Affinage

FZD4

Frizzled-4 · UniProt Q9ULV1

Length
537 aa
Mass
59.9 kDa
Annotated
2026-04-28
100 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FZD4 is a seven-transmembrane Wnt receptor that transduces canonical β-catenin signaling in response to Norrin and multiple Wnt ligands (Wnt2, Wnt2b, Wnt4, Wnt5a, Wnt6), functioning as a central regulator of vascular development, organogenesis, and tissue homeostasis. Its extracellular cysteine-rich domain (CRD) is essential for Norrin binding; CRD missense mutations abolish ligand engagement and β-catenin activation, while N-glycosylation at N59 and N144 is required for receptor maturation, plasma membrane trafficking, ligand interaction, and signaling competence (PMID:21177847, PMID:40230079). TSPAN12 selectively potentiates Norrin–FZD4 signaling by promoting FZD4 multimerization, and EMC3 is required upstream for FZD4 protein biogenesis in retinal endothelial cells (PMID:19837033, PMID:34128175). Loss-of-function mutations in FZD4 cause familial exudative vitreoretinopathy (FEVR), with disease-associated variants exhibiting ER retention, impaired Norrin binding, or defective DVL2 recruitment (PMID:24744206, PMID:38558095).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 High

    Establishing that FZD4 has essential in vivo roles beyond retinal vasculature: Fzd4-knockout mice revealed a Norrin-independent requirement for FZD4 in corpus luteum formation and female fertility, broadening FZD4 biology beyond its known retinal function.

    Evidence Fzd4 knockout mouse with histological, expression, and Ndph-null comparison

    PMID:16093361

    Open questions at the time
    • The Wnt ligand acting through FZD4 in the ovary was not identified
    • Downstream signaling pathway (canonical vs. non-canonical) in corpus luteum not resolved
  2. 2009 High

    Resolving how Norrin–FZD4 signaling specificity is achieved at the receptor level: TSPAN12 was identified as a co-receptor that physically associates with FZD4 and selectively amplifies Norrin- but not Wnt-dependent β-catenin signaling by promoting FZD4 multimerization.

    Evidence Co-immunoprecipitation, siRNA in retinal endothelial cells, luciferase reporter, and Tspan12/Norrin/Lrp5 mutant mouse epistasis

    PMID:19837033

    Open questions at the time
    • Structural basis of TSPAN12-mediated multimerization not determined
    • Whether TSPAN12 modulates non-canonical FZD4 signaling not tested
  3. 2010 High

    Defining the ligand-binding domain: the CRD of FZD4 was shown to be necessary and sufficient for Norrin binding, with specific cysteine residues (C45, C204) and Y58 required for engagement, establishing the molecular basis for FEVR-associated loss of function.

    Evidence Cell-surface binding assays, site-directed mutagenesis, luciferase reporter, and Xenopus embryo signaling assay

    PMID:21177847

    Open questions at the time
    • High-resolution structure of the Norrin–CRD interface not yet available at this time
    • Whether these residues also affect Wnt ligand binding was not tested
  4. 2010 Medium

    Placing FZD4 in an oncogenic transcriptional circuit: ERG was shown to transcriptionally upregulate FZD4 in prostate cancer, and FZD4 was positioned as the effector of ERG-driven EMT via Wnt/β-catenin signaling.

    Evidence ERG/FZD4 siRNA epistasis and FZD4 overexpression rescue in VCaP prostate cancer cells

    PMID:20713528

    Open questions at the time
    • The specific Wnt ligand operating through FZD4 in this cancer context was not identified
    • In vivo tumor model validation not reported
  5. 2014 High

    Revealing how FEVR mutations cause disease at the cellular level: systematic analysis of 15 FEVR-associated FZD4 missense mutations showed that most cause ER retention and defective plasma membrane trafficking, establishing haploinsufficiency through protein misfolding rather than solely ligand-binding defects.

