{"gene":"FZD9","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2005,"finding":"Wnt-7a and Frizzled-9 (Fzd9) interact directly (Wnt-7a detected in Fzd9 immunoprecipitates), and together they activate the JNK pathway (not β-catenin/TCF), inducing cadherin and Sprouty-4 expression, inhibiting anchorage-independent growth, and promoting epithelial differentiation in NSCLC cells.","method":"Co-immunoprecipitation, soft agar assay, 3D culture, JNK gain-of-function transfection, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP demonstrating direct Wnt7a–Fzd9 interaction, combined with functional gain-of-function experiments and multiple orthogonal readouts (JNK activation, cadherin induction, Sprouty-4 upregulation, anchorage-independent growth), all in a single rigorous study","pmids":["15705594"],"is_preprint":false},{"year":1999,"finding":"FZD9 protein localizes to the plasma membrane when expressed in transfected cells, consistent with its function as a transmembrane Wnt receptor; the mouse homolog Fzd9 encodes a 592-aa protein with 95% identity to human FZD9 and is expressed in neural tube, myotomes, limb skeletal anlagen, craniofacial regions, nephric ducts, heart, brain, testis, and skeletal muscle.","method":"Immunohistochemistry of transfected cells, RNA in situ hybridization, cDNA cloning and sequence analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — membrane localization confirmed by IHC in transfected cells; expression pattern characterized by in situ hybridization across multiple labs; no functional consequence linked directly to localization","pmids":["10198163"],"is_preprint":false},{"year":2004,"finding":"Fzd9 is required for normal B-cell development; Fzd9−/− mice display depletion of pre-B cells in bone marrow (particularly at the stage of immunoglobulin heavy chain expression and clonal expansion), with the pre-B defect being partially cell-intrinsic as shown by competitive bone marrow reconstitution.","method":"Fzd9 knockout mice, competitive bone marrow reconstitution, flow cytometry","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype, validated by cell-intrinsic competitive reconstitution experiment; single lab but two orthogonal approaches","pmids":["15572594"],"is_preprint":false},{"year":2008,"finding":"WNT2 interacts with FZD9 in human cumulus cells, as demonstrated by co-immunoprecipitation (WNT2 antibody precipitated FZD9 and FZD9 antibody precipitated WNT2); FZD9 co-localizes with DVL and AXIN at the plasma membrane and with β-CATENIN, suggesting FZD9-mediated canonical Wnt signaling that recruits β-catenin to the membrane and promotes adherens junction formation.","method":"Co-immunoprecipitation, immunofluorescence co-localization","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — reciprocal co-IP supporting WNT2–FZD9 interaction, but single lab, no functional validation beyond co-localization; downstream pathway inference is correlative","pmids":["19038973"],"is_preprint":false},{"year":2010,"finding":"Wnt-7a/Fzd9 signaling activates the Sprouty-4 (Spry4) promoter through peroxisome proliferator-activated receptor gamma (PPARγ), identifying Spry4 as a downstream transcriptional target of the Wnt7A/Fzd9 non-canonical pathway in NSCLC cells.","method":"Promoter-reporter assays, stable transfection, siRNA knockdown, gene expression analysis","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter activity assays and expression studies establish PPARγ as intermediary in Fzd9 signaling to Spry4; single lab with multiple methods","pmids":["20501643"],"is_preprint":false},{"year":2011,"finding":"Fzd9 is required for osteoblast function and bone formation; Fzd9−/− mice display low bone mass due to impaired bone formation (not resorption). Fzd9−/− primary osteoblasts show defects in matrix mineralization and reduced expression of chemokines and interferon-regulated genes (including Isg15 as a potential downstream mediator), without impairment of canonical Wnt/β-catenin signaling, indicating Fzd9 acts via a non-canonical pathway in osteoblasts.","method":"Fzd9 knockout mice, primary osteoblast culture, matrix mineralization assay, gene expression profiling, β-catenin pathway analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular and skeletal phenotype, primary osteoblast mechanistic characterization, pathway exclusion (β-catenin not involved), and downstream target identification; single lab but multiple orthogonal methods","pmids":["21402791"],"is_preprint":false},{"year":2013,"finding":"Fzd9 regulates intramembranous and endochondral bone formation during fracture healing via non-canonical Wnt signaling; Fzd9−/− mice show significantly reduced new bone formation at all healing time points and decreased mechanical competence of callus, while cartilage formation and osteoclast numbers are unaffected and β-catenin localization is unchanged. Chemokines Ccl2 and Cxcl5 appear reduced in Fzd9−/− fracture callus.","method":"Fzd9−/− mice, femur osteotomy fracture model, micro-CT, histomorphometry, immunohistochemistry, biomechanical testing","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with quantitative skeletal readouts, multiple imaging and mechanical methods, pathway exclusion (canonical Wnt unaffected), replicates findings from prior osteoblast study","pmids":["24391920"],"is_preprint":false},{"year":2014,"finding":"FZD9-mediated signaling impairs acetylcholine receptor (AChR) clustering in skeletal muscle: overexpression of Fzd9 in myotubes reduces agrin-induced AChR clustering and induces cytosolic accumulation of β-catenin; Fzd9 and β-catenin co-localize at embryonic NMJ postsynaptic domains in vivo. Loss-of-function experiments confirm that Fzd9 