{"gene":"FZD3","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2014,"finding":"Celsr3 and Fzd3 act in the same population of forebrain cells to regulate axon guidance; combined Celsr2/Celsr3 mutation mimics Fzd3 knockout, and forebrain wiring defects are Vangl1/Vangl2-independent, indicating a PCP mechanism distinct from classical epithelial PCP.","method":"Conditional knockout mice (cell-type-specific inactivation), genetic epistasis (double/triple mutants), axon tract tracing","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis with multiple conditional alleles across independent forebrain compartments, replicated phenotypes across multiple mutant combinations","pmids":["25002511"],"is_preprint":false},{"year":2016,"finding":"Celsr3 and Fzd3 expressed in immature cortical neurons (not progenitors) enable neurons to respond to Wnt7, upregulate Jag1, and thereby activate Notch signaling in neural progenitor cells, constituting a feedback loop that controls the timing of neurogenesis vs. gliogenesis.","method":"Conditional knockout mice (neuron-specific Celsr3/Fzd3 inactivation), in vivo gene expression analysis, Notch pathway readouts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO with defined signaling pathway readout (Jag1/Notch), multiple orthogonal approaches in a single study","pmids":["26939553"],"is_preprint":false},{"year":2016,"finding":"Celsr3 and Fzd3 are required in Isl1-positive guidepost/pioneer neurons (not thalamic or cortical neurons themselves) to form a pioneer axon scaffold that steers growing thalamocortical axons across the diencephalon-telencephalon junction.","method":"Cell-type-specific conditional knockout (Isl1-cre), axon tract tracing, embryonic projection analysis","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO in defined cell population with direct axon-guidance phenotype, multiple anatomical readouts","pmids":["27170656"],"is_preprint":false},{"year":2019,"finding":"Fzd3 expressed within inner ear afferent neurons (not hindbrain) mediates central pathfinding of vestibular afferents; ear transplantation from Fzd3 morpholino-treated Xenopus to control hosts recapitulated guidance defects, establishing a cell-autonomous role in the ear.","method":"Fzd3 null mice (axon tracing), Fzd3 morpholino knockdown in Xenopus, ear transplantation experiments","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in two vertebrate species plus transplantation experiment establishing tissue autonomy","pmids":["31311957"],"is_preprint":false},{"year":2022,"finding":"Fzd3 acts cell-autonomously within inner ear afferent neurons (Neurod1-cre conditional KO) to regulate central pathfinding in the hindbrain; conditional deletion from hair cells (Atoh1-cre) had no effect on afferent topography.","method":"Conditional knockout mice (Neurod1-cre and Atoh1-cre), central projection mapping","journal":"Frontiers in neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two complementary conditional KO lines with opposite outcomes establishing cell autonomy in defined neuronal population","pmids":["35153658"],"is_preprint":false},{"year":2024,"finding":"WNT5B binds FZD3, which recruits DVL3 to the plasma membrane in a WNT5B-dependent manner; DVL3 is then phosphorylated and activates RAC1, leading to JNK activation via the non-canonical WNT-PCP pathway. The DEP domain of DVL3 is required for this membrane recruitment and downstream signaling.","method":"Co-immunoprecipitation, DVL3 domain-deletion mutants, RAC1 and JNK activity assays, overexpression/knockdown in NSCLC cell lines","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, domain mutagenesis, and multiple signaling readouts in a single study; single lab","pmids":["39094673"],"is_preprint":false},{"year":2019,"finding":"FZD3 knockdown in patient-derived melanoma cells suppresses proliferation, colony formation, and invasion; in vivo xenotransplantation shows uniform suppression of tumor and metastasis formation. FZD3 activates MAPK signaling independently of nuclear β-catenin, establishing a non-canonical (β-catenin-independent) role for FZD3 in melanoma.","method":"shRNA knockdown, xenotransplantation, transcriptome pathway enrichment analysis, cell-cycle protein western blotting","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular and in vivo phenotype, pathway analysis, single lab with multiple orthogonal assays","pmids":["30792348"],"is_preprint":false},{"year":2020,"finding":"The lncRNA NEAT1 recruits the histone acetyltransferase P300 to the FZD3 promoter, promoting H3K27 acetylation and FZD3 transcription; FZD3 in turn signals through GSK3β to reduce phospho-tau and stabilize microtubules.","method":"ChIP assay, promoter reporter, siRNA knockdown, immunofluorescence of microtubules in SH-SY5Y cells and APP/PS1 mice","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating