Affinage

FZD4

Frizzled-4 · UniProt Q9ULV1

Length
537 aa
Mass
59.9 kDa
Annotated
2026-06-09
100 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FZD4 is a seven-transmembrane Frizzled receptor that drives canonical Wnt/β-catenin signaling and serves as the central receptor for Norrin in developmental and reparative vascularization, fertility, and tissue morphogenesis (PMID:21177847, PMID:27489958). Ligand recognition is governed by the extracellular cysteine-rich domain (CRD), which is essential for binding Norrin and for Norrin-dependent β-catenin reporter activation, with CRD missense mutations abolishing both (PMID:21177847). Receptor competence requires post-translational and trafficking control: N-glycosylation at N59 and N144 is needed for maturation, plasma-membrane trafficking, stability, and ligand/co-receptor interaction (PMID:40230079), and the ER membrane protein complex subunit EMC3 is required upstream for FZD4 protein expression and Norrin/β-catenin signaling in retinal endothelium (PMID:34128175). Signaling output is selectively amplified by TSPAN12, which physically associates with the Norrin–FZD4 complex and promotes receptor multimerization specifically for Norrin (not Wnt) signaling (PMID:19837033), and is transduced intracellularly through DVL2 recruitment (PMID:38558095). Disease-causing FEVR mutations impair function through distinct mechanisms spanning disrupted signal peptide, loss of disulfide bonds, defective Norrin binding, impaired ER-to-membrane trafficking, and reduced DVL2 recruitment (PMID:24744206, PMID:38558095, PMID:32420371). Beyond retinal vasculature, FZD4 acts as the receptor for multiple Wnt ligands in disparate contexts—Wnt2-driven cardiac fibrosis with LRP6 (PMID:34911029), WNT5A/YAP-dependent osteogenesis via JNK (PMID:37340863), WNT6-driven centrosome amplification in diabetes (PMID:31618077), and ERG- and WNT2b-driven epithelial-to-mesenchymal transition (PMID:20713528, PMID:31359032)—and its expression is controlled transcriptionally and epigenetically by factors including FOXF1, ERG, and chromatin-modifying complexes (PMID:20713528, PMID:38589650, PMID:31981860, PMID:34219513).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2005 High

    Established that FZD4 has an in vivo developmental role beyond the eye and that not all FZD4 functions depend on Norrin, defining ligand specificity questions.

    Evidence Fzd4-null mouse analysis with luteal/angiogenic marker readout and Ndph-null comparison

    PMID:16093361

    Open questions at the time
    • Wnt ligand responsible for corpus luteum development not identified
    • downstream effectors in luteal angiogenesis undefined
  2. 2009 High

    Resolved how Norrin signaling reaches physiological thresholds by showing TSPAN12 selectively amplifies Norrin–FZD4 signaling through receptor multimerization.

    Evidence Co-IP, siRNA, luciferase reporter, and Tspan12/Norrin/Lrp5 mouse genetics

    PMID:19837033

    Open questions at the time
    • structural basis of multimerization not resolved
    • stoichiometry of TSPAN12 in the complex unknown
  3. 2010 High

    Defined the FZD4 CRD as the essential Norrin-binding module and linked CRD mutations to loss of β-catenin activation.

    Evidence Cell-surface/overlay binding assays, luciferase reporter, Xenopus embryo marker expression

    PMID:21177847

    Open questions at the time
    • atomic-resolution Norrin–CRD interface not determined here
    • Wnt versus Norrin binding determinants not distinguished
  4. 2010 Medium

    Placed FZD4 downstream of ERG in driving epithelial-to-mesenchymal transition, extending FZD4 function into cancer.

    Evidence Reciprocal siRNA knockdown and overexpression in VCaP prostate cancer cells

    PMID:20713528

    Open questions at the time
    • Wnt ligand engaging FZD4 in this context not identified
    • direct ERG binding to FZD4 promoter not shown here
  5. 2014 High

    Identified defective ER-to-plasma-membrane trafficking as a major FEVR pathological mechanism and showed it is rescuable by chaperones/temperature.

    Evidence Confocal microscopy, glycosylation/ubiquitination profiling, chemical chaperone rescue in HeLa/COS-7

    PMID:24744206

    Open questions at the time
    • ER quality-control machinery recognizing mutants not defined
    • trafficking route to plasma membrane not mapped
  6. 2016 High

    Demonstrated dosage sensitivity of Norrin-FZD4 signaling specifically for revascularization of ischemic retina rather than vaso-obliteration.

    Evidence Fzd4 heterozygous mouse oxygen-induced retinopathy model with vascular phenotyping

    PMID:27489958

    Open questions at the time
    • molecular threshold underlying haploinsufficiency not quantified
    • endothelial-intrinsic versus systemic contribution not separated
  7. 2017 Medium

    Showed Norrin–FZD4 signaling expands cardiomyocyte output, identifying FZD4 as a cardiac progenitor surface marker and signaling node.

    Evidence Surface proteomics, FACS sorting, NORRIN/FZD4 signaling assay, cardiomyocyte differentiation

    PMID:29249665

    Open questions at the time
    • co-receptor requirement in CPCs not defined
    • in vivo necessity not established
  8. 2018 Medium

    Connected mechanical stimulation to FZD4-dependent osteogenesis through JNK and a WNT5A upstream input.