antagonizes postsynaptic AChR assembly at the neuromuscular junction.","method":"Gain- and loss-of-function transfection in cultured myotubes, AChR clustering assay, immunolocalization in embryonic NMJ, β-catenin accumulation assay","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both gain- and loss-of-function with defined AChR clustering readout, plus in vivo immunolocalization; single lab","pmids":["24860427"],"is_preprint":false},{"year":2016,"finding":"FZD9 is required for Wnt-5a-induced dendritic spine formation in hippocampal neurons. FZD9 localizes to the postsynaptic region, interacts with Wnt-5a, and forms a precoupled complex with Gαo that dissociates upon Wnt-5a stimulation. Gαo activation and Gβγ are downstream mediators of FZD9 signaling: Gαo controls Wnt-5a-induced spine density increase, while Gβγ is required for cytosolic calcium elevation and spinogenesis.","method":"Co-immunoprecipitation (FZD9–Gαo complex), siRNA knockdown of FZD9, G-protein inhibition experiments, calcium imaging, dendritic spine quantification in cultured hippocampal neurons","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of FZD9–Gαo complex, FZD9 knockdown with specific spine phenotype, G-protein pathway dissection with multiple inhibitors, and calcium readout; multiple orthogonal methods in a single rigorous study","pmids":["27402827"],"is_preprint":false},{"year":2016,"finding":"FZD9 deletion or loss is the single gene cause of increased neural progenitor cell doubling time and apoptosis observed in Williams syndrome iPSC-derived neural progenitors, narrowed by studying an individual with atypical Williams syndrome carrying a smaller deletion encompassing FZD9.","method":"iPSC-derived neural progenitor cells from Williams syndrome patients, atypical deletion mapping, cell proliferation and apoptosis assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetic epistasis using atypical deletion patient to map phenotype to FZD9; functional cellular readouts (doubling time, apoptosis) in isogenic human iPSC model; published in high-tier journal with rigorous controls","pmids":["27509850"],"is_preprint":false},{"year":2021,"finding":"Fzd9 is an essential effector downstream of Myc in pancreatic islet tumorigenesis: Fzd9 is a Myc transcriptional target, and its deletion impairs sustained tumor expansion and β-cell dedifferentiation in a Myc-driven insulinoma mouse model. Wnt signaling inhibition in Fzd9-competent mice recapitulates the suppression of proliferation caused by Fzd9 deficiency.","method":"Fzd9 knockout in Myc-driven insulinoma mouse model, Wnt signaling inhibitor treatment, global gene expression analysis, histology","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Fzd9 KO in Myc model), pharmacological Wnt inhibition corroborates result; Fzd9 shown to be Myc transcriptional target; multiple orthogonal approaches in single study","pmids":["33653688"],"is_preprint":false},{"year":2022,"finding":"FZD9 is required in vivo for iloprost (prostacyclin analogue) lung cancer chemoprevention: Fzd9−/− mice treated with inhaled iloprost in a urethane lung adenoma model are not protected from adenoma development and do not show increased activation of iloprost/PPARγ signaling pathways, establishing FZD9 as the essential receptor for iloprost chemopreventive action.","method":"Fzd9 knockout mice, urethane lung adenoma model, inhaled iloprost treatment, pathway activation assays","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO experiment with quantitative tumor outcome and pathway activation readout; validates prior in vitro mechanistic finding; single lab","pmids":["35707728"],"is_preprint":false},{"year":2022,"finding":"PPARγ is a transcriptional regulator of FZD9 in lung epithelium. Loss of FZD9 in bronchial epithelial cells alters EMT markers, decreases PPARγ activity, increases transformed growth and invasive behavior, and is associated with premalignant lesion development. Cigarette smoke reduces FZD9 expression and PPARγ activation in these cells.","method":"FZD9 knockdown in human bronchial epithelial cells, Fzd9−/− mouse urethane model, PPARγ reporter assays, EMT marker analysis, soft agar and invasion assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus KO mouse with defined phenotypic readouts; PPARγ as transcriptional regulator identified by reporter assay; single lab","pmids":["35924166"],"is_preprint":false},{"year":2016,"finding":"miR-31 represses FZD9 expression in lung cells; tobacco smoke carcinogens increase miR-31 expression, which reduces Fzd9 expression, while prostacyclin (iloprost) reduces miR-31 and maintains or increases Fzd9 expression, thereby enabling FZD9-dependent anti-tumor signaling.","method":"Mouse models, in vitro carcinogen treatment, miR-31 expression analysis, FZD9 expression assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — miR-31–FZD9 regulatory relationship established in multiple model systems (mouse and in vitro); no direct 3'UTR binding assay reported in abstract; single lab","pmids":["27339092"],"is_preprint":false},{"year":2022,"finding":"miR-520a-5p binds the FZD9 3'UTR and represses FZD9 expression and downstream target activity; cigarette smoke condensate increases miR-520a-5p expression (reducing FZD9), while iloprost decreases miR-520a-5p. miR-520a-5p mimic cancer-promoting effects are rescued by iloprost, confirming miR-520a-5p as a post-transcriptional regulator of FZD9.","method":"3'UTR luciferase reporter assay, miR-520a-5p mimic and inhibitor transfection, iloprost treatment, FZD9 downstream target assays in lung cell lines","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR reporter assay confirms direct miR-520a-5p binding to