P300 recruitment and H3K27ac at FZD3 promoter, functional rescue, single lab","pmids":["33221742"],"is_preprint":false},{"year":2017,"finding":"Overexpression of FZD3 in granulosa cells impairs FSH-induced CYP19A1 transactivation and reduces β-catenin recruitment to the CYP19A1 promoter, thereby suppressing estrogen synthesis; inhibition of FZD3 restores estrogen production in PCOS cumulus cells.","method":"Overexpression/knockdown in COV434 granulosa cells, ChIP for β-catenin at CYP19A1 promoter, estrogen ELISA","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional rescue experiments, single lab, multiple readouts","pmids":["28709873"],"is_preprint":false},{"year":2023,"finding":"The DNA hydroxymethylase TET2 promotes FZD3 transcription through DNA hydroxymethylation of its locus; reduced TET2 in cisplatin-resistant ovarian cancer cells leads to FZD3 silencing, and restoring TET2 sensitizes cells to cisplatin in an FZD3-dependent manner.","method":"TET2 overexpression/knockdown, 5hmC quantification, rescue experiments with FZD3 inhibition in vitro and in vivo","journal":"Journal of chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue (TET2 effect reversed by FZD3 knockdown), in vivo confirmation, single lab","pmids":["37300277"],"is_preprint":false},{"year":2025,"finding":"METTL3 promotes FZD3 expression via m6A modification of FZD3 mRNA; FZD3 then activates RUNX1 downstream of the Wnt pathway to stimulate osteoblast differentiation and inhibit osteoclast differentiation; FZD3 overexpression partially rescues the sh-METTL3 phenotype.","method":"m6A quantification, RIP assay, overexpression/knockdown in MC3T3-E1 cells and BMMs, OVX mouse model rescue experiments","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay establishing m6A-METTL3-FZD3 link, genetic rescue experiment, in vivo validation, single lab","pmids":["41250128"],"is_preprint":false},{"year":2014,"finding":"Hypermethylation of the FZD3 promoter in congenital hydrocephalus brain tissue alters chromatin accessibility and reduces FZD3 mRNA expression, implicating epigenetic silencing of FZD3 in hydrocephalus pathogenesis.","method":"MALDI-TOF mass spectrometry methylation analysis, chromatin accessibility assay, mRNA expression analysis in patient tissue","journal":"Brain research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlative methylation-expression data in patient tissue, no functional rescue or causal experiment","pmids":["24796881"],"is_preprint":false},{"year":2024,"finding":"FZD3 overexpression promotes vaginal wall fibroblast viability and extracellular matrix preservation while inhibiting apoptosis; these effects are reversed by the Wnt pathway inhibitor IWP-4, placing FZD3 activity upstream of canonical Wnt signaling in this cell type.","method":"Overexpression/knockdown in isolated vaginal wall fibroblasts, CCK-8 viability assay, flow cytometry apoptosis, western blot for ECM proteins, pharmacological Wnt inhibition","journal":"Journal of biochemical and molecular toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain/loss-of-function with pharmacological rescue, single lab, no direct pathway mechanistic readout beyond rescue","pmids":["38348712"],"is_preprint":false}],"current_model":"FZD3 is a seven-transmembrane Wnt receptor that functions cell-autonomously in axons (inner ear afferents, forebrain pioneer neurons) via a Celsr3-dependent, Vangl-independent planar-cell-polarity mechanism to guide axon navigation and wiring of CNS tracts; in non-neural contexts it transduces WNT5B signals by recruiting DVL3 (via its DEP domain) to the membrane and activating RAC1-JNK (non-canonical PCP), while also coupling to canonical Wnt/β-catenin signaling to regulate cell proliferation, steroidogenesis, and ECM homeostasis, and its transcription is epigenetically controlled by METTL3-mediated m6A modification and by NEAT1-recruited P300-dependent H3K27 acetylation."},"narrative":{"mechanistic_narrative":"FZD3 is a seven-transmembrane Wnt receptor whose best-characterized role is the cell-autonomous guidance and wiring of central axon tracts through a planar-cell-polarity (PCP) mechanism that operates with Celsr3 but independently of Vangl1/Vangl2 [PMID:25002511]. Genetic dissection in mice and Xenopus places FZD3 function within specific neuronal populations rather than their targets or progenitors: it acts in inner-ear afferent neurons to direct central pathfinding [PMID:31311957, PMID:35153658] and in Isl1-positive pioneer/guidepost neurons to build the scaffold that steers thalamocortical axons across the diencephalon-telencephalon junction [PMID:27170656]. Beyond pathfinding, FZD3 together with Celsr3 enables immature cortical neurons to respond to Wnt7 and upregulate Jag1, feeding back onto Notch signaling in progenitors to time the