization for Wnt3a, Brachyury, and Notch pathway genes

    PMID:22954964

    Open questions at the time
    • Individual contribution of FGF4 vs. FGF8 to tailbud progenitor maintenance not separable
  13. 2013 High

    Two advances refined FGF4's role in preimplantation development: ARTD1-mediated PARylation of Sox2 was shown to promote Sox2 occupancy at the FGF4 enhancer during reprogramming, and FGF4 dosage was identified as the primary determinant of primitive endoderm-to-epiblast ratio in the ICM.

    Evidence Artd1 KO fibroblasts with ChIP and FGF4 rescue of reprogramming; Fgf4 hypomorphic/null allelic series with quantitative lineage marker analysis

    PMID:23939864 PMID:24063807

    Open questions at the time
    • Whether PARylation of Sox2 is constitutive or signal-regulated not known
    • Identity of the FGFR mediating PE specification not confirmed
  14. 2017 High

    Downstream signaling was mapped: FGF4 activates a PKCζ–MEK–ERK1/2 cascade in ESCs (modulated by O-GlcNAcylation of PKCζ), and Klf5 was identified as an upstream transcriptional repressor of Fgf4 controlling PE specification.

    Evidence O-GlcNAc inhibitor/enhancer treatment with PKCζ mutagenesis and ERK phosphorylation readout; Klf5 KO embryos with FGFR/ERK inhibitor rescue

    PMID:28870993 PMID:29249667

    Open questions at the time
    • Whether PKCζ–ERK axis is the sole pathway downstream of FGFR in ESCs not tested
    • Direct Klf5 binding to Fgf4 promoter not shown
  15. 2022 High

    A hepatoprotective function was uncovered: hepatic FGF4 signals through FGFR4 to activate a Ca²⁺/CaMKKβ–AMPK–Caspase 6 axis that promotes fatty acid oxidation and reduces apoptosis in NAFLD.

    Evidence Hepatic Fgf4 conditional knockout, recombinant FGF4 treatment, FGFR4 blockade, and AMPK/Caspase 6 pathway analysis in dietary NAFLD/NASH models

    PMID:35152446

    Open questions at the time
    • Whether FGF4 hepatoprotection is relevant in human NAFLD not tested
    • Source cells producing hepatic FGF4 not fully characterized
  16. 2024 High

    Hepatic FGF4 was identified as a direct FXR transcriptional target that represses bile acid synthesis via an FGFR4–LRH-1 signaling node, functioning as an intrahepatic first-line checkpoint upstream of the peripheral FGF15/19 pathway.

    Evidence FXR ChIP at Fgf4, hepatic Fgf4 conditional KO, FGFR4/LRH-1 pathway analysis, cholestatic mouse models, recombinant FGF4 rescue

    PMID:39393353

    Open questions at the time
    • Whether human hepatocytes produce functionally equivalent FGF4 levels not demonstrated
    • Relative quantitative contribution of FGF4 vs. FGF15/19 axis under physiological conditions unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: which FGFRs mediate FGF4 signaling in trophoblast stem cells and in PE specification; whether the PKCζ–ERK and AMPK–Caspase 6 cascades represent tissue-specific or general FGF4 signaling modes; and whether hepatic FGF4 functions are conserved in human liver physiology and disease.
  • Receptor identity for FGF4 in trophoblast stem cells and PE specification not confirmed
  • Structural basis for FGF4/FGF8 interchangeability unknown
  • Human translational relevance of hepatic FGF4 functions not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 8 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 5
Pathway
R-HSA-1266738 Developmental Biology 8 R-HSA-162582 Signal Transduction 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1430728 Metabolism 2
Partners
ARTD1FGFR2FGFR4KDM7ALEF1POU5F1SOX2