FZD9, functional rescue experiment with iloprost; single lab","pmids":["35149732"],"is_preprint":false},{"year":2023,"finding":"Fzd9 overexpression in osteoblasts under simulated microgravity (SMG) rescues osteogenic markers (ALP, OPN, RUNX2) via a non-β-catenin mechanism: Fzd9 promotes Akt and ERK phosphorylation, induces F-actin polymerization and actin cap formation, increases nuclear pore size, and drives nuclear translocation of YAP (Yes-associated protein), thereby activating mechanotransduction signaling.","method":"Simulated microgravity rotating cell culture, Fzd9 overexpression construct, Western blot for pAkt/pERK/pGSK3β/β-catenin, F-actin staining, YAP nuclear translocation imaging","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with multiple mechanistic readouts (actin, YAP localization, kinase phosphorylation); pathway exclusion (β-catenin not affected); single lab","pmids":["37585277"],"is_preprint":false},{"year":2019,"finding":"Fzd9+ cochlear supporting cells (inner phalangeal cells, inner border cells, third-row Deiters' cells) function as hair cell progenitors: lineage tracing showed Fzd9+ cells generate new hair cells in vivo and in vitro (sphere-forming and differentiation assays) at similar efficiency to Lgr5+ progenitors, identifying Fzd9 as a marker of a restricted subset of cochlear hair cell progenitors.","method":"Fzd9-CreER lineage tracing, sphere-forming assay, flow cytometry sorting, in vivo and in vitro hair cell differentiation assays","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic lineage tracing with multiple functional assays (sphere forming, HC generation); single lab","pmids":["31427926"],"is_preprint":false}],"current_model":"FZD9 is a seven-transmembrane Wnt receptor that signals predominantly through non-canonical (JNK, Gαo/Gβγ, PPARγ, YAP) pathways rather than canonical β-catenin/TCF signaling; it directly binds Wnt-7a and Wnt-5a, couples to heterotrimeric G proteins (forming a basal Gαo complex) to regulate dendritic spine formation, activates PPARγ-dependent transcription (including Sprouty-4) to suppress lung epithelial transformation, drives non-canonical bone formation in osteoblasts (regulating ISG15 and chemokine expression), is required for pre-B cell development, promotes hair cell progenitor function in the cochlea, and is an essential downstream effector of Myc in pancreatic islet tumorigenesis; its expression is post-transcriptionally repressed by miR-31 and miR-520a-5p, and transcriptionally activated by PPARγ, while being epigenetically silenced by promoter methylation in multiple cancers."},"narrative":{"mechanistic_narrative":"FZD9 is a seven-transmembrane Frizzled Wnt receptor that signals predominantly through non-canonical, β-catenin-independent pathways to control tissue differentiation, bone formation, neuronal connectivity, and tumor suppression [PMID:15705594, PMID:21402791, PMID:27402827]. It binds Wnt-7a directly and activates JNK rather than β-catenin/TCF signaling, inducing cadherin and Sprouty-4 expression and promoting epithelial differentiation while suppressing anchorage-independent growth in lung cells [PMID:15705594]; this Wnt-7a/FZD9 axis activates the Sprouty-4 promoter through PPARγ, and a reciprocal regulatory loop exists in which PPARγ also transcriptionally activates FZD9 in lung epithelium [PMID:20501643, PMID:35924166]. In neurons, FZD9 localizes to postsynaptic regions, binds Wnt-5a, and forms a precoupled complex with Gαo that dissociates upon Wnt-5a stimulation, with Gαo driving spine density increases and Gβγ mediating cytosolic calcium elevation and spinogenesis [PMID:27402827]. FZD9 is required for normal bone formation, where in osteoblasts it acts independently of canonical Wnt to regulate matrix mineralization, chemokine and interferon-regulated gene expression (including Isg15), and fracture healing [PMID:21402791, PMID:24391920], and under mechanical stress it drives Akt/ERK phosphorylation, actin remodeling, and YAP nuclear translocation [PMID:37585277]. FZD9 is also required for pre-B cell development [PMID:15572594], marks a restricted subset of cochlear hair cell progenitors [PMID:31427926], and acts as an essential effector downstream of Myc in pancreatic islet tumorigenesis [PMID:33653688]. In lung carcinogenesis FZD9 functions as a tumor-suppressive receptor whose expression is post-transcriptionally repressed by miR-31 and by miR-520a-5p binding to its 3'UTR, and whose signaling is essential for the chemopreventive action of the prostacyclin analogue iloprost [PMID:35707728, PMID:27339092, PMID:35149732]. Deletion of FZD9 increases neural progenitor doubling time and apoptosis, identifying it as a contributory gene in the Williams syndrome deletion interval [PMID:27509850].","teleology":[{"year":1999,"claim":"Establishing that FZD9 is a bona fide membrane Wnt receptor with a broad developmental expression pattern set the stage for assigning it tissue-specific signaling roles.","evidence":"cDNA cloning, immunohistochemistry of transfected cells, and RNA in situ hybridization in mouse","pmids":["10198163"],"confidence":"Medium","gaps":["No ligand or downstream pathway identified at this stage","Localization shown only in overexpression context"]},{"year":2004,"claim":"A knockout established the first in vivo physiological requirement for FZD9, in pre-B cell development, showing the receptor is non-redundant in hematopoiesis.","evidence":"Fzd9-/- mice with competitive bone marrow reconstitution and flow cytometry","pmids":["15572594"],"confidence":"High","gaps":["Ligand and signaling pathway in B-cell development not defined","Cell-intrinsic defect only partial"]},{"year":2005,"claim":"Identifying