    Evidence Confocal microscopy, N-glycosylation profiling, polyubiquitination assays, chemical chaperone rescue in HeLa/COS-7 cells

    PMID:24744206

    Open questions at the time
    • Whether chemical chaperone rescue is therapeutically viable in vivo not tested
    • Contribution of proteasomal vs. lysosomal degradation of misfolded FZD4 not resolved
  6. 2016 Medium

    Demonstrating dose-sensitivity of FZD4 in retinal vascular repair: Fzd4 heterozygous mice showed delayed retinal revascularization after oxygen-induced retinopathy, confirming that even partial reduction of FZD4 levels is pathologically significant.

    Evidence Fzd4 heterozygous mouse, OIR model with quantitative vascular area measurements

    PMID:27489958

    Open questions at the time
    • Whether the haploinsufficiency is due to reduced Norrin or Wnt signaling was not distinguished
    • Therapeutic rescue by FZD4 supplementation not attempted
  7. 2018 Medium

    Expanding FZD4's non-canonical signaling: Wnt5a was shown to signal through FZD4 via JNK (not β-catenin) to mediate mechanical stretch-induced osteogenic differentiation, establishing FZD4 as a receptor for both canonical and non-canonical Wnt pathways depending on context.

    Evidence siRNA knockdown, cyclic stretch in vitro, western blot for JNK, and hindlimb unloading mouse model

    PMID:30007964

    Open questions at the time
    • Direct Wnt5a–FZD4 physical interaction not demonstrated by binding assay
    • Co-receptor identity for this non-canonical pathway not identified
  8. 2021 High

    Identifying an upstream biogenesis factor: EMC3 was shown to be required for FZD4 protein expression and ER-to-plasma-membrane trafficking in retinal endothelial cells, connecting ER membrane protein complex function to Norrin/β-catenin signaling and retinal vascularization.

    Evidence Endothelial-specific Emc3 conditional knockout mouse, RNA-seq, luciferase reporter, LiCl rescue

    PMID:34128175

    Open questions at the time
    • Whether EMC3 acts as a direct chaperone for FZD4 or affects it indirectly not resolved
    • Whether EMC3 regulates other Frizzled family members in the same cells not tested
  9. 2024 High

    Comprehensive mechanistic classification of FEVR mutations: 34 FZD4 mutations were functionally categorized into five classes—signal peptide (reduced expression), CRD cysteine (disulfide disruption), extracellular (impaired Norrin binding), transmembrane (mislocalization), and intracellular (defective DVL2 recruitment)—providing a genotype-mechanism framework.

    Evidence Mutagenesis, expression assays, Norrin/β-catenin reporter, confocal localization, DVL2 co-IP in HEK293T/HeLa cells

    PMID:38558095

    Open questions at the time
    • In vivo validation of the five-class model not performed
    • Whether mutation class predicts disease severity in patients not established
  10. 2024 High

    Identifying a transcriptional activator of FZD4 in endothelium: FOXF1 was shown to directly activate FZD4 transcription; nanoparticle delivery of Fzd4 cDNA to FOXF1-deficient endothelial cells rescued Wnt/β-catenin signaling and normalized tumor vasculature, demonstrating FZD4 as the critical FOXF1 effector.

    Evidence Endothelial-specific Foxf1 KO/OE mice, CUT&Tag ChIP-seq, nanoparticle Fzd4 rescue, RNA-seq

    PMID:38558650

    Open questions at the time
    • Whether FOXF1 regulates FZD4 in non-lung endothelial beds not tested
    • Therapeutic durability of nanoparticle FZD4 delivery not assessed
  11. 2025 High

    Defining post-translational requirements for FZD4 function: N-glycosylation at N59 and N144 was shown to be essential for FZD4 maturation, surface trafficking, Wnt/Norrin binding, and β-catenin signaling, resolving a long-standing gap in understanding FZD4 quality control.