    Evidence Cyclic stretch of BMSCs, FZD4 siRNA, WNT5A treatment, osteogenic assays, hindlimb unloading mouse model

    PMID:30007964

    Open questions at the time
    • co-receptor and direct WNT5A–FZD4 binding not shown
    • branch from canonical β-catenin not delineated
  9. 2018 Medium

    Identified FZD4 as a direct retinoic-acid target gene required for pancreas specification, extending its developmental roles.

    Evidence RNA-seq of RA-treated explants and morpholino knockdown in Xenopus

    PMID:29769220

    Open questions at the time
    • ligand driving FZD4 signaling in pancreas not identified
    • downstream targets in progenitors undefined
  10. 2019 Medium

    Defined a Wnt6–FZD4–β-catenin axis upstream of ROCK1/14-3-3σ driving diabetes-associated centrosome amplification.

    Evidence siRNA, neutralizing antibodies, β-catenin translocation, centrosome counting, diabetic mouse model

    PMID:31618077

    Open questions at the time
    • co-receptor in this axis not defined
    • direct Wnt6–FZD4 binding not biochemically resolved
  11. 2019 Medium

    Positioned FZD4 downstream of YAP/WNT5A in mechanically induced osteogenesis via JNK signaling.

    Evidence siRNA, YAP inhibitor/activator, recombinant WNT5A rescue, osteogenic assays in hPDLCs

    PMID:37340863

    Open questions at the time
    • mechanism linking YAP to FZD4 expression not resolved
    • direct receptor–ligand binding not shown
  12. 2020 Medium

    Established loss of Norrin–receptor binding as a pathogenic FEVR mechanism for novel FZD4 mutations.

    Evidence TOPflash reporter assay and Norrin–FZD4 co-IP

    PMID:32420371

    Open questions at the time
    • structural consequences of mutations not modeled
    • trafficking status of these mutants not assessed
  13. 2020 Medium

    Identified FZD4 as the receptor mediating WNT2b-driven EMT relevant to Crohn's disease penetrating behaviour.

    Evidence WNT2b treatment of HT29 cells with FZD4 knockdown, WNT2b/FZD4 co-IP, patient tissue analysis

    PMID:31359032

    Open questions at the time
    • co-receptor requirement not defined
    • causality in patient phenotype not established
  14. 2020 Medium

    Showed FZD4 is epigenetically silenced by GATA6-AS1/EZH2-mediated H3K27me3, linking chromatin control to Wnt pathway output.

    Evidence EZH2 co-IP, H3K27me3 ChIP at FZD4 promoter, GATA6-AS1 manipulation, LiCl rescue, xenograft

    PMID:31981860

    Open questions at the time
    • direct GATA6-AS1 binding to FZD4 locus not mapped
    • generality across tumor types untested
  15. 2021 High

    Placed EMC3 upstream of FZD4 as a requirement for receptor expression and retinal vascular Norrin/β-catenin signaling.

    Evidence Endothelial Emc3 conditional KO, RNA-seq, reporter assay, LiCl rescue, tube formation

    PMID:34128175

    Open questions at the time
    • mechanism of EMC3-assisted FZD4 biogenesis not resolved
    • selectivity of EMC3 for FZD4 versus other clients not addressed
  16. 2021 Medium

    Defined FZD4 as part of a Wnt2/LRP6 pro-fibrotic receptor complex driving cardiac fibrosis through β-catenin/NF-κB.

    Evidence siRNA in cardiac fibroblasts, β-catenin/NF-κB reporter, MI mouse model

    PMID:34911029

    Open questions at the time
    • direct Wnt2–FZD4–LRP6 ternary complex not biochemically reconstituted
    • ligand pairing specificity basis unknown
  17. 2021 Medium

    Showed SIRT6-mediated H3K9 deacetylation suppresses FZD4 transcription, adding an additional epigenetic control layer on Wnt output.

    Evidence SIRT6 manipulation, H3K9ac ChIP at FZD4 promoter, FZD4 rescue, xenograft in hepatoblastoma

    PMID:34219513

    Open questions at the time
    • direct SIRT6 recruitment mechanism to FZD4 promoter not defined
    • context specificity untested
  18. 2022 Medium

    Demonstrated that pharmacological FZD4/LRP5 agonism can therapeutically normalize pathological retinal vasculature.

    Evidence Norrin mimetic SZN-413 in endothelial reporter assay, OIR mouse model, VEGF-induced rabbit leakage model

    PMID:36149648

    Open questions at the time
    • binding mode of mimetic on FZD4 not structurally defined
    • long-term efficacy/safety not assessed
  19. 2023 Medium

    Identified FZD4 as a miR-136-5p-gated component of Wnt signaling controlling myoblast proliferation and muscle regeneration.

    Evidence miR-136-5p manipulation, shFZD4, β-catenin/LEF/TCF complex assay, BaCl2 muscle injury model

    PMID:37218742

    Open questions at the time
    • direct miR-136-5p–FZD4 3'UTR interaction extent not detailed
    • ligand engaging FZD4 in myogenesis not identified
  20. 2024 High

    Provided a comprehensive mutational map classifying FZD4 pathogenicity into five mechanistic classes, including intracellular DVL2-recruitment defects.

    Evidence Site-directed mutagenesis of 34 mutations, reporter, membrane localization, Norrin binding, DVL2 co-IP

    PMID:38558095

    Open questions at the time
    • genotype–phenotype severity correlation not established
    • structural basis of DVL2 recruitment not resolved
  21. 2024 High

    Established FOXF1 as a direct transcriptional activator of Fzd4 in lung endothelium and showed Fzd4 restoration normalizes tumor vasculature.