Wnt-7a as a direct FZD9 ligand that activates JNK rather than β-catenin defined FZD9 as a non-canonical receptor with tumor-suppressive output in lung epithelium.","evidence":"Co-IP, soft agar and 3D culture assays, JNK gain-of-function, and gene expression analysis in NSCLC cells","pmids":["15705594"],"confidence":"High","gaps":["Coupling mechanism to JNK not resolved","Whether other Wnts engage FZD9 in this context unknown"]},{"year":2008,"claim":"A report of WNT2 binding and β-catenin/DVL/AXIN co-localization raised the possibility of FZD9 also driving canonical signaling, contrasting with the non-canonical model.","evidence":"Reciprocal co-IP and immunofluorescence co-localization in human cumulus cells","pmids":["19038973"],"confidence":"Medium","gaps":["No functional validation beyond co-localization","Canonical pathway inference correlative","Not reconciled with non-canonical findings in other tissues"]},{"year":2010,"claim":"Placing PPARγ between Wnt-7a/FZD9 and Sprouty-4 transcription provided a defined molecular intermediary for the receptor's anti-transformation program.","evidence":"Promoter-reporter assays, stable transfection, and siRNA knockdown in NSCLC cells","pmids":["20501643"],"confidence":"Medium","gaps":["Mechanism linking FZD9 to PPARγ activation not defined","Single cell-type context"]},{"year":2011,"claim":"Knockout analysis defined FZD9 as a non-canonical driver of osteoblast function and bone formation, with chemokine and interferon-regulated genes including Isg15 as candidate effectors.","evidence":"Fzd9-/- mice, primary osteoblast mineralization assays, expression profiling, and β-catenin pathway exclusion","pmids":["21402791"],"confidence":"High","gaps":["Ligand and proximal signaling in osteoblasts unidentified","Isg15 role causal vs correlative not established"]},{"year":2013,"claim":"Extending the bone phenotype to fracture repair confirmed FZD9 is required for new bone formation in regenerative contexts via non-canonical Wnt signaling.","evidence":"Fzd9-/- femur osteotomy model with micro-CT, histomorphometry, and biomechanical testing","pmids":["24391920"],"confidence":"High","gaps":["Chemokine reductions (Ccl2, Cxcl5) not mechanistically tied to phenotype","Proximal signaling unresolved"]},{"year":2014,"claim":"Demonstrating FZD9 antagonizes agrin-induced AChR clustering revealed a role at the neuromuscular junction linked to cytosolic β-catenin accumulation.","evidence":"Gain- and loss-of-function in myotubes, AChR clustering assays, and embryonic NMJ immunolocalization","pmids":["24860427"],"confidence":"Medium","gaps":["Ligand driving NMJ effect not identified","Single lab, mechanism of β-catenin accumulation unclear"]},{"year":2016,"claim":"Resolving FZD9 coupling to a precoupled Gαo complex that dissociates on Wnt-5a binding, with Gαo and Gβγ controlling spine density and calcium, provided the receptor's clearest G-protein signaling mechanism.","evidence":"Co-IP of FZD9-Gαo, FZD9 knockdown, G-protein inhibitors, and calcium imaging in hippocampal neurons","pmids":["27402827"],"confidence":"High","gaps":["Structural basis of Gαo precoupling not defined","Downstream effectors of calcium in spinogenesis incompletely mapped"]},{"year":2016,"claim":"Mapping the Williams syndrome neural progenitor phenotype to FZD9 via an atypical deletion established a contributory developmental role in human neurogenesis.","evidence":"Patient iPSC-derived neural progenitors, atypical deletion mapping, proliferation and apoptosis assays","pmids":["27509850"],"confidence":"High","gaps":["Signaling pathway mediating progenitor defect not identified","Contribution relative to other deletion-interval genes in full syndrome unresolved"]},{"year":2016,"claim":"Identifying miR-31 as a repressor of FZD9 connected tobacco carcinogen exposure and prostacyclin chemoprevention to receptor abundance.","evidence":"Mouse models and in vitro carcinogen treatment with miR-31 and FZD9 expression analysis","pmids":["27339092"],"confidence":"Medium","gaps":["No direct 3'UTR binding assay reported","Single lab"]},{"year":2019,"claim":"Lineage tracing established Fzd9 as a marker of a restricted subset of cochlear supporting cells that act as hair cell progenitors.","evidence":"Fzd9-CreER lineage tracing, sphere-forming, sorting, and hair cell differentiation assays","pmids":["31427926"],"confidence":"Medium","gaps":["Functional requirement for FZD9 (vs marker status) not tested","Signaling role in progenitor function undefined"]},{"year":2021,"claim":"Genetic epistasis placed FZD9 as an essential Wnt-pathway effector downstream of Myc required for sustained pancreatic islet tumor expansion and β-cell dedifferentiation.","evidence":"Fzd9 KO in Myc-driven insulinoma mice, pharmacological Wnt inhibition, and expression analysis","pmids":["33653688"],"confidence":"High","gaps":["Ligand driving the oncogenic FZD9 signal not identified","Branch of Wnt signaling operative in this context unresolved"]},{"year":2022,"claim":"In vivo and in vitro studies established a reciprocal FZD9-PPARγ relationship and confirmed FZD9 as the essential receptor for iloprost lung cancer chemoprevention.","evidence":"Fzd9-/- urethane lung adenoma model with iloprost, bronchial epithelial knockdown, PPARγ reporter and EMT/invasion assays","pmids":["35707728","35924166"],"confidence":"High","gaps":["Direct molecular link between FZD9 and PPARγ activation not defined","Smoke-induced FZD9 downregulation mechanism only partly explained"]},{"year":2022,"claim":"A 3'UTR reporter assay identified miR-520a-5p as a direct post-transcriptional repressor of FZD9, with iloprost rescuing its pro-tumor effects.","evidence":"3'UTR luciferase reporter, miR-520a-5p