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 The hst (FGF4) gene encodes a 206 amino acid open reading frame that is sufficient for transforming activity when expressed in NIH3T3 cells via an SV40 promoter-containing vector. cDNA cloning, expression vector transfection, NIH3T3 transformation assay Proceedings of the National Academy of Sciences of the United States of America High 2953031
1991 FGF4 (K-fgf/hst) transforms cells through an autocrine mechanism that requires secretion and extracellular receptor activation at the cell surface; deletion of the signal peptide or retention of the protein in the ER (KDEL motif) abolishes transforming activity, and anti-FGF4 neutralizing antibodies reverse the transformed phenotype. Signal peptide deletion mutants, KDEL retention mutants, NIH3T3 focus formation assay, neutralizing antibody treatment, soft-agar and serum-free growth assays Molecular and cellular biology High 1990270
1991 Cell transformation by kFGF requires secretion but not glycosylation; cytoplasmic or ER-retained kFGF mutants fail to transform NIH3T3 cells, and suramin reverses transformation by both glycosylated and unglycosylated secreted forms. Glycosylation site mutagenesis, KDEL retention mutant, NIH3T3 transformation assay, suramin inhibition The Journal of cell biology High 1655808
1991 The kFGF/FGF4 gene enhancer contains an octamer-binding sequence that binds Oct1 and Oct4 (but not Oct1 alone after differentiation), indicating that Oct4 positively regulates FGF4 transcription in undifferentiated embryonal carcinoma and embryonic stem cells. CAT reporter assays, electrophoretic mobility shift assay (EMSA), transfection into EC/ES cells Mechanisms of development Medium 1723621
1992 FGF4 signaling for myoblast repression requires heparan sulfate proteoglycans (HSPG); chlorate-mediated inhibition of glycosaminoglycan sulfation abrogates FGF4 biological activity, which is restored by heparin or sodium sulfate co-addition. Chlorate treatment of MM14 myoblasts, heparitinase treatment, FGF binding assay, differentiation assay The Journal of cell biology High 1379245
1994 FGF4 protein expressed in the enamel knot stimulates proliferation of both dental epithelial and mesenchymal cells in vitro, while the enamel knot cells themselves do not divide, supporting a paracrine growth-stimulating role during tooth cusp morphogenesis. In situ hybridization, in vitro FGF4 protein addition to isolated dental tissues, cell proliferation assessment The International journal of developmental biology Medium 7848830
1994 FGF4 promotes differentiation of parietal endoderm from isolated inner cell mass (ICM) cells and increases secretion of 92 kDa gelatinase and tissue plasminogen activator; FGFR-3 and FGFR-4 receptors are expressed on all blastocyst cells. Immunosurgery ICM isolation, recombinant FGF4 culture, morphological analysis, zymography, receptor expression by Northern blot Development (Cambridge, England) Medium 7925026
1994 FGF4 angiogenic activity is demonstrated in vivo by chick chorioallantoic membrane assay and rat cornea assay using recombinant hst-1 protein produced in E. coli. Recombinant protein production in E. coli, CAM assay, rat cornea assay, nude mouse tumor vascularization Cancer letters Medium 7520355
1994 The FGF4 gene is positively regulated by an upstream NF-Y binding site (sequence CTGATTGGCA) in its promoter that cooperates with the downstream octamer enhancer in F9 embryonal carcinoma cells. CAT reporter assays, deletion/mutation analysis, EMSA, methylation interference, anti-NF-Y antibody supershift The Journal of biological chemistry Medium 7929190
1994 Adenovirus-mediated HST-1/FGF4 gene transfer in vivo causes a twofold increase in peripheral platelet count and increased megakaryocyte numbers in bone marrow and spleen, demonstrating an in vivo thrombopoietic role. Adenovirus-mediated gene transfer in nude mice, platelet counting, histology of bone marrow and spleen, recombinant protein injection Proceedings of the National Academy of Sciences of the United States of America Medium 7809043