    Evidence FOXF1 conditional KO/OE mice, CUT&Tag at Fzd4 promoter, Wnt reporter, nanoparticle Fzd4 rescue, lung tumor model

    PMID:38589650

    Open questions at the time
    • regulatory interplay with other FZD4 transcription factors not integrated
    • endothelial subtype specificity not fully mapped
  22. 2025 High

    Defined N59/N144 N-glycosylation as a requirement for FZD4 maturation, trafficking, stability, and ligand/co-receptor binding.

    Evidence Glycosylation-site mutagenesis, surface localization, co-IP with Wnt/Norrin, TOPflash, xenograft in A549 cells

    PMID:40230079

    Open questions at the time
    • glycan structures and biosynthetic enzymes not identified
    • differential glycan effects on Wnt versus Norrin binding not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct Wnt ligand–FZD4 pairings, co-receptor choices, and canonical versus JNK/NF-κB branch selection are encoded structurally and used to specify the diverse tissue outcomes remains unresolved.
  • no atomic structure of FZD4 with different ligands/co-receptors in the corpus
  • rules governing ligand-co-receptor specificity not defined
  • switch between β-catenin and non-canonical outputs not mechanistically explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 6 GO:0048018 receptor ligand activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3
Partners
DVL2EMC3LRP5LRP6NDPTSPAN12WNT2WNT6
Complex memberships
Norrin-FZD4-LRP5 receptor complexNorrin-FZD4-TSPAN12 complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 TSPAN12 physically associates with the Norrin-FZD4 receptor complex (shown by co-expression/co-immunoprecipitation) and selectively amplifies Norrin/β-catenin but not Wnt/β-catenin signaling; overexpressed TSPAN12 rescues signaling defects caused by FZD4 mutations predicted to impair receptor multimerization, indicating TSPAN12 promotes FZD4 multimerization specifically in the context of Norrin signaling. Co-immunoprecipitation, siRNA knockdown, luciferase reporter assay, genetic epistasis in Tspan12/Norrin/Lrp5 mutant mice Cell High 19837033
2010 The cysteine-rich domain (CRD) of FZD4 is essential for Norrin binding and Norrin-dependent activation of canonical Wnt/β-catenin signaling; CRD missense mutations C45Y, Y58C, and C204R abolish Norrin binding as measured by cell-surface and overlay binding assays and eliminate Norrin-induced Wnt/β-catenin reporter activity in HEK293 cells and in Xenopus embryos (decreased Siamois and Xnr3 expression). Cell-surface binding assay, overlay binding assay, luciferase reporter assay (HEK293), Xenopus embryo injection with marker gene expression The Journal of biological chemistry High 21177847
2014 Multiple FEVR-associated missense mutations in FZD4 (P33S, G36N, H69Y, M105T, M105V, C181R, C204R, C204Y, G488D) cause predominant ER retention rather than plasma membrane localization, establishing defective ER-to-plasma-membrane trafficking as a major pathological mechanism; this trafficking defect could be partially rescued for M105T and C204Y mutants by reduced temperature or chemical chaperones. Mutant FZD4 does not trap co-expressed wild-type FZD4. Confocal fluorescence microscopy, N-glycosylation profiling, polyubiquitination assays, chemical chaperone rescue experiments in HeLa and COS-7 cells Investigative ophthalmology & visual science High 24744206
2024 Systematic functional analysis of 34 FZD4 missense mutations categorized pathogenic mechanisms into five classes: (1) signal peptide mutations, (2) cysteine mutations disrupting disulfide bonds, (3) extracellular domain mutations impairing Norrin binding, (4) transmembrane domain 1 and TM7 mutations impairing membrane localization, and (5) intracellular domain mutations reducing DVL2 recruitment, as assessed by protein expression, Norrin/β-catenin luciferase reporter, membrane localization, Norrin binding, and DVL2 co-immunoprecipitation assays in HEK293T, HEK293STF, and HeLa cells. Site-directed mutagenesis, luciferase reporter assay (Norrin/β-catenin TOPflash), confocal microscopy for membrane localization, Norrin binding assay, DVL2 co-immunoprecipitation Investigative ophthalmology & visual science High 38558095
2025 FZD4 is N-glycosylated at asparagine residues N59 and N144 (both highly conserved); N-glycosylation is required for FZD4 maturation, plasma membrane trafficking, protein stability, and interaction with Wnt ligands and co-receptor Norrin. Glycosylation-deficient FZD4 mutants fail to activate Wnt/β-catenin signaling and cannot rescue proliferation/migration in FZD4-knockout A549 cells in vitro or in vivo. Site-directed mutagenesis at N-glycosylation sites, cell surface localization assay, co-immunoprecipitation with Wnt ligands/Norrin, TOPflash luciferase reporter, xenograft tumor model Journal of cellular and molecular medicine High 40230079