mimic/inhibitor, and iloprost rescue in lung cell lines","pmids":["35149732"],"confidence":"Medium","gaps":["Relative contribution of miR-520a-5p versus miR-31 not weighted","Single lab"]},{"year":2023,"claim":"Under simulated microgravity FZD9 was shown to drive osteogenic mechanotransduction via Akt/ERK phosphorylation, actin remodeling, and YAP nuclear translocation independent of β-catenin.","evidence":"Fzd9 overexpression under rotating culture with Western blot, F-actin staining, and YAP localization imaging","pmids":["37585277"],"confidence":"Medium","gaps":["Overexpression-based; endogenous requirement not tested","Connection between FZD9 and YAP activation not mechanistically resolved"]},{"year":null,"claim":"How a single receptor selects among JNK, Gαo/Gβγ, PPARγ, and YAP outputs in different tissues, and which Wnt ligand drives each context, remains unresolved.","evidence":"No timeline discovery defines the structural or contextual determinants of FZD9 pathway selection","pmids":[],"confidence":"Low","gaps":["No structural basis for ligand- or tissue-specific coupling","Apparent canonical (β-catenin) versus non-canonical roles not reconciled","Proximal effectors in B cells, cochlea, and islet tumors unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11,12]}],"complexes":[],"partners":["WNT7A","WNT5A","WNT2","GNAO1","DVL","AXIN","CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00144","full_name":"Frizzled-9","aliases":["FzE6"],"length_aa":591,"mass_kda":64.5,"function":"Receptor for WNT2 that is 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 (By similarity). Plays a role in neuromuscular junction (NMJ) assembly by negatively regulating the clustering of acetylcholine receptors (AChR) through the beta-catenin canonical signaling pathway (By similarity). May play a role in neural progenitor cells (NPCs) viability through the beta-catenin canonical signaling pathway by negatively regulating cell cycle arrest leading to inhibition of neuron apoptotic process (PubMed:27509850). During hippocampal development, regulates neuroblast proliferation and apoptotic cell death. Controls bone formation through non canonical Wnt signaling mediated via ISG15. Positively regulates bone regeneration through non canonical Wnt signaling (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O00144/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FZD9","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FZD9","total_profiled":1310},"omim":[{"mim_id":"609757","title":"WILLIAMS-BEUREN REGION DUPLICATION SYNDROME","url":"https://www.omim.org/entry/609757"},{"mim_id":"606147","title":"FRIZZLED CLASS RECEPTOR 10; FZD10","url":"https://www.omim.org/entry/606147"},{"mim_id":"604579","title":"FRIZZLED CLASS RECEPTOR 4; FZD4","url":"https://www.omim.org/entry/604579"},{"mim_id":"601766","title":"FRIZZLED CLASS RECEPTOR 9; FZD9","url":"https://www.omim.org/entry/601766"},{"mim_id":"194050","title":"WILLIAMS-BEUREN SYNDROME; WBS","url":"https://www.omim.org/entry/194050"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":5.3},{"tissue":"skeletal muscle","ntpm":6.8},{"tissue":"testis","ntpm":4.4}],"url":"https://www.proteinatlas.org/search/FZD9"},"hgnc":{"alias_symbol":["FZD3","CD349"],"prev_symbol":[]},"alphafold":{"accession":"O00144","domains":[{"cath_id":"1.10.2000.10","chopping":"41-142","consensus_level":"high","plddt":91.6835,"start":41,"end":142},{"cath_id":"1.20.1070.10","chopping":"206-486_496-536","consensus_level":"high","plddt":91.2052,"start":206,"end":536}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00144","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00144-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00144-F1-predicted_aligned_error_v6.png","plddt_mean":80.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FZD9","jax_strain_url":"https://www.jax.org/strain/search?query=FZD9"},"sequence":{"accession":"O00144","fasta_url":"https://rest.uniprot.org/uniprotkb/O00144.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00144/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00144"}},"corpus_meta":[{"pmid":"25408172","id":"PMC_25408172","title":"The soft agar colony formation assay.","date":"2014","source":"Journal of visualized experiments : JoVE","url":"https://pubmed.ncbi.nlm.nih.gov/25408172","citation_count":473,"is_preprint":false},{"pmid":"17395729","id":"PMC_17395729","title":"Novel markers for the prospective isolation of human MSC.","date":"2007","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17395729","citation_count":346,"is_preprint":false},{"pmid":"18832655","id":"PMC_18832655","title":"Aberrant DNA methylation is a dominant mechanism in MDS progression to AML.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18832655","citation_count":318,"is_preprint":false},{"pmid":"10953236","id":"PMC_10953236","title":"VI. 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culture, JNK gain-of-function transfection, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP demonstrating direct Wnt7a–Fzd9 interaction, combined with functional gain-of-function experiments and multiple orthogonal readouts (JNK activation, cadherin induction, Sprouty-4 upregulation, anchorage-independent growth), all in a single rigorous study\",\n      \"pmids\": [\"15705594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FZD9 protein localizes to the plasma membrane when expressed in transfected cells, consistent with its function as a transmembrane Wnt receptor; the mouse homolog Fzd9 encodes a 592-aa protein with 95% identity to human FZD9 and is expressed in neural tube, myotomes, limb skeletal anlagen, craniofacial regions, nephric ducts, heart, brain, testis, and skeletal muscle.