1995 FGF-4 gene expression requires synergistic action of Sox2 and Oct-3 on adjacent binding sites in the downstream enhancer; Sox2 forms a ternary complex with Oct-3 (but not Oct-1) on FGF-4 enhancer DNA, and only the Sox2/Oct-3 complex drives transcriptional activation. cDNA cloning of Sox2 from F9 cells, CAT reporter assays, EMSA, ternary complex formation experiments Genes & development High 7590241
1995 Homozygous disruption of Fgf4 by gene targeting causes early postimplantation lethality with severely impaired inner cell mass proliferation; this ICM proliferation defect is rescued by exogenous FGF4 protein in vitro, demonstrating an essential mitogenic role for FGF4 in early embryogenesis. Gene targeting (knockout), embryo culture, exogenous FGF4 protein rescue experiment Science (New York, N.Y.) High 7809630
1995 HST-1/FGF4 antisense oligodeoxynucleotides block mouse limb bud outgrowth in an organ culture system, while sense and scrambled ODNs have no effect, establishing a required role for FGF4 in limb development. Antisense oligodeoxynucleotide treatment, limb bud organ culture, morphological assessment The Journal of cell biology Medium 7642715
1995 Adenovirus-mediated FGF4 gene transfer effectively prevents chemotherapy- and irradiation-induced thrombocytopenia in mice by stimulating megakaryocyte production, with sustained serum FGF4 elevation for ≥30 days. Adenoviral gene transfer, thrombocytopenic mouse model (chemotherapy/irradiation), platelet counting, bone marrow histology The Journal of clinical investigation Medium 7635948
1998 FGF4 produced by the AER promotes trophoblast stem cell proliferation; culture of mouse blastocysts or early postimplantation trophoblasts with FGF4 allows isolation of permanent trophoblast stem cell lines that differentiate in vitro upon FGF4 withdrawal. Blastocyst culture with recombinant FGF4, trophoblast stem cell line derivation, in vitro differentiation, in vivo chimera analysis Science (New York, N.Y.) High 9851926
1998 FGF4 antagonizes BMP-induced apoptosis and BMP-induced chondrogenesis in chick limb buds; FGF4 prevents BMP-mediated mesenchyme apoptosis and nullifies BMP4-induced ectopic chondrogenesis when co-applied. Bead implantation into chick limb buds, apoptosis assessment, chondrocyte condensation analysis Mechanisms of development Medium 9507096
1999 FGF4 in the AER is maintained by a SHH/FGF4 feedback loop: SHH signaling in the posterior mesenchyme induces Gremlin (a BMP antagonist) which relays the signal to induce Fgf4 expression in the AER; grafting Gremlin-expressing cells into limb deformity mutant limb buds rescues Fgf4 expression. Mouse mutant analysis (Shh-null, limb deformity mutants), Gremlin cell grafting rescue experiment, in situ hybridization Nature High 10524628
1999 FGF4 provides a vertical signal (from notochord) that induces En1 expression in the midbrain neural plate; exogenous FGF4 mimics the notochord requirement for En1 induction in neural plate explants in vitro. Avian embryo tissue recombination, notochord ablation, FGF4 protein addition to neural plate explants in vitro Development (Cambridge, England) Medium 9927596
2000 Conditional inactivation of Fgf4 in the mouse AER using Cre/loxP results in normal limb development with normal Shh, Bmp2, Fgf8, and Fgf10 expression, demonstrating that FGF4 alone is not essential for AER-mediated limb patterning and that the FGF4-SHH feedback loop is not required. Conditional knockout (Cre/loxP), limb morphology analysis, in situ hybridization for target genes Development (Cambridge, England) High 10662638
2000 Conditional inactivation of Fgf4 in the mouse AER does not impair Shh expression or limb formation, but Shh is required for maintenance of Fgf9 and Fgf17 (but not Fgf8) in the AER; combined activities of multiple AER-FGFs function in the positive feedback loop with Shh. Conditional knockout (Cre/loxP), double mutant analysis, in situ hybridization Nature genetics High 10802662
2001 Misexpression of Fgf-4 in the chick limb inhibits myogenesis by downregulating the FGF receptor Frek in muscle progenitors, leading to decreased myoblast proliferation and inhibition of terminal differentiation. Replication-competent retrovirus (RCAS) overexpression in chick limb, quail-chick transplantation cell tracking, in situ hybridization for muscle markers Developmental biology Medium 11319857