neurogenic-to-gliogenic switch [PMID:26939553]. At the molecular level FZD3 transduces WNT5B by recruiting DVL3 to the plasma membrane through the DVL3 DEP domain, driving DVL3 phosphorylation and RAC1-JNK activation via the non-canonical Wnt-PCP pathway [PMID:39094673], and it can also drive β-catenin-independent MAPK signaling [PMID:30792348]. In non-neural contexts FZD3 couples to canonical Wnt/β-catenin signaling to regulate proliferation and ECM homeostasis [PMID:38348712], steroidogenesis via β-catenin recruitment to the CYP19A1 promoter [PMID:28709873], and osteoblast/osteoclast differentiation through RUNX1 [PMID:41250128]. FZD3 transcription is epigenetically gated by METTL3-mediated m6A modification of its mRNA [PMID:41250128], NEAT1/P300-dependent H3K27 acetylation at its promoter [PMID:33221742], and TET2-mediated DNA hydroxymethylation [PMID:37300277].","teleology":[{"year":2014,"claim":"Established that FZD3 guides axons through a non-canonical PCP mechanism distinct from epithelial PCP, answering whether forebrain wiring uses the classical Vangl-dependent module.","evidence":"Conditional/double/triple mutant mice with genetic epistasis and axon tract tracing in forebrain","pmids":["25002511"],"confidence":"High","gaps":["Molecular intermediates linking Fzd3/Celsr3 to growth-cone steering not defined","Does not identify the relevant Wnt ligand in vivo"]},{"year":2016,"claim":"Showed FZD3 acts in neurons (not progenitors) to couple Wnt7 sensing to Jag1/Notch signaling, revealing a neuron-to-progenitor feedback loop timing neurogenesis vs gliogenesis.","evidence":"Neuron-specific Celsr3/Fzd3 conditional KO mice with Jag1/Notch pathway readouts","pmids":["26939553"],"confidence":"High","gaps":["Direct biochemical link between Fzd3 activation and Jag1 induction not resolved"]},{"year":2016,"claim":"Localized FZD3 requirement to Isl1+ pioneer/guidepost neurons that scaffold thalamocortical projections, clarifying which cells need the receptor for tract formation.","evidence":"Isl1-cre conditional KO mice, axon tract tracing, embryonic projection analysis","pmids":["27170656"],"confidence":"High","gaps":["Signal received by guidepost neurons not identified","Mechanism of scaffold-to-axon communication unknown"]},{"year":2019,"claim":"Demonstrated FZD3 acts cell-autonomously within inner-ear afferent neurons across two species, settling whether the ear or hindbrain provides the guidance cue.","evidence":"Fzd3 null mice, Xenopus morpholino knockdown, and ear transplantation establishing tissue autonomy","pmids":["31311957"],"confidence":"High","gaps":["Downstream effectors in afferent growth cones not defined"]},{"year":2022,"claim":"Confirmed afferent-neuron autonomy of FZD3 in central hindbrain pathfinding by contrasting neuronal vs hair-cell deletion, excluding a hair-cell-intrinsic requirement.","evidence":"Neurod1-cre vs Atoh1-cre conditional KO mice with central projection mapping","pmids":["35153658"],"confidence":"High","gaps":["Molecular pathway transducing the guidance signal not addressed"]},{"year":2024,"claim":"Defined the proximal biochemistry: WNT5B-bound FZD3 recruits DVL3 via its DEP domain to activate RAC1-JNK, providing a molecular mechanism for non-canonical PCP signaling.","evidence":"Reciprocal Co-IP, DVL3 domain-deletion mutants, RAC1/JNK activity assays in NSCLC cell lines","pmids":["39094673"],"confidence":"Medium","gaps":["Single lab, single cell-type context","Not connected to the in vivo axon-guidance phenotypes","Structural basis of WNT5B-FZD3 binding undefined"]},{"year":2019,"claim":"Showed FZD3 drives melanoma proliferation and invasion via β-catenin-independent MAPK signaling, extending its non-canonical role to tumor biology.","evidence":"shRNA knockdown, xenotransplantation, transcriptome pathway enrichment","pmids":["30792348"],"confidence":"Medium","gaps":["Direct receptor-to-MAPK coupling not mapped","Ligand driving signaling in melanoma unidentified"]},{"year":2017,"claim":"Identified a canonical-Wnt function in which FZD3 suppresses β-catenin recruitment to CYP19A1 and impairs estrogen synthesis, linking FZD3 to steroidogenesis and PCOS.","evidence":"Overexpression/knockdown in COV434 granulosa cells, ChIP for β-catenin, estrogen ELISA","pmids":["28709873"],"confidence":"Medium","gaps":["How FZD3 negatively regulates β-catenin at this promoter is unresolved","Single lab"]},{"year":2020,"claim":"Showed NEAT1/P300-dependent H3K27 acetylation activates FZD3 transcription and that FZD3 acts through GSK3β to reduce phospho-tau, connecting FZD3 regulation to microtubule stability.","evidence":"ChIP, promoter reporter, siRNA, microtubule immunofluorescence in SH-SY5Y cells and APP/PS1 mice","pmids":["33221742"],"confidence":"Medium","gaps":["Direct FZD3-GSK3β mechanism not biochemically dissected","Single