\",\n      \"method\": \"Immunohistochemistry of transfected cells, RNA in situ hybridization, cDNA cloning and sequence analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — membrane localization confirmed by IHC in transfected cells; expression pattern characterized by in situ hybridization across multiple labs; no functional consequence linked directly to localization\",\n      \"pmids\": [\"10198163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Fzd9 is required for normal B-cell development; Fzd9−/− mice display depletion of pre-B cells in bone marrow (particularly at the stage of immunoglobulin heavy chain expression and clonal expansion), with the pre-B defect being partially cell-intrinsic as shown by competitive bone marrow reconstitution.\",\n      \"method\": \"Fzd9 knockout mice, competitive bone marrow reconstitution, flow cytometry\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype, validated by cell-intrinsic competitive reconstitution experiment; single lab but two orthogonal approaches\",\n      \"pmids\": [\"15572594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"WNT2 interacts with FZD9 in human cumulus cells, as demonstrated by co-immunoprecipitation (WNT2 antibody precipitated FZD9 and FZD9 antibody precipitated WNT2); FZD9 co-localizes with DVL and AXIN at the plasma membrane and with β-CATENIN, suggesting FZD9-mediated canonical Wnt signaling that recruits β-catenin to the membrane and promotes adherens junction formation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — reciprocal co-IP supporting WNT2–FZD9 interaction, but single lab, no functional validation beyond co-localization; downstream pathway inference is correlative\",\n      \"pmids\": [\"19038973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Wnt-7a/Fzd9 signaling activates the Sprouty-4 (Spry4) promoter through peroxisome proliferator-activated receptor gamma (PPARγ), identifying Spry4 as a downstream transcriptional target of the Wnt7A/Fzd9 non-canonical pathway in NSCLC cells.\",\n      \"method\": \"Promoter-reporter assays, stable transfection, siRNA knockdown, gene expression analysis\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter activity assays and expression studies establish PPARγ as intermediary in Fzd9 signaling to Spry4; single lab with multiple methods\",\n      \"pmids\": [\"20501643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fzd9 is required for osteoblast function and bone formation; Fzd9−/− mice display low bone mass due to impaired bone formation (not resorption). Fzd9−/− primary osteoblasts show defects in matrix mineralization and reduced expression of chemokines and interferon-regulated genes (including Isg15 as a potential downstream mediator), without impairment of canonical Wnt/β-catenin signaling, indicating Fzd9 acts via a non-canonical pathway in osteoblasts.\",\n      \"method\": \"Fzd9 knockout mice, primary osteoblast culture, matrix mineralization assay, gene expression profiling, β-catenin pathway analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular and skeletal phenotype, primary osteoblast mechanistic characterization, pathway exclusion (β-catenin not involved), and downstream target identification; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21402791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fzd9 regulates intramembranous and endochondral bone formation during fracture healing via non-canonical Wnt signaling; Fzd9−/− mice show significantly reduced new bone formation at all healing time points and decreased mechanical competence of callus, while cartilage formation and osteoclast numbers are unaffected and β-catenin localization is unchanged. Chemokines Ccl2 and Cxcl5 appear reduced in Fzd9−/− fracture callus.\",\n      \"method\": \"Fzd9−/− mice, femur osteotomy fracture model, micro-CT, histomorphometry, immunohistochemistry, biomechanical testing\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with quantitative skeletal readouts, multiple imaging and mechanical methods, pathway exclusion (canonical Wnt unaffected), replicates findings from prior osteoblast study\",\n      \"pmids\": [\"24391920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FZD9-mediated signaling impairs acetylcholine receptor (AChR) clustering in skeletal muscle: overexpression of Fzd9 in myotubes reduces agrin-induced AChR clustering and induces cytosolic accumulation of β-catenin; Fzd9 and β-catenin co-localize at embryonic NMJ postsynaptic domains in vivo. Loss-of-function experiments confirm that Fzd9 antagonizes postsynaptic AChR assembly at the neuromuscular junction.\",\n      \"method\": \"Gain- and loss-of-function transfection in cultured myotubes, AChR clustering assay, immunolocalization in embryonic NMJ, β-catenin accumulation assay\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both gain- and loss-of-function with defined AChR clustering readout, plus in vivo immunolocalization; single lab\",\n      \"pmids\": [\"24860427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FZD9 is required for Wnt-5a-induced dendritic spine formation in hippocampal neurons. FZD9 localizes to the postsynaptic region, interacts with Wnt-5a, and forms a precoupled complex with Gαo that dissociates upon Wnt-5a stimulation. Gαo activation and Gβγ are downstream mediators of FZD9 signaling: Gαo controls Wnt-5a-induced spine density increase, while Gβγ is required for cytosolic calcium elevation and spinogenesis.