Affinage

FZD3

Frizzled-3 · UniProt Q9NPG1

Length
666 aa
Mass
76.3 kDa
Annotated
2026-06-09
40 papers in source corpus 13 papers cited in narrative 13 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

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2014 High

    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

    PMID:25002511

    Open questions at the time
    • Molecular intermediates linking Fzd3/Celsr3 to growth-cone steering not defined
    • Does not identify the relevant Wnt ligand in vivo
  2. 2016 High

    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

    PMID:26939553

    Open questions at the time
    • Direct biochemical link between Fzd3 activation and Jag1 induction not resolved
  3. 2016 High

    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

    PMID:27170656

    Open questions at the time
    • Signal received by guidepost neurons not identified
    • Mechanism of scaffold-to-axon communication unknown
  4. 2019 High

    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

    PMID:31311957

    Open questions at the time
    • Downstream effectors in afferent growth cones not defined
  5. 2022 High

    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

    PMID:35153658

    Open questions at the time
    • Molecular pathway transducing the guidance signal not addressed
  6. 2024 Medium

    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

    PMID:39094673

    Open questions at the time
    • Single lab, single cell-type context
    • Not connected to the in vivo axon-guidance phenotypes
    • Structural basis of WNT5B-FZD3 binding undefined
  7. 2019 Medium

    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

    PMID:30792348

    Open questions at the time
    • Direct receptor-to-MAPK coupling not mapped
    • Ligand driving signaling in melanoma unidentified
  8. 2017 Medium

    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

    PMID:28709873

    Open questions at the time
    • How FZD3 negatively regulates β-catenin at this promoter is unresolved
    • Single lab
  9. 2020 Medium

    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

    PMID:33221742

    Open questions at the time
    • Direct FZD3-GSK3β mechanism not biochemically dissected
    • Single lab
  10. 2023 Medium

    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

    PMID:37300277

    Open questions at the time
    • Mechanism by which FZD3 modulates chemosensitivity downstream not defined
    • Single lab
  11. 2025 Medium

    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

    PMID:41250128

    Open questions at the time
    • Direct FZD3-to-RUNX1 signaling steps unmapped
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the proximal WNT5B-FZD3-DVL3-RAC1-JNK biochemistry mechanistically executes the cell-autonomous axon-guidance and tract-scaffolding phenotypes in vivo remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 1 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 2
Partners
CELSR3DVL3WNT5B

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 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. Conditional knockout mice (cell-type-specific inactivation), genetic epistasis (double/triple mutants), axon tract tracing Proceedings of the National Academy of Sciences of the United States of America High 25002511
2016 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. Conditional knockout mice (neuron-specific Celsr3/Fzd3 inactivation), in vivo gene expression analysis, Notch pathway readouts Nature communications High 26939553
2016 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. Cell-type-specific conditional knockout (Isl1-cre), axon tract tracing, embryonic projection analysis Cerebral cortex High 27170656
2019 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. Fzd3 null mice (axon tracing), Fzd3 morpholino knockdown in Xenopus, ear transplantation experiments Scientific reports High 31311957
2022 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. Conditional knockout mice (Neurod1-cre and Atoh1-cre), central projection mapping Frontiers in neuroscience High 35153658
2024 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. Co-immunoprecipitation, DVL3 domain-deletion mutants, RAC1 and JNK activity assays, overexpression/knockdown in NSCLC cell lines Cellular signalling Medium 39094673
2019 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. shRNA knockdown, xenotransplantation, transcriptome pathway enrichment analysis, cell-cycle protein western blotting Proceedings of the National Academy of Sciences of the United States of America Medium 30792348
2020 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. ChIP assay, promoter reporter, siRNA knockdown, immunofluorescence of microtubules in SH-SY5Y cells and APP/PS1 mice Aging Medium 33221742
2017 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. Overexpression/knockdown in COV434 granulosa cells, ChIP for β-catenin at CYP19A1 promoter, estrogen ELISA Biochemical and biophysical research communications Medium 28709873
2023 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. TET2 overexpression/knockdown, 5hmC quantification, rescue experiments with FZD3 inhibition in vitro and in vivo Journal of chemotherapy Medium 37300277
2025 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. m6A quantification, RIP assay, overexpression/knockdown in MC3T3-E1 cells and BMMs, OVX mouse model rescue experiments European journal of medical research Medium 41250128
2014 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. MALDI-TOF mass spectrometry methylation analysis, chromatin accessibility assay, mRNA expression analysis in patient tissue Brain research Low 24796881
2024 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. Overexpression/knockdown in isolated vaginal wall fibroblasts, CCK-8 viability assay, flow cytometry apoptosis, western blot for ECM proteins, pharmacological Wnt inhibition Journal of biochemical and molecular toxicology Low 38348712