2021 The ER membrane protein complex subunit EMC3 is required for FZD4 expression; endothelial-specific deletion of Emc3 in mice reduces FZD4 levels and impairs Norrin/β-catenin signaling, causing defective retinal vascularization that is partially rescued by lithium chloride (Wnt activator), placing EMC3 upstream of FZD4 in the Norrin/β-catenin pathway in retinal endothelial cells. Conditional knockout mice (endothelial Emc3 deletion), RNA-seq, RT-qPCR, luciferase reporter assay, LiCl rescue experiment, tube formation assay Science China. Life sciences High 34128175
2017 FZD4 marks lateral plate mesoderm in cardiac progenitor cells (CPCs); NORRIN presented to FZD4 increases cardiomyocyte output from CPCs via canonical WNT/β-catenin signaling-driven proliferation; FZD4 was used together with FLK1 and PDGFRA to purify CPCs and enhance cardiomyocyte enrichment from mouse and human pluripotent stem cells. Surface proteomics (mass spectrometry), microarray transcriptomics, FACS sorting with FZD4 antibody, NORRIN/FZD4 signaling assay, cardiomyocyte differentiation assay Stem cell reports Medium 29249665
2005 Fzd4-null (Fzd4−/−) mice are infertile due to failure of corpus luteum formation and function; markers of luteal cell identity (Lhcgr, Prlr, Cyp11a1, Sfrp4) and angiogenesis (Efnb1, Efnb2, Ephb4, Vegfa, Vegfc) are reduced in Fzd4−/− corpora lutea. Ndph-null mice do not phenocopy this, indicating that Norrin is not the Fzd4 ligand responsible for corpus luteum development. Fzd4-null mouse analysis, timed mating, histology, RT-PCR of luteal markers, Ndph-null mouse comparison Biology of reproduction High 16093361
2021 Wnt2 and Wnt4 activate β-catenin/NF-κB signaling to promote cardiac fibrosis in fibroblasts through cooperation of FZD4 (or FZD2) with LRP6; Wnt2 specifically pairs with FZD4 and LRP6, while Wnt4 pairs with FZD2 and LRP6, establishing FZD4 as part of a pro-fibrotic Wnt receptor complex following myocardial infarction. siRNA knockdown of Wnt2, Wnt4, Fzd4/Fzd2, LRP6 in neonatal rat cardiac fibroblasts; β-catenin/NF-κB reporter assay; MI mouse model with LAD ligation; ELISA EBioMedicine Medium 34911029
2019 Secreted Wnt6 binds FZD4 to activate canonical β-catenin signaling, which is upstream of ROCK1 and 14-3-3σ, and this Wnt6-FZD4-β-catenin axis mediates centrosome amplification induced by diabetic factors (high glucose/insulin/palmitate and advanced glycation end-products); blocking Wnt6 or FZD4 with siRNA or antibodies attenuates centrosome amplification. siRNA knockdown of Wnt6, FZD4, β-catenin; neutralizing antibodies against Wnt6 and FZD4; β-catenin nuclear translocation assay; centrosome counting; in vivo diabetic mouse model American journal of physiology. Cell physiology Medium 31618077
2010 ERG transcription factor upregulates FZD4 expression in prostate cancer cells; FZD4 silencing mimics ERG knockdown by inducing active β1-integrin and E-cadherin expression (mesenchymal-to-epithelial reversion), while FZD4 overexpression reverses the ERG-knockdown phenotype, placing FZD4 downstream of ERG in WNT signaling-driven epithelial-to-mesenchymal transition. siRNA knockdown of ERG and FZD4, FZD4 overexpression in VCaP prostate cancer cells, RT-PCR, immunostaining, β1-integrin/E-cadherin expression analysis Cancer research Medium 20713528
2020 WNT2b induces epithelial-to-mesenchymal transition (EMT) in HT29 intestinal epithelial cells through FZD4 activation; increased WNT2b/FZD4 interaction was detected in intestinal tissue from Crohn's disease patients with penetrating behaviour, placing FZD4 as the receptor mediating WNT2b-driven EMT. In vitro WNT2b treatment of HT29 cells with FZD4 knockdown/activation, confocal microscopy, co-immunoprecipitation of WNT2b/FZD4, RT-PCR, WB in patient tissues Journal of Crohn's & colitis Medium 31359032
2018 Mechanical cyclic stretch upregulates FZD4 and activates JNK signaling in bone mesenchymal stem cells; FZD4 knockdown inhibits stretch-induced osteogenesis and JNK activity; WNT5A acts upstream and FZD4 mediates WNT5A-dependent osteogenic differentiation under mechanical stimulation. Cyclic mechanical stretch of BMSCs, siRNA knockdown of FZD4, WNT5A treatment, ALP staining, Alizarin Red staining, RT-PCR, WB, hindlimb unloading mouse model Cellular physiology and biochemistry Medium 30007964