\",\n      \"method\": \"Co-immunoprecipitation (FZD9–Gαo complex), siRNA knockdown of FZD9, G-protein inhibition experiments, calcium imaging, dendritic spine quantification in cultured hippocampal neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of FZD9–Gαo complex, FZD9 knockdown with specific spine phenotype, G-protein pathway dissection with multiple inhibitors, and calcium readout; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"27402827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FZD9 deletion or loss is the single gene cause of increased neural progenitor cell doubling time and apoptosis observed in Williams syndrome iPSC-derived neural progenitors, narrowed by studying an individual with atypical Williams syndrome carrying a smaller deletion encompassing FZD9.\",\n      \"method\": \"iPSC-derived neural progenitor cells from Williams syndrome patients, atypical deletion mapping, cell proliferation and apoptosis assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetic epistasis using atypical deletion patient to map phenotype to FZD9; functional cellular readouts (doubling time, apoptosis) in isogenic human iPSC model; published in high-tier journal with rigorous controls\",\n      \"pmids\": [\"27509850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fzd9 is an essential effector downstream of Myc in pancreatic islet tumorigenesis: Fzd9 is a Myc transcriptional target, and its deletion impairs sustained tumor expansion and β-cell dedifferentiation in a Myc-driven insulinoma mouse model. Wnt signaling inhibition in Fzd9-competent mice recapitulates the suppression of proliferation caused by Fzd9 deficiency.\",\n      \"method\": \"Fzd9 knockout in Myc-driven insulinoma mouse model, Wnt signaling inhibitor treatment, global gene expression analysis, histology\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Fzd9 KO in Myc model), pharmacological Wnt inhibition corroborates result; Fzd9 shown to be Myc transcriptional target; multiple orthogonal approaches in single study\",\n      \"pmids\": [\"33653688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FZD9 is required in vivo for iloprost (prostacyclin analogue) lung cancer chemoprevention: Fzd9−/− mice treated with inhaled iloprost in a urethane lung adenoma model are not protected from adenoma development and do not show increased activation of iloprost/PPARγ signaling pathways, establishing FZD9 as the essential receptor for iloprost chemopreventive action.\",\n      \"method\": \"Fzd9 knockout mice, urethane lung adenoma model, inhaled iloprost treatment, pathway activation assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO experiment with quantitative tumor outcome and pathway activation readout; validates prior in vitro mechanistic finding; single lab\",\n      \"pmids\": [\"35707728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PPARγ is a transcriptional regulator of FZD9 in lung epithelium. Loss of FZD9 in bronchial epithelial cells alters EMT markers, decreases PPARγ activity, increases transformed growth and invasive behavior, and is associated with premalignant lesion development. Cigarette smoke reduces FZD9 expression and PPARγ activation in these cells.\",\n      \"method\": \"FZD9 knockdown in human bronchial epithelial cells, Fzd9−/− mouse urethane model, PPARγ reporter assays, EMT marker analysis, soft agar and invasion assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus KO mouse with defined phenotypic readouts; PPARγ as transcriptional regulator identified by reporter assay; single lab\",\n      \"pmids\": [\"35924166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-31 represses FZD9 expression in lung cells; tobacco smoke carcinogens increase miR-31 expression, which reduces Fzd9 expression, while prostacyclin (iloprost) reduces miR-31 and maintains or increases Fzd9 expression, thereby enabling FZD9-dependent anti-tumor signaling.\",\n      \"method\": \"Mouse models, in vitro carcinogen treatment, miR-31 expression analysis, FZD9 expression assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — miR-31–FZD9 regulatory relationship established in multiple model systems (mouse and in vitro); no direct 3'UTR binding assay reported in abstract; single lab\",\n      \"pmids\": [\"27339092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-520a-5p binds the FZD9 3'UTR and represses FZD9 expression and downstream target activity; cigarette smoke condensate increases miR-520a-5p expression (reducing FZD9), while iloprost decreases miR-520a-5p. miR-520a-5p mimic cancer-promoting effects are rescued by iloprost, confirming miR-520a-5p as a post-transcriptional regulator of FZD9.\",\n      \"method\": \"3'UTR luciferase reporter assay, miR-520a-5p mimic and inhibitor transfection, iloprost treatment, FZD9 downstream target assays in lung cell lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR reporter assay confirms direct miR-520a-5p binding to FZD9, functional rescue experiment with iloprost; single lab\",\n      \"pmids\": [\"35149732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Fzd9 overexpression in osteoblasts under simulated microgravity (SMG) rescues osteogenic markers (ALP, OPN, RUNX2) via a non-β-catenin mechanism: Fzd9 promotes Akt and ERK phosphorylation, induces F-actin polymerization and actin cap formation, increases nuclear pore size, and drives nuclear translocation of YAP (Yes-associated protein), thereby activating mechanotransduction signaling.