lab"]},{"year":2023,"claim":"Established TET2-mediated DNA hydroxymethylation as a positive regulator of FZD3 transcription whose loss confers cisplatin resistance, defined by FZD3-dependent rescue.","evidence":"TET2 overexpression/knockdown, 5hmC quantification, FZD3-inhibition rescue in vitro and in vivo","pmids":["37300277"],"confidence":"Medium","gaps":["Mechanism by which FZD3 modulates chemosensitivity downstream not defined","Single lab"]},{"year":2025,"claim":"Showed METTL3-deposited m6A on FZD3 mRNA promotes its expression, with FZD3 activating RUNX1 to balance osteoblast vs osteoclast differentiation.","evidence":"m6A quantification, RIP assay, knockdown/overexpression rescue in MC3T3-E1 cells and OVX mice","pmids":["41250128"],"confidence":"Medium","gaps":["Direct FZD3-to-RUNX1 signaling steps unmapped","Single lab"]},{"year":null,"claim":"How the proximal WNT5B-FZD3-DVL3-RAC1-JNK biochemistry mechanistically executes the cell-autonomous axon-guidance and tract-scaffolding phenotypes in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FZD3 ligand engagement","In vitro signaling not linked to in vivo PCP wiring","Relevant Wnt ligand(s) in each neuronal context unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,3]}],"complexes":[],"partners":["WNT5B","DVL3","CELSR3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPG1","full_name":"Frizzled-3","aliases":[],"length_aa":666,"mass_kda":76.3,"function":"Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. Activation by Wnt5A stimulates PKC activity via a G-protein-dependent mechanism. Involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Plays a role in controlling early axon growth and guidance processes necessary for the formation of a subset of central and peripheral major fiber tracts. Required for the development of major fiber tracts in the central nervous system, including: the anterior commissure, the corpus callosum, the thalamocortical, corticothalamic and nigrostriatal tracts, the corticospinal tract, the fasciculus retroflexus, the mammillothalamic tract, the medial lemniscus, and ascending fiber tracts from the spinal cord to the brain. In the peripheral nervous system, controls axon growth in distinct populations of cranial and spinal motor neurons, including the facial branchimotor nerve, the hypoglossal nerve, the phrenic nerve, and motor nerves innervating dorsal limbs. Involved in the migration of cranial neural crest cells. May also be implicated in the transmission of sensory information from the trunk and limbs to the brain. Controls commissural sensory axons guidance after midline crossing along the anterior-posterior axis in the developing spinal cord in a Wnt-dependent signaling pathway. Together with FZD6, is involved in the neural tube closure and plays a role in the regulation of the establishment of planar cell polarity (PCP), particularly in the orientation of asymmetric bundles of stereocilia on the apical faces of a subset of auditory and vestibular sensory cells located in the inner ear. Promotes neurogenesis by maintaining sympathetic neuroblasts within the cell cycle in a beta-catenin-dependent manner (By similarity)","subcellular_location":"Membrane; Cell membrane; Cell surface; Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9NPG1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FZD3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FZD3","total_profiled":1310},"omim":[{"mim_id":"610635","title":"COLLAGEN TRIPLE-HELIX REPEAT-CONTAINING PROTEIN 1; CTHRC1","url":"https://www.omim.org/entry/610635"},{"mim_id":"606227","title":"MEMBRANE-TYPE FRIZZLED-RELATED PROTEIN; MFRP","url":"https://www.omim.org/entry/606227"},{"mim_id":"606143","title":"FRIZZLED CLASS RECEPTOR 3; FZD3","url":"https://www.omim.org/entry/606143"},{"mim_id":"604264","title":"CADHERIN EGF LAG SEVEN-PASS G-TYPE RECEPTOR 3; CELSR3","url":"https://www.omim.org/entry/604264"},{"mim_id":"601766","title":"FRIZZLED CLASS RECEPTOR 9; FZD9","url":"https://www.omim.org/entry/601766"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":13.6}],"url":"https://www.proteinatlas.org/search/FZD3"},"hgnc":{"alias_symbol":["Fz-3"],"prev_symbol":[]},"alphafold":{"accession":"Q9NPG1","domains":[{"cath_id":"1.10.2000.10","chopping":"27-159","consensus_level":"high","plddt":81.3362,"start":27,"end":159},{"cath_id":"1.20.1070.10","chopping":"194-502","consensus_level":"high","plddt":91.2651,"start":194,"end":502}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPG1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPG1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPG1-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FZD3","jax_strain_url":"https://www.jax.org/strain/search?query=FZD3"},"sequence":{"accession":"Q9NPG1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPG1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPG1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPG1"}},"corpus_meta":[{"pmid":"31078732","id":"PMC_31078732","title":"A tRNA fragment, 5'-tiRNAVal, suppresses the Wnt/β-catenin signaling pathway by targeting FZD3 in breast cancer.