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 A tRNA fragment, 5'-tiRNAVal, suppresses the Wnt/β-catenin signaling pathway by targeting FZD3 in breast cancer. Cancer letters 142 31078732
2018 Circular RNA circ-CBFB promotes proliferation and inhibits apoptosis in chronic lymphocytic leukemia through regulating miR-607/FZD3/Wnt/β-catenin pathway. Biochemical and biophysical research communications 113 29902450
2018 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. Molecular neurobiology 75 30143969
1999 Detection of an atypical 7q11.23 deletion in Williams syndrome patients which does not include the STX1A and FZD3 genes. Journal of medical genetics 75 10874638
2003 The human frizzled-3 (FZD3) gene on chromosome 8p21, a receptor gene for Wnt ligands, is associated with the susceptibility to schizophrenia. Neuroscience letters 70 14642436
2014 Genetic evidence that Celsr3 and Celsr2, together with Fzd3, regulate forebrain wiring in a Vangl-independent manner. Proceedings of the National Academy of Sciences of the United States of America 68 25002511
2021 Circular RNA CircPVT1 Inhibits 5-Fluorouracil Chemosensitivity by Regulating Ferroptosis Through MiR-30a-5p/FZD3 Axis in Esophageal Cancer Cells. Frontiers in oncology 61 34966683
2003 Association study of the human FZD3 locus with schizophrenia. Biological psychiatry 56 14643098
2019 Down-regulation of FZD3 receptor suppresses growth and metastasis of human melanoma independently of canonical WNT signaling. Proceedings of the National Academy of Sciences of the United States of America 45 30792348
2004 Positive association of the human frizzled 3 (FZD3) gene haplotype with schizophrenia in Chinese Han population. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 44 15274031
2020 NEAT1 regulates microtubule stabilization via FZD3/GSK3β/P-tau pathway in SH-SY5Y cells and APP/PS1 mice. Aging 43 33221742
2016 Feedback regulation of apical progenitor fate by immature neurons through Wnt7-Celsr3-Fzd3 signalling. Nature communications 37 26939553
2016 Celsr3 and Fzd3 Organize a Pioneer Neuron Scaffold to Steer Growing Thalamocortical Axons. Cerebral cortex (New York, N.Y. : 1991) 33 27170656
2000 Identification, gene structure, and expression of human frizzled-3 (FZD3). Biochemical and biophysical research communications 32 10873558
2017 Deregulation of WNT2/FZD3/β-catenin pathway compromises the estrogen synthesis in cumulus cells from patients with polycystic ovary syndrome. Biochemical and biophysical research communications 31 28709873
2015 Celsr3 and Fzd3 in axon guidance. The international journal of biochemistry & cell biology 30 25813877
2020 Non-coding variants in MYH11, FZD3, and SORCS3 are associated with dementia in women. Alzheimer's & dementia : the journal of the Alzheimer's Association 27 32966694
2004 Genetic and expression analyses of FZD3 in schizophrenia. Biological psychiatry 26 15364045
2006 Investigation of genetic association between human Frizzled homolog 3 gene (FZD3) and schizophrenia: results in a Korean population and evidence from meta-analysis. Psychiatry research 22 16707163
2005 Association study of the frizzled-3 (FZD3) gene with schizophrenia and mood disorders. Journal of neural transmission (Vienna, Austria : 1996) 19 15657645