    Evidence Site-directed mutagenesis of glycosylation sites, surface biotinylation, co-IP with Wnt/Norrin, luciferase reporter in A549 cells

    PMID:40230079

    Open questions at the time
    • Whether glycosylation affects TSPAN12-mediated multimerization not tested
    • Structural impact of glycan chains on CRD conformation not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FZD4 selects between canonical (β-catenin) and non-canonical (JNK/PCP) signaling outputs depending on the Wnt ligand and cellular context remains mechanistically undefined, and structural models of the full-length receptor in complex with co-receptors (LRP5/6, TSPAN12) are lacking.
  • No full-length FZD4 structure with co-receptors available
  • Mechanism of canonical vs. non-canonical pathway selection at FZD4 not resolved
  • Relative contributions of individual Wnt ligands to FZD4 signaling in specific tissues not systematically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 8 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 3
Partners
DVL2EMC3LRP5LRP6NDPTSPAN12WNT5AWNT6
Complex memberships
Norrin–FZD4–LRP5/6–TSPAN12 receptor complex

Evidence

Reading pass · 23 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-immunoprecipitation), selectively enhancing Norrin/β-catenin but not Wnt/β-catenin signaling by promoting FZD4 multimerization; overexpression of TSPAN12 rescues signaling defects caused by FZD4 mutations predicted to impair receptor multimerization. Co-immunoprecipitation, siRNA knockdown in retinal endothelial cells, luciferase reporter assay, genetic epistasis in Tspan12/Norrin/Lrp5 mutant mice Cell High 19837033
2010 The cysteine-rich domain (CRD) of FZD4 is required for Norrin binding and Norrin-dependent activation of the canonical Wnt/β-catenin pathway; CRD missense mutations C45Y, Y58C, and C204R abolish Norrin binding and fail to transduce β-catenin signaling both in HEK293 cells and in Xenopus embryos (decreased Siamois and Xnr3 expression). Cell-surface and overlay binding assays, luciferase reporter assay, Xenopus embryo in vivo assay, site-directed mutagenesis The Journal of biological chemistry High 21177847
2014 Multiple FEVR-associated FZD4 missense mutations (P33S, G36N, H69Y, M105T, M105V, C181R, C204R, C204Y, G488D) cause ER retention and defective trafficking to the plasma membrane, resulting in haploinsufficiency; some mutants (M105T, C204Y) show partial rescue of trafficking by reduced temperature or chemical chaperones. Confocal fluorescence microscopy, N-glycosylation profiling, polyubiquitination studies, chemical chaperone rescue experiments in HeLa and COS-7 cells Investigative ophthalmology & visual science High 24744206
2005 Fzd4-null mice are infertile due to failure of corpus luteum formation; Fzd4-/- corpora lutea show reduced expression of luteal markers (Lhcgr, Prlr, Cyp11a1), altered cell morphology, and reduced angiogenesis markers, while Norrin-null mice do not phenocopy this, indicating FZD4 regulates corpus luteum formation through a Norrin-independent mechanism. Fzd4 knockout mouse model, histological analysis, mRNA expression profiling, timed mating experiments Biology of reproduction High 16093361
2021 EMC3 (ER membrane protein complex subunit) is required for FZD4 protein expression and Norrin/β-catenin signaling in retinal endothelial cells; endothelial-specific Emc3 deletion reduces FZD4 levels and impairs retinal vascular development, which is partially rescued by LiCl-mediated activation of β-catenin signaling. Endothelial-specific conditional knockout mouse, RNA sequencing, RT-qPCR, luciferase reporter assay, LiCl rescue experiment, tube formation assay in HRECs Science China. Life sciences High 34128175
2017 FZD4 marks lateral plate mesoderm in cardiac progenitor cells; NORRIN presented to FZD4 increases cardiomyocyte output from pluripotent stem cell-derived cardiac progenitors via proliferation through the canonical WNT pathway. Surface proteomics (mass spectrometry), microarray transcriptomics, FACS-based cell sorting using FZD4/FLK1/PDGFRA, WNT reporter assay, functional differentiation assays in mouse and human PSC systems Stem cell reports High 29249665