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/31078732","citation_count":142,"is_preprint":false},{"pmid":"29902450","id":"PMC_29902450","title":"Circular RNA circ-CBFB promotes proliferation and inhibits apoptosis in chronic lymphocytic leukemia through regulating miR-607/FZD3/Wnt/β-catenin pathway.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29902450","citation_count":113,"is_preprint":false},{"pmid":"30143969","id":"PMC_30143969","title":"Silencing of Long Noncoding RNA SOX21-AS1 Relieves Neuronal Oxidative Stress Injury in Mice with Alzheimer's Disease by Upregulating FZD3/5 via the Wnt Signaling Pathway.","date":"2018","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/30143969","citation_count":75,"is_preprint":false},{"pmid":"10874638","id":"PMC_10874638","title":"Detection of an atypical 7q11.23 deletion in Williams syndrome patients which does not include the STX1A and FZD3 genes.","date":"1999","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10874638","citation_count":75,"is_preprint":false},{"pmid":"14642436","id":"PMC_14642436","title":"The human frizzled-3 (FZD3) gene on chromosome 8p21, a receptor gene for Wnt ligands, is associated with the susceptibility to schizophrenia.","date":"2003","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/14642436","citation_count":70,"is_preprint":false},{"pmid":"25002511","id":"PMC_25002511","title":"Genetic evidence that Celsr3 and Celsr2, together with Fzd3, regulate forebrain wiring in a Vangl-independent manner.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25002511","citation_count":68,"is_preprint":false},{"pmid":"34966683","id":"PMC_34966683","title":"Circular RNA CircPVT1 Inhibits 5-Fluorouracil Chemosensitivity by Regulating Ferroptosis Through MiR-30a-5p/FZD3 Axis in Esophageal Cancer Cells.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34966683","citation_count":61,"is_preprint":false},{"pmid":"14643098","id":"PMC_14643098","title":"Association study of the human FZD3 locus with schizophrenia.","date":"2003","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/14643098","citation_count":56,"is_preprint":false},{"pmid":"30792348","id":"PMC_30792348","title":"Down-regulation of FZD3 receptor suppresses growth and metastasis of human melanoma independently of canonical WNT signaling.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30792348","citation_count":45,"is_preprint":false},{"pmid":"15274031","id":"PMC_15274031","title":"Positive association of the human frizzled 3 (FZD3) gene haplotype with schizophrenia in Chinese Han population.","date":"2004","source":"American journal of medical genetics. 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combined Celsr2/Celsr3 mutation mimics Fzd3 knockout, and forebrain wiring defects are Vangl1/Vangl2-independent, indicating a PCP mechanism distinct from classical epithelial PCP.\",\n      \"method\": \"Conditional knockout mice (cell-type-specific inactivation), genetic epistasis (double/triple mutants), axon tract tracing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis with multiple conditional alleles across independent forebrain compartments, replicated phenotypes across multiple mutant combinations\",\n      \"pmids\": [\"25002511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Celsr3 and Fzd3 expressed in immature cortical neurons (not progenitors) enable neurons to respond to Wnt7, upregulate Jag1, and thereby activate Notch signaling in neural progenitor cells, constituting a feedback loop that controls the timing of neurogenesis vs. gliogenesis.\",\n      \"method\": \"Conditional knockout mice (neuron-specific Celsr3/Fzd3 inactivation), in vivo gene expression analysis, Notch pathway readouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO with defined signaling pathway readout (Jag1/Notch), multiple orthogonal approaches in a single study\",\n      \"pmids\": [\"26939553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Celsr3 and Fzd3 are required in Isl1-positive guidepost/pioneer neurons (not thalamic or cortical neurons themselves) to form a pioneer axon scaffold that steers growing thalamocortical axons across the diencephalon-telencephalon junction.\",\n      \"method\": \"Cell-type-specific conditional knockout (Isl1-cre), axon tract tracing, embryonic projection analysis\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO in defined cell population with direct axon-guidance phenotype, multiple anatomical readouts\",\n      \"pmids\": [\"27170656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fzd3 expressed within inner ear afferent neurons (not hindbrain) mediates central pathfinding of vestibular afferents; ear transplantation from Fzd3 morpholino-treated Xenopus to control hosts recapitulated guidance defects, establishing a cell-autonomous role in the ear.