2024 FOXF1 directly transcriptionally activates Fzd4 in lung endothelial cells; endothelial-specific FOXF1 deletion decreases FZD4 and impairs Wnt/β-catenin signaling in tumor-associated endothelial cells, promoting tumor vessel leakiness and lung cancer progression; nanoparticle delivery of Fzd4 cDNA to FOXF1-deficient endothelial cells rescues Wnt/β-catenin signaling and normalizes tumor vessels. Endothelial-specific conditional KO and OE of FOXF1 in mice, nanoparticle Fzd4 cDNA delivery, ChIP-seq/CUT&Tag for FOXF1 binding to Fzd4 promoter, Wnt reporter assay, lung tumor growth assay EMBO molecular medicine High 38589650
2020 GATA6-AS1 lncRNA downregulates FZD4 expression by recruiting EZH2 and promoting H3K27me3 at the FZD4 promoter, thereby inactivating Wnt/β-catenin signaling and inhibiting gastric cancer progression; this was demonstrated by ChIP showing H3K27me3 enrichment at the FZD4 promoter and rescued by a Wnt/β-catenin activator (LiCl). EZH2 co-immunoprecipitation, ChIP for H3K27me3 at FZD4 promoter, GATA6-AS1 overexpression/ASO knockdown, LiCl rescue, xenograft mouse model Molecular therapy. Nucleic acids Medium 31981860
2021 SIRT6 suppresses FZD4 transcription by deacetylating histone H3K9 at the FZD4 promoter; overexpression of SIRT6 reduces FZD4 protein and H3K9ac levels, inhibiting Wnt/β-catenin signaling and hepatoblastoma cell proliferation/invasion; FZD4 overexpression reverses these effects. SIRT6 overexpression/knockdown in hepatoblastoma cells, H3K9ac ChIP at FZD4 promoter, FZD4 rescue overexpression, WB, xenograft tumor model Human & experimental toxicology Medium 34219513
2022 A Norrin mimetic (SZN-413) targeting FZD4 and LRP5 induces Wnt/β-catenin signaling and upregulates blood-retina barrier gene expression in endothelial cells; in an oxygen-induced retinopathy mouse model, SZN-413 significantly reduces neovascularization and avascular areas; in a VEGF-induced rabbit model, it reduces retinal vascular leakage by ~80%, demonstrating FZD4 agonism can normalize pathological retinal vasculature. In vitro Wnt/β-catenin reporter assay in endothelial cells, oxygen-induced retinopathy mouse model (avascular/neovascularization area measurement), VEGF-induced rabbit vascular leakage model (fluorescein leakage quantification) Translational vision science & technology Medium 36149648
2016 Fzd4 heterozygous mice show delayed retinal revascularization after oxygen-induced retinopathy (OIR) but normal vaso-obliteration during hyperoxia, demonstrating that partial reduction of Norrin-Fzd4 signaling specifically impairs revascularization of the avascular retina following ischemic injury. Fzd4 heterozygous mouse OIR model, retinal vascular area/pattern quantification, vessel number and caliber measurement PloS one High 27489958
2020 Novel FZD4 mutations identified in FEVR patients were shown by TOPflash luciferase reporter assay to cause at least 50% loss of wild-type Norrin/β-catenin signaling activity, and by co-immunoprecipitation to degrade the Norrin-FZD4 binding interaction, establishing loss of Norrin-receptor binding as a pathogenic mechanism. TOPflash luciferase reporter assay, co-immunoprecipitation of Norrin-FZD4 BioMed research international Medium 32420371
2018 Retinoic acid (RA) signaling directly induces Fzd4 expression during Xenopus pancreas development; loss of Fzd4/Fzd4s function impairs pancreatic progenitor formation and differentiation, establishing FZD4 as a direct RA target gene required for pancreas specification. RNA sequencing of RA-treated pancreatic explants, morpholino knockdown of Fzd4/Fzd4s in Xenopus embryos, pancreatic progenitor differentiation assay Development (Cambridge, England) Medium 29769220
2019 Wnt5a/FZD4 axis activates JNK signaling and mediates osteogenic differentiation in human periodontal ligament cells; FZD4 knockdown attenuates both WNT5A-induced and YAP-induced osteogenesis, while recombinant WNT5A rescues YAP inhibitor-suppressed differentiation, placing FZD4 downstream of YAP/WNT5A in mechanically stimulated osteogenesis. siRNA knockdown of FZD4 and WNT5A, YAP inhibitor (verteporfin) and activator (Lats-IN-1), recombinant WNT5A rescue, ALP activity, Alizarin Red staining, WB, cyclic stretch of hPDLCs Journal of periodontal research Medium 37340863
2023 miR-136-5p targets FZD4 to inhibit Wnt/β-catenin signaling, specifically preventing formation of the β-catenin/LEF/TCF transcriptional complex, thereby promoting myoblast proliferation and differentiation; in vivo, miR-136-5p knockdown accelerates skeletal muscle regeneration after BaCl2-induced injury, and this is suppressed by shFZD4, placing FZD4 as a gating component of Wnt signaling in myogenesis. miR-136-5p overexpression/knockdown in C2C12 cells, shFZD4 lentiviral infection, β-catenin/LEF/TCF complex formation assay, BaCl2 muscle injury mouse model with histological quantification Journal of cellular physiology Medium 37218742