2019 Secreted Wnt6 binds FZD4 to activate canonical Wnt6/β-catenin signaling upstream of ROCK1 and 14-3-3σ, driving diabetes-associated centrosome amplification; siRNA knockdown of FZD4 or antibody blockade of FZD4 attenuates centrosome amplification induced by high glucose, insulin, palmitic acid, or advanced glycation end products. siRNA knockdown, neutralizing antibodies, centrosome quantification, β-catenin nuclear translocation assays in cell culture American journal of physiology. Cell physiology Medium 31618077
2021 Wnt2 and Wnt4 activate β-catenin/NF-κB signaling in cardiac fibroblasts through cooperation of Fzd4 (or Fzd2) with LRP6; Fzd4 knockdown attenuates Wnt2/Wnt4-induced pro-fibrotic effects. siRNA knockdown, co-receptor interaction analysis, NF-κB/β-catenin reporter assays in neonatal rat cardiac fibroblasts, MI mouse model EBioMedicine Medium 34911029
2020 WNT2b induces epithelial-to-mesenchymal transition in HT29 intestinal epithelial cells through FZD4 activation, and FZD4/WNT2b interaction is elevated in intestinal tissue from penetrating Crohn's disease patients. In vitro EMT assay in HT29 cells with WNT2b treatment, FZD4 siRNA knockdown, confocal microscopy, RT-PCR, western blot, immunofluorescence on patient tissue Journal of Crohn's & colitis Medium 31359032
2018 Wnt5a/FZD4 signaling activates the JNK pathway to mediate mechanical stretch-induced osteogenic differentiation of bone marrow stromal cells; FZD4 knockdown inhibits mechanical stimuli-induced osteogenesis and JNK activity, and Wnt5a or FZD4 activation partly rescues hindlimb unloading-induced osteoporosis in mice. siRNA knockdown, cyclic mechanical stretch in vitro model, ALP and Alizarin red staining, western blot, hindlimb unloading mouse model Cellular physiology and biochemistry Medium 30007964
2010 ERG oncogene transcriptionally upregulates FZD4 in prostate cancer cells; FZD4 silencing mimics ERG knockdown by inducing active β1-integrin and E-cadherin expression, while FZD4 overexpression reverses the EMT phenotype caused by ERG knockdown, placing FZD4 downstream of ERG in WNT-mediated EMT. ERG and FZD4 siRNA knockdown, FZD4 overexpression rescue, flow cytometry for integrins, immunostaining, RT-PCR in VCaP cells Cancer research Medium 20713528
2020 GATA6-AS1 lncRNA downregulates FZD4 expression by recruiting EZH2 and promoting H3K27me3 at the FZD4 promoter, thereby inactivating Wnt/β-catenin signaling and suppressing gastric cancer progression. Chromatin immunoprecipitation, EZH2 co-immunoprecipitation/interaction assay, luciferase reporter, siRNA knockdown and overexpression, xenograft mouse model Molecular therapy. Nucleic acids Medium 31981860
2021 SIRT6 suppresses FZD4 transcription by deacetylating histone H3K9 at the FZD4 locus; overexpression of SIRT6 reduces FZD4 protein and H3K9ac levels, and quercetin activates SIRT6 to repress FZD4 and the Wnt/β-catenin pathway in hepatoblastoma cells. SIRT6 overexpression/knockdown, H3K9ac ChIP, FZD4 overexpression rescue, Wnt pathway reporter, xenograft mouse model Human & experimental toxicology Medium 34219513
2024 FOXF1 transcriptionally activates FZD4 in lung endothelial cells; FOXF1 deficiency decreases FZD4 expression and Wnt/β-catenin signaling, and nanoparticle delivery of Fzd4 cDNA to FOXF1-deficient endothelial cells rescues Wnt/β-catenin signaling, normalizes tumor vessels, and inhibits lung cancer progression. Endothelial-specific Foxf1 KO and overexpression mouse models, nanoparticle cDNA delivery rescue, RNA-seq, ChIP-seq (CUT&Tag), vessel permeability/pericyte coverage assays EMBO molecular medicine High 38589650
2023 METTL3-dependent m6A methylation of HLF mRNA upregulates HLF, which transcriptionally activates FZD4 to drive WNT/β-catenin signaling in intrahepatic cholangiocarcinoma; FOXQ1 forms a positive feedback loop by transcriptionally activating METTL3. RNA-seq, CUT&Tag chromatin profiling, loss/gain-of-function experiments, m6A methylation assays, in vitro and in vivo tumor assays Cancer letters Medium 36958694