2002 FGF4 is a direct transcriptional target of LEF1/Wnt signaling; LEF1 binds the Fgf4 promoter, Fgf4 is absent in Lef1-null tooth rudiments, and FGF4-soaked beads fully rescue the developmental arrest of Lef1-/- tooth germs. FGF4 then induces Fgf3 in dental mesenchyme and both epithelial and mesenchymal FGFs induce Shh. Lef1 knockout analysis, chromatin immunoprecipitation/reporter assay for LEF1 binding to Fgf4, bead rescue experiment in Lef1-/- tooth organ culture Genes & development High 12502739
2002 Fgf4 expressed in limb muscle is required for maintenance of tendon markers scleraxis and tenascin; exogenous FGF4 restores scleraxis and tenascin expression in muscleless and aneural limbs, but does not restore Fgf8 expression in tendons. Muscleless and aneural chick limb models, FGF4 bead implantation, in situ hybridization for tendon markers Developmental biology Medium 12086472
2003 FGF4 acts paraculturally to maintain trophectoderm and primitive endoderm identity at E4.5; loss of zygotic FGF4 leads to failure of differentiation and function of extraembryonic cell types rather than a strictly mitogenic defect. Fgf4 null embryo analysis, in vitro culture experiments with FGF4 protein Genesis (New York, N.Y. : 2000) Medium 12748966
2003 FGF-4 induces proliferation of cardiac cushion mesenchymal cells; FGF-4 protein localizes in cushion mesenchyme and activates FGFR2, and retroviral overexpression of FGF-4 in vivo expands cushion mesenchyme toward the lumen, promoting early valve leaflet formation. Immunolocalization, in situ hybridization for FGFRs, BrdU incorporation assay, retroviral FGF-4 overexpression in chick embryo, FGF-4 microinjection with BrdU Developmental biology Medium 12798286
2004 Combined loss of Fgf4 and Fgf8 in the forelimb AER causes failure of limb bud mesenchyme survival and loss of Shh and Fgf10 expression, demonstrating that FGF4 functionally compensates for FGF8 in supporting limb mesenchyme viability. Double conditional knockout (Cre/loxP for Fgf4 and Fgf8), apoptosis analysis, in situ hybridization for Shh and Fgf10 Developmental biology High 15328019
2004 HST-1/FGF-4 protects male germ cells from heat-stress-induced apoptosis by activating the MAPK survival cascade in germ cells and by stimulating lactate production from Sertoli cells, which is an indispensable nutrient for germ cell survival. Adenoviral FGF4 gene delivery to mouse testes, hyperthermia model, TUNEL apoptosis assay, MAPK activation by western blot, lactate production measurement Experimental cell research Medium 14980503
2005 FGF4 can functionally replace FGF8 in limb skeletal development: when Fgf4 is expressed in place of Fgf8 via conditional allele switching, all Fgf8 inactivation-induced skeletal defects are rescued; excess FGF4 signaling causes polydactyly and syndactyly. Conditional Fgf4 gain-of-function allele activation simultaneous with Fgf8 inactivation via Cre recombinase, skeletal preparation analysis Development (Cambridge, England) High 16308330
2010 The histone demethylase KDM7A (KIAA1718) directly activates FGF4 transcription by removing repressive H3K9me2 and H3K27me2 marks at the FGF4 locus; knockdown of KDM7A blocks neural differentiation and this is rescued by wild-type but not catalytically inactive KDM7A; this pro-neural effect is mediated through FGF4. KDM7A knockdown in mouse ESCs, rescue with wild-type vs. catalytic mutant KDM7A, ChIP for histone marks at Fgf4 locus, neural differentiation assays Cell research High 20084082
2012 Loss of both Fgf4 and Fgf8 during late gastrulation results in failure to maintain paraxial mesoderm progenitors in the epiblast/tailbud, causing severe vertebral/rib defects, loss of Wnt3a and Brachyury expression, and cessation of somitogenesis after ~15–20 somites. Double conditional knockout (Cre/loxP) for Fgf4 and Fgf8, skeletal preparation, in situ hybridization for Wnt3a, Brachyury, and Notch pathway genes, BrdU/apoptosis analysis Developmental biology High 22954964