\",\n      \"method\": \"Fzd3 null mice (axon tracing), Fzd3 morpholino knockdown in Xenopus, ear transplantation experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in two vertebrate species plus transplantation experiment establishing tissue autonomy\",\n      \"pmids\": [\"31311957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Fzd3 acts cell-autonomously within inner ear afferent neurons (Neurod1-cre conditional KO) to regulate central pathfinding in the hindbrain; conditional deletion from hair cells (Atoh1-cre) had no effect on afferent topography.\",\n      \"method\": \"Conditional knockout mice (Neurod1-cre and Atoh1-cre), central projection mapping\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary conditional KO lines with opposite outcomes establishing cell autonomy in defined neuronal population\",\n      \"pmids\": [\"35153658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WNT5B binds FZD3, which recruits DVL3 to the plasma membrane in a WNT5B-dependent manner; DVL3 is then phosphorylated and activates RAC1, leading to JNK activation via the non-canonical WNT-PCP pathway. The DEP domain of DVL3 is required for this membrane recruitment and downstream signaling.\",\n      \"method\": \"Co-immunoprecipitation, DVL3 domain-deletion mutants, RAC1 and JNK activity assays, overexpression/knockdown in NSCLC cell lines\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, domain mutagenesis, and multiple signaling readouts in a single study; single lab\",\n      \"pmids\": [\"39094673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FZD3 knockdown in patient-derived melanoma cells suppresses proliferation, colony formation, and invasion; in vivo xenotransplantation shows uniform suppression of tumor and metastasis formation. FZD3 activates MAPK signaling independently of nuclear β-catenin, establishing a non-canonical (β-catenin-independent) role for FZD3 in melanoma.\",\n      \"method\": \"shRNA knockdown, xenotransplantation, transcriptome pathway enrichment analysis, cell-cycle protein western blotting\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular and in vivo phenotype, pathway analysis, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"30792348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The lncRNA NEAT1 recruits the histone acetyltransferase P300 to the FZD3 promoter, promoting H3K27 acetylation and FZD3 transcription; FZD3 in turn signals through GSK3β to reduce phospho-tau and stabilize microtubules.\",\n      \"method\": \"ChIP assay, promoter reporter, siRNA knockdown, immunofluorescence of microtubules in SH-SY5Y cells and APP/PS1 mice\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating P300 recruitment and H3K27ac at FZD3 promoter, functional rescue, single lab\",\n      \"pmids\": [\"33221742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpression of FZD3 in granulosa cells impairs FSH-induced CYP19A1 transactivation and reduces β-catenin recruitment to the CYP19A1 promoter, thereby suppressing estrogen synthesis; inhibition of FZD3 restores estrogen production in PCOS cumulus cells.\",\n      \"method\": \"Overexpression/knockdown in COV434 granulosa cells, ChIP for β-catenin at CYP19A1 promoter, estrogen ELISA\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional rescue experiments, single lab, multiple readouts\",\n      \"pmids\": [\"28709873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The DNA hydroxymethylase TET2 promotes FZD3 transcription through DNA hydroxymethylation of its locus; reduced TET2 in cisplatin-resistant ovarian cancer cells leads to FZD3 silencing, and restoring TET2 sensitizes cells to cisplatin in an FZD3-dependent manner.\",\n      \"method\": \"TET2 overexpression/knockdown, 5hmC quantification, rescue experiments with FZD3 inhibition in vitro and in vivo\",\n      \"journal\": \"Journal of chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue (TET2 effect reversed by FZD3 knockdown), in vivo confirmation, single lab\",\n      \"pmids\": [\"37300277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3 promotes FZD3 expression via m6A modification of FZD3 mRNA; FZD3 then activates RUNX1 downstream of the Wnt pathway to stimulate osteoblast differentiation and inhibit osteoclast differentiation; FZD3 overexpression partially rescues the sh-METTL3 phenotype.