2025 FZD4 is N-glycosylated at asparagine residues N59 and N144; N-glycosylation is required for FZD4 maturation, plasma membrane trafficking, protein stability, interaction with Wnt ligands and Norrin co-receptor, and Wnt/β-catenin signaling activity. Site-directed mutagenesis of N-glycosylation sites, surface biotinylation, co-immunoprecipitation with Wnt/Norrin, luciferase reporter assay, in vitro and in vivo tumor assays in NSCLC A549 cells Journal of cellular and molecular medicine High 40230079
2020 FZD4 mutations identified in FEVR patients reduce Norrin/β-catenin transcriptional activity in Topflash reporter assays and impair Norrin-FZD4 protein binding as shown by immunoprecipitation; all six tested NDP and FZD4 mutants showed ≥50% loss of wild-type signaling activity. Topflash luciferase reporter assay, co-immunoprecipitation of Norrin-FZD4 complex with mutant proteins in transfected cells BioMed research international Medium 32420371
2018 Retinoic acid directly induces FZD4/FZD4s expression in Xenopus pancreatic explants; functional knockdown of Fzd4/Fzd4s impairs pancreatic progenitor formation and differentiation, establishing FZD4 as a direct RA target gene required for pancreas specification. RNA sequencing of pancreatic explants, morpholino knockdown of Fzd4/Fzd4s in Xenopus embryos and explants, loss-of-function phenotypic analysis of pancreatic progenitor markers Development (Cambridge, England) Medium 29769220
2016 Fzd4 heterozygous mice show delayed retinal revascularization after oxygen-induced retinopathy (OIR), demonstrating that reduced Norrin-Fzd4 signaling dose-dependently impairs retinal vascular recovery. Fzd4 heterozygous mouse model, OIR treatment, quantification of avascular and vascular retinal areas, vessel caliber/number measurements PloS one Medium 27489958
2024 Five novel FZD4 FEVR missense mutations (S91F, V103E, C145S, E160K, C377F) were functionally categorized: signal peptide mutations reduce expression; CRD cysteine mutations disrupt disulfide bonds; extracellular domain mutations impair Norrin binding; TM1/TM7 mutations disrupt membrane localization; intracellular domain mutations reduce DVL2 recruitment. Site-directed mutagenesis, protein expression assays, Norrin/β-catenin luciferase reporter, membrane localization by confocal microscopy, DVL2 co-immunoprecipitation in HEK293T, HEK293STF, and HeLa cells Investigative ophthalmology & visual science High 38558095
2016 Let-7b inhibits Wnt signaling by targeting FZD4 mRNA in megakaryocytes; let-7b downregulation leads to increased FZD4 expression and regulates mitochondrial biogenesis (PGC-1α, NRF1) during megakaryocyte development. miRNA microarray, let-7b mimic/inhibitor transfection, Dami cell line validation, mitochondrial biogenesis marker quantification The international journal of biochemistry & cell biology Low 27510711
2023 YAP positively regulates WNT5A and FZD4 expression in human periodontal ligament cells (hPDLCs) under cyclic stretch; FZD4 knockdown attenuates both YAP-induced and stretch-induced osteogenic differentiation, and recombinant WNT5A rescues osteogenesis suppressed by YAP inhibition except when FZD4 is knocked down. YAP inhibitor (verteporfin) and activator (LATS-IN-1), siRNA knockdown of WNT5A and FZD4, recombinant WNT5A rescue, ALP activity, Alizarin Red staining, qRT-PCR, western blot in hPDLCs under cyclic stretch Journal of periodontal research Medium 37340863
2023 WNT5A binds FZD4 to regulate the WNT/β-catenin signaling pathway in ALS motor neurons; knockdown of FZD4 or WNT5A reduces β-catenin signaling and affects proliferation and apoptosis of hSOD1-G93A mutant NSC34 cells. hSOD1-G93A transgenic mouse model, hSOD1-G93A mutant NSC34 cells, siRNA knockdown, western blot, immunofluorescence for β-catenin pathway components Biochemical and biophysical research communications Low 35413536