2013 ARTD1/PARP1 PARylates Sox2, promoting Sox2 binding to the FGF4 enhancer and activating FGF4 expression during early reprogramming; exogenous FGF4 restores reprogramming capacity of Artd1-/- fibroblasts to wild-type levels, placing FGF4 downstream of ARTD1-Sox2 in the reprogramming pathway. Artd1 knockout fibroblasts, ARTD1 inhibitor treatment, ChIP for Sox2 at Fgf4 enhancer, exogenous FGF4 rescue of reprogramming efficiency Stem cells (Dayton, Ohio) High 23939864
2013 FGF4 is the major limiting FGF in the preimplantation embryo controlling the ratio of primitive endoderm (PE) to epiblast (EPI) in the ICM; titrated exogenous FGF4 progressively increases PE proportions in a dose-dependent manner regardless of embryo genotype. Fgf4 hypomorphic/null mutant embryo series, exogenous FGF4 dose-response treatment, lineage marker analysis (GATA6/Nanog immunofluorescence) Developmental biology High 24063807
2017 FGF4 signaling (via FGFR and ERK) is required for primitive endoderm specification in the ICM; Klf5 acts as an upstream repressor of Fgf4, as Klf5 knockout embryos show markedly upregulated Fgf4 and skewed PE specification, which is reversed by FGFR/ERK inhibitors. Klf5 knockout embryo analysis, FGFR/ERK inhibitor treatment, immunofluorescence for PE/EPI markers, Klf5 overexpression embryos Development (Cambridge, England) High 28870993
2017 O-GlcNAcylation of PKCζ at its phosphorylation site inhibits PKCζ activation and consequently suppresses the FGF4-PKCζ-MEK-ERK1/2 signaling pathway in mouse embryonic stem cells, maintaining the undifferentiated state. O-GlcNAc inhibitor/enhancer treatment in ESCs, PKCζ mutagenesis, MEK/ERK phosphorylation western blot, FGF4 stimulation assays Stem cell reports Medium 29249667
2018 Sox2 expression level (more than Oct4) drives synergistic binding to the Fgf4 Sox/Oct composite motif; quantitative fluorescence correlation spectroscopy shows that binding affinity of Oct4/Sox2 heterodimer to the Fgf4 regulatory element is primarily determined by the Sox2 concentration, explaining how Sox2 fluctuations control epiblast/PE lineage segregation via FGF4. Fluorescence correlation spectroscopy (FCS) binding affinity measurements for Oct4 and Sox2 on Fgf4 Sox/Oct motif The Biochemical journal Medium 29487166
2021 FGF4 acts as a short-range paracrine signal mediating cell-cell communication that generates and maintains robust proportions of epiblast-like and primitive endoderm-like cells in mouse ESC cultures; FGF4 signaling enables autonomous re-establishment of cell-type proportions after perturbation. ESC culture with FGF4 signaling manipulation, cell-type proportion quantification, mathematical modeling, perturbation-restoration experiments Development (Cambridge, England) Medium 34651174
2022 FGF4 protects the liver from NAFLD by activating hepatic FGFR4, which triggers a Ca2+/CaMKKβ-dependent AMPK-Caspase 6 signaling axis, leading to enhanced fatty acid oxidation and reduced hepatocellular apoptosis; hepatic Fgf4 deletion aggravates steatosis. Hepatic Fgf4 knockout mouse, recombinant FGF4 pharmacological treatment, FGFR4 blocking, AMPK and Caspase 6 pathway analysis, dietary NAFLD/NASH models Hepatology (Baltimore, Md.) High 35152446
2023 FGF4 inhibits hepatocyte ferroptosis in autoimmune hepatitis by upregulating CISD3 and activating Nrf2/HO-1 signaling; Fgf4 depletion increases lipid peroxidation and iron accumulation, while recombinant FGF4 rescues ferroptotic markers (xCT, GPX4) in an erastin-induced model. Hepatic Fgf4 knockout mouse, recombinant FGF4 treatment, CISD3 overexpression/knockdown, Erastin-induced ferroptosis model in AML12 cells, TUNEL/lipid peroxidation assays International immunopharmacology Medium 36702076
2024 Hepatic FGF4 is a direct transcriptional target of FXR that acts as a paracrine signal to downregulate bile acid synthesis genes Cyp7a1 and Cyp8b1 via an intracellular FGFR4-LRH-1 signaling node; this pathway functions upstream of the peripheral FXR-FGF15/19 pathway as a first-line checkpoint for intrahepatic bile acid homeostasis. Hepatic Fgf4 conditional knockout, FXR chromatin immunoprecipitation, FGFR4 signaling analysis, LRH-1 pathway analysis, cholestatic mouse models, recombinant FGF4 treatment Cell metabolism High 39393353