\",\n      \"method\": \"m6A quantification, RIP assay, overexpression/knockdown in MC3T3-E1 cells and BMMs, OVX mouse model rescue experiments\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay establishing m6A-METTL3-FZD3 link, genetic rescue experiment, in vivo validation, single lab\",\n      \"pmids\": [\"41250128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Hypermethylation of the FZD3 promoter in congenital hydrocephalus brain tissue alters chromatin accessibility and reduces FZD3 mRNA expression, implicating epigenetic silencing of FZD3 in hydrocephalus pathogenesis.\",\n      \"method\": \"MALDI-TOF mass spectrometry methylation analysis, chromatin accessibility assay, mRNA expression analysis in patient tissue\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlative methylation-expression data in patient tissue, no functional rescue or causal experiment\",\n      \"pmids\": [\"24796881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FZD3 overexpression promotes vaginal wall fibroblast viability and extracellular matrix preservation while inhibiting apoptosis; these effects are reversed by the Wnt pathway inhibitor IWP-4, placing FZD3 activity upstream of canonical Wnt signaling in this cell type.\",\n      \"method\": \"Overexpression/knockdown in isolated vaginal wall fibroblasts, CCK-8 viability assay, flow cytometry apoptosis, western blot for ECM proteins, pharmacological Wnt inhibition\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain/loss-of-function with pharmacological rescue, single lab, no direct pathway mechanistic readout beyond rescue\",\n      \"pmids\": [\"38348712\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD3 is a seven-transmembrane Wnt receptor that functions cell-autonomously in axons (inner ear afferents, forebrain pioneer neurons) via a Celsr3-dependent, Vangl-independent planar-cell-polarity mechanism to guide axon navigation and wiring of CNS tracts; in non-neural contexts it transduces WNT5B signals by recruiting DVL3 (via its DEP domain) to the membrane and activating RAC1-JNK (non-canonical PCP), while also coupling to canonical Wnt/β-catenin signaling to regulate cell proliferation, steroidogenesis, and ECM homeostasis, and its transcription is epigenetically controlled by METTL3-mediated m6A modification and by NEAT1-recruited P300-dependent H3K27 acetylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FZD3 is a seven-transmembrane Wnt receptor whose best-characterized role is the cell-autonomous guidance and wiring of central axon tracts through a planar-cell-polarity (PCP) mechanism that operates with Celsr3 but independently of Vangl1/Vangl2 [#0]. Genetic dissection in mice and Xenopus places FZD3 function within specific neuronal populations rather than their targets or progenitors: it acts in inner-ear afferent neurons to direct central pathfinding [#3, #4] and in Isl1-positive pioneer/guidepost neurons to build the scaffold that steers thalamocortical axons across the diencephalon-telencephalon junction [#2]. Beyond pathfinding, FZD3 together with Celsr3 enables immature cortical neurons to respond to Wnt7 and upregulate Jag1, feeding back onto Notch signaling in progenitors to time the neurogenic-to-gliogenic switch [#1]. At the molecular level FZD3 transduces WNT5B by recruiting DVL3 to the plasma membrane through the DVL3 DEP domain, driving DVL3 phosphorylation and RAC1-JNK activation via the non-canonical Wnt-PCP pathway [#5], and it can also drive \\u03b2-catenin-independent MAPK signaling [#6]. In non-neural contexts FZD3 couples to canonical Wnt/\\u03b2-catenin signaling to regulate proliferation and ECM homeostasis [#12], steroidogenesis via \\u03b2-catenin recruitment to the CYP19A1 promoter [#8], and osteoblast/osteoclast differentiation through RUNX1 [#10]. FZD3 transcription is epigenetically gated by METTL3-mediated m6A modification of its mRNA [#10], NEAT1/P300-dependent H3K27 acetylation at its promoter [#7], and TET2-mediated DNA hydroxymethylation [#9].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that FZD3 guides axons through a non-canonical PCP mechanism distinct from epithelial PCP, answering whether forebrain wiring uses the classical Vangl-dependent module.\",\n      \"evidence\": \"Conditional/double/triple mutant mice with genetic epistasis and axon tract tracing in forebrain\",\n      \"pmids\": [\"25002511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular intermediates linking Fzd3/Celsr3 to growth-cone steering not defined\", \"Does not identify the relevant Wnt ligand in vivo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed FZD3 acts in neurons (not progenitors) to couple Wnt7 sensing to Jag1/Notch signaling, revealing a neuron-to-progenitor feedback loop timing neurogenesis vs gliogenesis.\",\n      \"evidence\": \"Neuron-specific Celsr3/Fzd3 conditional KO mice with Jag1/Notch pathway readouts\",\n      \"pmids\": [\"26939553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between Fzd3 activation and Jag1 induction not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Localized FZD3 requirement to Isl1+ pioneer/guidepost neurons that scaffold thalamocortical projections, clarifying which cells need the receptor for tract formation.