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 323 19837033
2004 Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. American journal of human genetics 301 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 125 20340138
2005 Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes. Human mutation 113 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 87 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
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
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 46 30007964
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 31 36279670
2004 Autosomal dominant familial exudative vitreoretinopathy in two Japanese families with FZD4 mutations (H69Y and C181R). Ophthalmic genetics 31 15370539
2016 Mutation spectrum of the FZD-4, TSPAN12 AND ZNF408 genes in Indian FEVR patients. BMC ophthalmology 30 27316669
2018 MicroRNA-101 inhibits cell migration and invasion in bladder cancer via targeting FZD4. Experimental and therapeutic medicine 29 30680031
2021 Circ-ACAP2 facilitates the progression of colorectal cancer through mediating miR-143-3p/FZD4 axis. European journal of clinical investigation 28 34085707
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
2016 Novel mutations in FZD4 and phenotype-genotype correlation in Chinese patients with familial exudative vitreoretinopathy. Molecular vision 28 27555740
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
2005 Further evidence of genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of EVR1, EVR3, and EVR4 in a large autosomal dominant pedigree. The British journal of ophthalmology 26 15665352
2023 m6A RNA methylation-mediated upregulation of HLF promotes intrahepatic cholangiocarcinoma progression by regulating the FZD4/β-catenin signaling pathway. Cancer letters 24 36958694
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 22 24744206
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
2022 SZN-413, a FZD4 Agonist, as a Potential Novel Therapeutic for the Treatment of Diabetic Retinopathy. Translational vision science & technology 19 36149648
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 15 37340863
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 Identification of a Schistosoma japonicum MicroRNA That Suppresses Hepatoma Cell Growth and Migration by Targeting Host FZD4 Gene. Frontiers in cellular and infection microbiology 14 35174106
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 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 miR-129-5p in exosomes inhibits diabetes-associated osteogenesis in the jaw via targeting FZD4. Biochemical and biophysical research communications 13 34119828
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 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
2022 FZD4 in a Large Chinese Population With Familial Exudative Vitreoretinopathy: Molecular Characteristics and Clinical Manifestations. Investigative ophthalmology & visual science 11 35394490
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
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
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2022 MicroRNA-200a regulates skin pigmentation by targeting WNT5A and FZD4 in Cashmere goats. Research in veterinary science 9 35461010
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
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2023 miR-136-5p/FZD4 axis is critical for Wnt signaling-mediated myogenesis and skeletal muscle regeneration. Journal of cellular physiology 8 37218742
2022 Severe Familial Exudative Vitreoretinopathy, Congenital Hearing Loss, and Developmental Delay in a Child With Biallelic Variants in FZD4. JAMA ophthalmology 8 35951321
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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
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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
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2000 Mouse fzd4 maps within a region of chromosome 7 important for thymus and cardiac development. Genesis (New York, N.Y. : 2000) 6 10890980
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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
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
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
2019 Variable reduction in Norrin signaling activity caused by novel mutations in FZD4 identified in patients with familial exudative vitreoretinopathy. Molecular vision 4 30820142
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2025 N-Glycosylation Modification of Fzd4 Is Essential for the Fzd4-Wnt-β-Catenin Signalling Axis. Journal of cellular and molecular medicine 3 40230079
2021 Discovering the Role of FZD4 Gene in Human Cutaneous Squamous Cell Carcinoma. Indian journal of dermatology 3 35068502
2017 WITHDRAWN: MicroRNA-505 modulates cancer proliferation and migration in human non-small cell lung cancer through inverse regulation of FZD4. Lung cancer (Amsterdam, Netherlands) 3 28438350