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4/beta-catenin signaling. Cell 329 19837033
2004 Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. American journal of human genetics 302 15024691
2010 FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer research 233 20713528
2010 Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Human mutation 126 20340138
2005 Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes. Human mutation 114 15981244
2018 CircRNA_100290 promotes colorectal cancer progression through miR-516b-induced downregulation of FZD4 expression and Wnt/β-catenin signaling. Biochemical and biophysical research communications 107 30173892
2005 Mice null for Frizzled4 (Fzd4-/-) are infertile and exhibit impaired corpora lutea formation and function. Biology of reproduction 107 16093361
2011 Tumor suppressor microRNA-493 decreases cell motility and migration ability in human bladder cancer cells by downregulating RhoC and FZD4. Molecular cancer therapeutics 89 22057916
2003 Frizzled 4 gene (FZD4) mutations in patients with familial exudative vitreoretinopathy with variable expressivity. The British journal of ophthalmology 88 14507768
2004 Spectrum and frequency of FZD4 mutations in familial exudative vitreoretinopathy. Investigative ophthalmology & visual science 80 15223780
2019 Long noncoding RNA DLX6-AS1 promotes tumorigenesis by modulating miR-497-5p/FZD4/FZD6/Wnt/β-catenin pathway in pancreatic cancer. Cancer management and research 62 31118816
2017 Mutations in LRP5,FZD4, TSPAN12, NDP, ZNF408, or KIF11 Genes Account for 38.7% of Chinese Patients With Familial Exudative Vitreoretinopathy. Investigative ophthalmology & visual science 58 28494495
2018 MiR-1292 Targets FZD4 to Regulate Senescence and Osteogenic Differentiation of Stem Cells in TE/SJ/Mesenchymal Tissue System via the Wnt/β-catenin Pathway. Aging and disease 56 30574422
2009 Clinical presentation and genetic correlation of patients with mutations affecting the FZD4 gene. Archives of ophthalmology (Chicago, Ill. : 1960) 52 20008721
2021 Elevated Wnt2 and Wnt4 activate NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 following myocardial infarction. EBioMedicine 51 34911029
2013 Genetic variants of FZD4 and LRP5 genes in patients with advanced retinopathy of prematurity. Molecular vision 51 23441120
2015 Molecular Characterization of FZD4, LRP5, and TSPAN12 in Familial Exudative Vitreoretinopathy. Investigative ophthalmology & visual science 49 26244290
2018 HOXD-AS1 promotes cell proliferation, migration and invasion through miR-608/FZD4 axis in ovarian cancer. American journal of cancer research 47 29416930
2018 Wnt5a/FZD4 Mediates the Mechanical Stretch-Induced Osteogenic Differentiation of Bone Mesenchymal Stem Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 47 30007964
2009 Phenotypic overlap of familial exudative vitreoretinopathy (FEVR) with persistent fetal vasculature (PFV) caused by FZD4 mutations in two distinct pedigrees. Ophthalmic genetics 47 19172507
2019 Overexpressed lncRNA GATA6-AS1 Inhibits LNM and EMT via FZD4 through the Wnt/β-Catenin Signaling Pathway in GC. Molecular therapy. Nucleic acids 46 31981860
2020 CCL18-induced LINC00319 promotes proliferation and metastasis in oral squamous cell carcinoma via the miR-199a-5p/FZD4 axis. Cell death & disease 43 32948745
2020 WNT2b Activates Epithelial-mesenchymal Transition Through FZD4: Relevance in Penetrating Crohn´s Disease. Journal of Crohn's & colitis 41 31359032
2018 Downregulation of miR-3127-5p promotes epithelial-mesenchymal transition via FZD4 regulation of Wnt/β-catenin signaling in non-small-cell lung cancer. Molecular carcinogenesis 40 29566281
2010 Severe retinopathy of prematurity associated with FZD4 mutations. Ophthalmic genetics 39 20141357
2012 Identification of FZD4 and LRP5 mutations in 11 of 49 families with familial exudative vitreoretinopathy. Molecular vision 36 23077402
2021 EIF4A3-induced circular RNA PRKAR1B promotes osteosarcoma progression by miR-361-3p-mediated induction of FZD4 expression. Cell death & disease 35 34716310
2010 An essential role of the cysteine-rich domain of FZD4 in Norrin/Wnt signaling and familial exudative vitreoretinopathy. The Journal of biological chemistry 33 21177847
2022 Clematichinenoside AR inhibits the pathology of rheumatoid arthritis by blocking the circPTN/miR-145-5p/FZD4 signal axis. International immunopharmacology 32 36279670
2004 Autosomal dominant familial exudative vitreoretinopathy in two Japanese families with FZD4 mutations (H69Y and C181R). Ophthalmic genetics 32 15370539
2016 Mutation spectrum of the FZD-4, TSPAN12 AND ZNF408 genes in Indian FEVR patients. BMC ophthalmology 31 27316669
2021 Circ-ACAP2 facilitates the progression of colorectal cancer through mediating miR-143-3p/FZD4 axis. European journal of clinical investigation 29 34085707
2018 MicroRNA-101 inhibits cell migration and invasion in bladder cancer via targeting FZD4. Experimental and therapeutic medicine 29 30680031
2016 Novel mutations in FZD4 and phenotype-genotype correlation in Chinese patients with familial exudative vitreoretinopathy. Molecular vision 29 27555740
2017 FZD4 Marks Lateral Plate Mesoderm and Signals with NORRIN to Increase Cardiomyocyte Induction from Pluripotent Stem Cell-Derived Cardiac Progenitors. Stem cell reports 28 29249665
2023 m6A RNA methylation-mediated upregulation of HLF promotes intrahepatic cholangiocarcinoma progression by regulating the FZD4/β-catenin signaling pathway. Cancer letters 26 36958694