\",\n      \"evidence\": \"Isl1-cre conditional KO mice, axon tract tracing, embryonic projection analysis\",\n      \"pmids\": [\"27170656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal received by guidepost neurons not identified\", \"Mechanism of scaffold-to-axon communication unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated FZD3 acts cell-autonomously within inner-ear afferent neurons across two species, settling whether the ear or hindbrain provides the guidance cue.\",\n      \"evidence\": \"Fzd3 null mice, Xenopus morpholino knockdown, and ear transplantation establishing tissue autonomy\",\n      \"pmids\": [\"31311957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors in afferent growth cones not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed afferent-neuron autonomy of FZD3 in central hindbrain pathfinding by contrasting neuronal vs hair-cell deletion, excluding a hair-cell-intrinsic requirement.\",\n      \"evidence\": \"Neurod1-cre vs Atoh1-cre conditional KO mice with central projection mapping\",\n      \"pmids\": [\"35153658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway transducing the guidance signal not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the proximal biochemistry: WNT5B-bound FZD3 recruits DVL3 via its DEP domain to activate RAC1-JNK, providing a molecular mechanism for non-canonical PCP signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, DVL3 domain-deletion mutants, RAC1/JNK activity assays in NSCLC cell lines\",\n      \"pmids\": [\"39094673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single cell-type context\", \"Not connected to the in vivo axon-guidance phenotypes\", \"Structural basis of WNT5B-FZD3 binding undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed FZD3 drives melanoma proliferation and invasion via \\u03b2-catenin-independent MAPK signaling, extending its non-canonical role to tumor biology.\",\n      \"evidence\": \"shRNA knockdown, xenotransplantation, transcriptome pathway enrichment\",\n      \"pmids\": [\"30792348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor-to-MAPK coupling not mapped\", \"Ligand driving signaling in melanoma unidentified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a canonical-Wnt function in which FZD3 suppresses \\u03b2-catenin recruitment to CYP19A1 and impairs estrogen synthesis, linking FZD3 to steroidogenesis and PCOS.\",\n      \"evidence\": \"Overexpression/knockdown in COV434 granulosa cells, ChIP for \\u03b2-catenin, estrogen ELISA\",\n      \"pmids\": [\"28709873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How FZD3 negatively regulates \\u03b2-catenin at this promoter is unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed NEAT1/P300-dependent H3K27 acetylation activates FZD3 transcription and that FZD3 acts through GSK3\\u03b2 to reduce phospho-tau, connecting FZD3 regulation to microtubule stability.\",\n      \"evidence\": \"ChIP, promoter reporter, siRNA, microtubule immunofluorescence in SH-SY5Y cells and APP/PS1 mice\",\n      \"pmids\": [\"33221742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct FZD3-GSK3\\u03b2 mechanism not biochemically dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established TET2-mediated DNA hydroxymethylation as a positive regulator of FZD3 transcription whose loss confers cisplatin resistance, defined by FZD3-dependent rescue.\",\n      \"evidence\": \"TET2 overexpression/knockdown, 5hmC quantification, FZD3-inhibition rescue in vitro and in vivo\",\n      \"pmids\": [\"37300277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FZD3 modulates chemosensitivity downstream not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed METTL3-deposited m6A on FZD3 mRNA promotes its expression, with FZD3 activating RUNX1 to balance osteoblast vs osteoclast differentiation.\",\n      \"evidence\": \"m6A quantification, RIP assay, knockdown/overexpression rescue in MC3T3-E1 cells and OVX mice\",\n      \"pmids\": [\"41250128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct FZD3-to-RUNX1 signaling steps unmapped\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the proximal WNT5B-FZD3-DVL3-RAC1-JNK biochemistry mechanistically executes the cell-autonomous axon-guidance and tract-scaffolding phenotypes in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FZD3 ligand engagement\", \"In vitro signaling not linked to in vivo PCP wiring\", \"Relevant Wnt ligand(s) in each neuronal context unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WNT5B\", \"DVL3\", \"CELSR3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}