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Promotion of trophoblast stem cell proliferation by FGF4. Science (New York, N.Y.) 1135 9851926
1992 Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse. Development (Cambridge, England) 621 1618140
1995 Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes & development 607 7590241
1995 Requirement of FGF-4 for postimplantation mouse development. Science (New York, N.Y.) 605 7809630
1999 Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Nature 378 10524628
1994 Evidence for the role of the enamel knot as a control center in mammalian tooth cusp formation: non-dividing cells express growth stimulating Fgf-4 gene. The International journal of developmental biology 343 7848830
1987 cDNA sequence of human transforming gene hst and identification of the coding sequence required for transforming activity. Proceedings of the National Academy of Sciences of the United States of America 328 2953031
2009 An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science (New York, N.Y.) 252 19608863
2000 Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development. Nature genetics 242 10802662
1992 Repression of myogenic differentiation by aFGF, bFGF, and K-FGF is dependent on cellular heparan sulfate. The Journal of cell biology 223 1379245
2002 FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Genes & development 204 12502739
1989 Amplification of FGF-related genes in human tumors: possible involvement of HST in breast carcinomas. Oncogene 193 2474139
1999 Sequential roles for Fgf4, En1 and Fgf8 in specification and regionalisation of the midbrain. Development (Cambridge, England) 181 9927596
1991 Expression of the hst-1 and c-kit protooncogenes in human testicular germ cell tumors. Cancer research 179 1706218
1989 High incidence of coamplification of hst-1 and int-2 genes in human esophageal carcinomas. Cancer research 178 2529025
1996 Combined BMP-2 and FGF-4, but neither factor alone, induces cardiogenesis in non-precardiac embryonic mesoderm. Developmental biology 166 8812122
2004 The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Developmental biology 158 15328019
2007 Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nature genetics 156 17906623
1989 Mesoderm-inducing properties of INT-2 and kFGF: two oncogene-encoded growth factors related to FGF. Development (Cambridge, England) 156 2483371
1994 Expression and function of FGF-4 in peri-implantation development in mouse embryos. Development (Cambridge, England) 153 7925026
2002 Fgf4 positively regulates scleraxis and tenascin expression in chick limb tendons. Developmental biology 145 12086472
1988 Chromosomal localization of the hst oncogene and its co-amplification with the int.2 oncogene in a human melanoma. Oncogene 145 3283658
2013 FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma. Hepatology (Baltimore, Md.) 126 22890726
2002 Early embryonic expression of FGF4/6/9 gene and its role in the induction of mesenchyme and notochord in Ciona savignyi embryos. Development (Cambridge, England) 126 11923208
2003 Evolutionary conservation of CCND1-ORAOV1-FGF19-FGF4 locus from zebrafish to human. International journal of molecular medicine 116 12792807
2017 FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs. Proceedings of the National Academy of Sciences of the United States of America 110 29073074
2013 FGF4 is a limiting factor controlling the proportions of primitive endoderm and epiblast in the ICM of the mouse blastocyst. Developmental biology 110 24063807
2020 In vitro generation of functional murine heart organoids via FGF4 and extracellular matrix. Nature communications 106 32883967
2000 Normal limb development in conditional mutants of Fgf4. Development (Cambridge, England) 106 10662638
2003 Paracrine action of FGF4 during periimplantation development maintains trophectoderm and primitive endoderm. Genesis (New York, N.Y. : 2000) 104 12748966
2012 Signaling by FGF4 and FGF8 is required for axial elongation of the mouse embryo. Developmental biology 95 22954964
2010 Dual-specificity histone demethylase KIAA1718 (KDM7A) regulates neural differentiation through FGF4. Cell research 93 20084082
2009 FGF4 and retinoic acid direct differentiation of hESCs into PDX1-expressing foregut endoderm in a time- and concentration-dependent manner. PloS one 86 19277121
1990 Expression of the K-fgf proto-oncogene is controlled by 3' regulatory elements which are specific for embryonal carcinoma cells. Molecular and cellular biology 86 2188089
2005 Increasing Fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function. Development (Cambridge, England) 80 16308330
1988 Coamplification of the hst-1 and int-2 genes in human cancers. Japanese journal of cancer research : Gann 79 3133332
1998 Antagonistic effects of FGF4 on BMP induction of apoptosis and chondrogenesis in the chick limb bud. Mechanisms of development 78 9507096
1989 Expression of the K-fgf protooncogene is repressed during differentiation of F9 cells. Oncogene research 69 2780052
2022 Exosomes from mmu_circ_0001052-modified adipose-derived stem cells promote angiogenesis of DFU via miR-106a-5p and FGF4/p38MAPK pathway. Stem cell research & therapy 68 35870977
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2003 Fibroblast growth factor (FGF)-4 can induce proliferation of cardiac cushion mesenchymal cells during early valve leaflet formation. Developmental biology 62 12798286
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