2006 Karyotype-phenotype insights from 11q14.1-q23.2 interstitial deletions: FZD4 haploinsufficiency and exudative vitreoretinopathy in a patient with a complex chromosome rearrangement. American journal of medical genetics. Part A 26 17103440
2021 Quercetin inhibited the proliferation and invasion of hepatoblastoma cells through facilitating SIRT6-medicated FZD4 silence. Human & experimental toxicology 24 34219513
2019 LncRNA ASB16-AS1 Promotes Growth And Invasion Of Hepatocellular Carcinoma Through Regulating miR-1827/FZD4 Axis And Activating Wnt/β-Catenin Pathway. Cancer management and research 24 31807066
2006 Identification of novel FZD4 mutations in Indian patients with familial exudative vitreoretinopathy. Molecular vision 24 17093393
2014 Identification of the cellular mechanisms that modulate trafficking of frizzled family receptor 4 (FZD4) missense mutants associated with familial exudative vitreoretinopathy. Investigative ophthalmology & visual science 23 24744206
2022 SZN-413, a FZD4 Agonist, as a Potential Novel Therapeutic for the Treatment of Diabetic Retinopathy. Translational vision science & technology 21 36149648
2017 A miR-SNP biomarker linked to an increased lung cancer survival by miRNA-mediated down-regulation of FZD4 expression and Wnt signaling. Scientific reports 21 28831115
2021 The ER membrane protein complex subunit Emc3 controls angiogenesis via the FZD4/WNT signaling axis. Science China. Life sciences 20 34128175
2019 MiR-144-3p Inhibits BMSC Proliferation and Osteogenic Differentiation Via Targeting FZD4 in Steroid-Associated Osteonecrosis. Current pharmaceutical design 20 31566128
2004 Novel mutation in FZD4 gene in a Japanese pedigree with familial exudative vitreoretinopathy. American journal of ophthalmology 19 15488808
2020 LncRNA LINC00963 promotes proliferation and migration through the miR-124-3p/FZD4 pathway in colorectal cancer. European review for medical and pharmacological sciences 18 32744689
2020 MicroRNA-101a-3p could be involved in the pathogenesis of temporomandibular joint osteoarthritis by mediating UBE2D1 and FZD4. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 18 33187014
2020 SNHG1 represses the anti-cancer roles of baicalein in cervical cancer through regulating miR-3127-5p/FZD4/Wnt/β-catenin signaling. Experimental biology and medicine (Maywood, N.J.) 17 32883110
2023 YAP/WNT5A/FZD4 axis regulates osteogenic differentiation of human periodontal ligament cells under cyclic stretch. Journal of periodontal research 16 37340863
2022 Identification of a Schistosoma japonicum MicroRNA That Suppresses Hepatoma Cell Growth and Migration by Targeting Host FZD4 Gene. Frontiers in cellular and infection microbiology 15 35174106
2020 MicroRNA-1286 inhibits osteogenic differentiation of mesenchymal stem cells to promote the progression of osteoporosis via regulating FZD4 expression. European review for medical and pharmacological sciences 15 31957812
2022 Circ_0088036 facilitates the proliferation and inflammation and inhibits the apoptosis of fibroblast-like synoviocytes through targeting miR-326/FZD4 axis in rheumatoid arthritis. Autoimmunity 14 35352610
2021 miR-129-5p in exosomes inhibits diabetes-associated osteogenesis in the jaw via targeting FZD4. Biochemical and biophysical research communications 14 34119828
2021 Circ_0003972 Promotes the Proliferation and Inflammation of Fibroblast-like Synovial Cells in Rheumatoid Arthritis through Regulation of the miR-654-5p/FZD4 Axis. Immunological investigations 14 34325604
2020 Role of NDP- and FZD4-Related Novel Mutations Identified in Patients with FEVR in Norrin/β-Catenin Signaling Pathway. BioMed research international 14 32420371
2017 Variable Familial Exudative Vitreoretinopathy in a family harbouring variants in both FZD4 and TSPAN12. Acta ophthalmologica 14 28211206
2021 Hsa_circ_0004712 downregulation attenuates ovarian cancer malignant development by targeting the miR-331-3p/FZD4 pathway. Journal of ovarian research 13 34507595
2024 FOXF1 promotes tumor vessel normalization and prevents lung cancer progression through FZD4. EMBO molecular medicine 12 38589650
2022 LINC01119 negatively regulates osteogenic differentiation of mesenchymal stem cells via the Wnt pathway by targeting FZD4. Stem cell research & therapy 12 35093173
2022 FZD4 in a Large Chinese Population With Familial Exudative Vitreoretinopathy: Molecular Characteristics and Clinical Manifestations. Investigative ophthalmology & visual science 12 35394490
2022 CircRNA has_circ_0017109 promotes lung tumor progression via activation of Wnt/β-catenin signaling due to modulating miR-671-5p/FZD4 axis. BMC pulmonary medicine 12 36434577
2016 Comparison of the homogeneity of mRNAs encoding SFRP5, FZD4, and Fosl1 in post-injury intervals: Subcellular localization of markers may influence wound age estimation. Journal of forensic and legal medicine 12 27497723
2015 Identification and functional analysis of novel FZD4 mutations in Han Chinese with familial exudative vitreoretinopathy. Scientific reports 12 26530129
2021 Circ_FBLN1 promotes the proliferation and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by regulating let-7i-5p/FZD4 axis and Wnt/β-catenin pathway. Journal of bioenergetics and biomembranes 11 34424449
2022 MicroRNA-200a regulates skin pigmentation by targeting WNT5A and FZD4 in Cashmere goats. Research in veterinary science 10 35461010
2021 CircRASSF2 facilitates the proliferation and metastasis of colorectal cancer by mediating the activity of Wnt/β-catenin signaling pathway by regulating the miR-195-5p/FZD4 axis. Anti-cancer drugs 10 33929991