2014 DNA methylation aberrations rather than polymorphisms of FZD3 gene increase the risk of spina bifida in a high-risk region for neural tube defects. Birth defects research. Part A, Clinical and molecular teratology 14 25131656
2023 In silico analysis reveals mir-98-5p as a potential inhibitor of tumor cell proliferation and metastasis in colorectal cancer by targeting the fzd3 receptor of the Wnt signaling pathway. Journal, genetic engineering & biotechnology 12 37466730
2019 Topologically correct central projections of tetrapod inner ear afferents require Fzd3. Scientific reports 12 31311957
2014 Polymorphisms in FZD3 and FZD6 genes and risk of neural tube defects in a northern Han Chinese population. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 11 24816679
2024 WNT5B promotes the malignant phenotype of non-small cell lung cancer via the FZD3-DVL3-RAC1-PCP-JNK pathway. Cellular signalling 9 39094673
2016 Deregulation of the planar cell polarity genes CELSR3 and FZD3 in Hirschsprung disease. Experimental and molecular pathology 9 27619161
2024 LncRNA NEAT1 promotes proliferation, migration, and invasion of laryngeal squamous cell carcinoma cells through miR-411-3p/FZD3-mediated Wnt signaling pathway. BMC cancer 8 39068410
2016 A meta-analysis of FZD3 gene polymorphisms and their association with schizophrenia. Psychiatric genetics 7 27755292
2007 FZD3 is not a risk gene for schizophrenia: a case-control study in a Caucasian sample. Journal of neural transmission. Supplementum 7 17982906
2023 Aberrant epigenetic regulation of FZD3 by TET2 is involved in ovarian cancer cell resistance to cisplatin. Journal of chemotherapy (Florence, Italy) 6 37300277
2021 MicroRNA-186-5p inhibits the metastasis of cervical cancer by targeting FZD3. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 6 34268920
2019 Over-expressed LOC101927196 suppressed oxidative stress levels and neuron cell proliferation in a rat model of autism through disrupting the Wnt signaling pathway by targeting FZD3. Cellular signalling 6 31145996
2024 FZD3 regulates the viability, apoptosis, and extracellular matrix degradation of vaginal wall fibroblasts in pelvic organ prolapse via the Wnt signaling pathway. Journal of biochemical and molecular toxicology 5 38348712
2022 Fzd3 Expression Within Inner Ear Afferent Neurons Is Necessary for Central Pathfinding. Frontiers in neuroscience 5 35153658
2014 Impaired methylation modifications of FZD3 alter chromatin accessibility and are involved in congenital hydrocephalus pathogenesis. Brain research 5 24796881
2024 SOX21-AS1 Augmented Cervical Cancer Growth by Triggering FZD3 to Activate the Wnt/β-Catenin Signaling Pathway. Biochemical genetics 4 38512584
2022 LncRNA FGD5-AS1 drives the malignant development of gastric cancer by negatively interacting with FZD3. Polish journal of pathology : official journal of the Polish Society of Pathologists 4 35848483
2024 CircTEC Inhibits the Follicular Atresia in Buffalo (Bubalus bubalis) via Targeting miR-144-5p/FZD3 Signaling Axis. International journal of molecular sciences 3 39796015
2025 METTL3 inhibits osteoporosis by promoting osteoblast differentiation through m6A-mediated activation of the FZD3/RUNX1 signaling axis. European journal of medical research 2 41250128
2026 The Wnt receptor Frizzled3 (FZD3) drives aggressive phenotypes in small cell lung cancer. Respiratory research 0 41862898

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