2020 Up-Regulation of Nfat5 mRNA and Fzd4 mRNA as a Marker of Poor Outcome in Neonatal Hypoxic-Ischemic Encephalopathy. The Journal of pediatrics 10 32828883
2020 lncRNA SNHG5 promotes cell proliferation, migration and invasion in oral squamous cell carcinoma by sponging miR-655-3p/FZD4 axis. Oncology letters 10 33093919
2019 Molecular evolutionary and structural analysis of familial exudative vitreoretinopathy associated FZD4 gene. BMC evolutionary biology 10 30849938
2019 Secreted Wnt6 mediates diabetes-associated centrosome amplification via its receptor FZD4. American journal of physiology. Cell physiology 10 31618077
2018 Retinoic acid-induced expression of Hnf1b and Fzd4 is required for pancreas development in Xenopus laevis. Development (Cambridge, England) 10 29769220
2017 Mutation spectrum of NDP, FZD4 and TSPAN12 genes in Indian patients with retinopathy of prematurity. The British journal of ophthalmology 10 28982955
2016 Role of let-7b/Fzd4 axis in mitochondrial biogenesis through wnt signaling: In neonatal and adult megakaryocytes. The international journal of biochemistry & cell biology 10 27510711
2023 Silencing hsa_circ_0049271 attenuates hypoxia-reoxygenation (H/R)-induced myocardial cell injury via the miR-17-3p/FZD4 signaling axis. Annals of translational medicine 9 36819541
2023 miR-136-5p/FZD4 axis is critical for Wnt signaling-mediated myogenesis and skeletal muscle regeneration. Journal of cellular physiology 9 37218742
2022 Severe Familial Exudative Vitreoretinopathy, Congenital Hearing Loss, and Developmental Delay in a Child With Biallelic Variants in FZD4. JAMA ophthalmology 9 35951321
2020 Identification of Novel Mutations in the FZD4 and NDP Genes in Patients with Familial Exudative Vitreoretinopathy in South India. Genetic testing and molecular biomarkers 9 31999491
2016 Fzd4 Haploinsufficiency Delays Retinal Revascularization in the Mouse Model of Oxygen Induced Retinopathy. PloS one 9 27489958
2016 A family harboring homozygous FZD4 deletion supports the existence of recessive FZD4-related familial exudative vitreoretinopathy. Ophthalmic genetics 9 27668459
2021 Whole-Gene Deletions of FZD4 Cause Familial Exudative Vitreoretinopathy. Genes 8 34199009
2018 A Novel Variant of the FZD4 Gene in a Chinese Family Causes Autosomal Dominant Familial Exudative Vitreoretinopathy. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 8 30537745
2012 Familial retinal detachment associated with COL2A1 exon 2 and FZD4 mutations. Clinical & experimental ophthalmology 8 22574936
2024 Identification of Novel FZD4 Mutations in Familial Exudative Vitreoretinopathy and Investigating the Pathogenic Mechanisms of FZD4 Mutations. Investigative ophthalmology & visual science 7 38558095
2020 Novel FZD4 and LRP5 mutations in a small cohort of patients with familial exudative vitreoretinopathy (FEVR). Ophthalmic genetics 7 33302760
2022 Whole exome sequencing revealed 14 variants in NDP, FZD4, LRP5, and TSPAN12 genes for 20 families with familial exudative vitreoretinopathy. BMC medical genomics 6 35277167
2019 Detection of FZD4, LRP5 and TSPAN12 Genes Variants in Malay Premature Babies with Retinopathy of Prematurity. Journal of ophthalmic & vision research 6 31114654
2013 Simultaneous fzd4 and lrp5 mutation in autosomal dominant familial exudative vitreoretinopathy. Retinal cases & brief reports 6 25390515
2000 Mouse fzd4 maps within a region of chromosome 7 important for thymus and cardiac development. Genesis (New York, N.Y. : 2000) 6 10890980
2022 The mechanism of the WNT5A and FZD4 receptor mediated WNT/β-catenin pathway in the degeneration of ALS spinal cord motor neurons. Biochemical and biophysical research communications 5 35413536
2019 Variable reduction in Norrin signaling activity caused by novel mutations in FZD4 identified in patients with familial exudative vitreoretinopathy. Molecular vision 5 30820142
2019 Identification of novel variants in the FZD4 gene associated with familial exudative vitreoretinopathy in Chinese families. Clinical & experimental ophthalmology 5 31765079
2018 Genetic association of single nucleotide polymorphisms of FZD4 and BDNF genes with retinopathy of prematurity. Ophthalmic genetics 5 29465286
2023 Folate deficiency promotes cervical squamous carcinoma SiHa cells progression by targeting miR-375/FZD4/β-catenin signaling. The Journal of nutritional biochemistry 4 37926400
2022 Decrease of FZD4 exon 1 methylation in probands from FZD4-associated FEVR family of phenotypic heterogeneity. Frontiers in medicine 4 36353221
2021 Overexpressed miR-375-Loaded Restrains Development of Cervical Cancer Through Down-Regulation of Frizzled Class Receptor 4 (FZD4) with Liposome Nanoparticle as a Carrier. Journal of biomedical nanotechnology 4 34688334
2025 N-Glycosylation Modification of Fzd4 Is Essential for the Fzd4-Wnt-β-Catenin Signalling Axis. Journal of cellular and molecular medicine 3 40230079
2022 Circ_0001971 makes progress of oral squamous cell carcinoma by targeting miR-107/FZD4 axis. Oral diseases 3 35403775
2022 A regulatory circuit of lncRNA NLGN1-AS1 and Wnt signalling controls clear cell renal cell carcinoma phenotypes through FZD4-modulated pathways. Aging 3 36170021
2021 Discovering the Role of FZD4 Gene in Human Cutaneous Squamous Cell Carcinoma. Indian journal of dermatology 3 35068502

Missed literature

Know a paper Affinage missed for FZD4? Flag it for the maintainers and the community.

No submissions yet.