\",\n      \"method\": \"Simulated microgravity rotating cell culture, Fzd9 overexpression construct, Western blot for pAkt/pERK/pGSK3β/β-catenin, F-actin staining, YAP nuclear translocation imaging\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with multiple mechanistic readouts (actin, YAP localization, kinase phosphorylation); pathway exclusion (β-catenin not affected); single lab\",\n      \"pmids\": [\"37585277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fzd9+ cochlear supporting cells (inner phalangeal cells, inner border cells, third-row Deiters' cells) function as hair cell progenitors: lineage tracing showed Fzd9+ cells generate new hair cells in vivo and in vitro (sphere-forming and differentiation assays) at similar efficiency to Lgr5+ progenitors, identifying Fzd9 as a marker of a restricted subset of cochlear hair cell progenitors.\",\n      \"method\": \"Fzd9-CreER lineage tracing, sphere-forming assay, flow cytometry sorting, in vivo and in vitro hair cell differentiation assays\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic lineage tracing with multiple functional assays (sphere forming, HC generation); single lab\",\n      \"pmids\": [\"31427926\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD9 is a seven-transmembrane Wnt receptor that signals predominantly through non-canonical (JNK, Gαo/Gβγ, PPARγ, YAP) pathways rather than canonical β-catenin/TCF signaling; it directly binds Wnt-7a and Wnt-5a, couples to heterotrimeric G proteins (forming a basal Gαo complex) to regulate dendritic spine formation, activates PPARγ-dependent transcription (including Sprouty-4) to suppress lung epithelial transformation, drives non-canonical bone formation in osteoblasts (regulating ISG15 and chemokine expression), is required for pre-B cell development, promotes hair cell progenitor function in the cochlea, and is an essential downstream effector of Myc in pancreatic islet tumorigenesis; its expression is post-transcriptionally repressed by miR-31 and miR-520a-5p, and transcriptionally activated by PPARγ, while being epigenetically silenced by promoter methylation in multiple cancers.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FZD9 is a seven-transmembrane Frizzled Wnt receptor that signals predominantly through non-canonical, β-catenin-independent pathways to control tissue differentiation, bone formation, neuronal connectivity, and tumor suppression [#0, #5, #8]. It binds Wnt-7a directly and activates JNK rather than β-catenin/TCF signaling, inducing cadherin and Sprouty-4 expression and promoting epithelial differentiation while suppressing anchorage-independent growth in lung cells [#0]; this Wnt-7a/FZD9 axis activates the Sprouty-4 promoter through PPARγ, and a reciprocal regulatory loop exists in which PPARγ also transcriptionally activates FZD9 in lung epithelium [#4, #12]. In neurons, FZD9 localizes to postsynaptic regions, binds Wnt-5a, and forms a precoupled complex with Gαo that dissociates upon Wnt-5a stimulation, with Gαo driving spine density increases and Gβγ mediating cytosolic calcium elevation and spinogenesis [#8]. FZD9 is required for normal bone formation, where in osteoblasts it acts independently of canonical Wnt to regulate matrix mineralization, chemokine and interferon-regulated gene expression (including Isg15), and fracture healing [#5, #6], and under mechanical stress it drives Akt/ERK phosphorylation, actin remodeling, and YAP nuclear translocation [#15]. FZD9 is also required for pre-B cell development [#2], marks a restricted subset of cochlear hair cell progenitors [#16], and acts as an essential effector downstream of Myc in pancreatic islet tumorigenesis [#10]. In lung carcinogenesis FZD9 functions as a tumor-suppressive receptor whose expression is post-transcriptionally repressed by miR-31 and by miR-520a-5p binding to its 3'UTR, and whose signaling is essential for the chemopreventive action of the prostacyclin analogue iloprost [#11, #13, #14]. Deletion of FZD9 increases neural progenitor doubling time and apoptosis, identifying it as a contributory gene in the Williams syndrome deletion interval [#9].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that FZD9 is a bona fide membrane Wnt receptor with a broad developmental expression pattern set the stage for assigning it tissue-specific signaling roles.\",\n      \"evidence\": \"cDNA cloning, immunohistochemistry of transfected cells, and RNA in situ hybridization in mouse\",\n      \"pmids\": [\"10198163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligand or downstream pathway identified at this stage\", \"Localization shown only in overexpression context\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"A knockout established the first in vivo physiological requirement for FZD9, in pre-B cell development, showing the receptor is non-redundant in hematopoiesis.\",\n      \"evidence\": \"Fzd9-/- mice with competitive bone marrow reconstitution and flow cytometry\",\n      \"pmids\": [\"15572594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand and signaling pathway in B-cell development not defined\", \"Cell-intrinsic defect only partial\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying Wnt-7a as a direct FZD9 ligand that activates JNK rather than β-catenin defined FZD9 as a non-canonical receptor with tumor-suppressive output in lung epithelium.\",\n      \"evidence\": \"Co-IP, soft agar and 3D culture assays, JNK gain-of-function, and gene expression analysis in NSCLC cells\",\n      \"pmids\": [\"15705594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling mechanism to JNK not resolved\", \"Whether other Wnts engage FZD9 in this context unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"A report of WNT2 binding and β-catenin/DVL/AXIN co-localization raised the possibility of FZD9 also driving canonical signaling, contrasting with the non-canonical model.\",\n      \"evidence\": \"Reciprocal co-IP and immunofluorescence co-localization in human cumulus cells\",\n      \"pmids\": [\"19038973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional validation beyond co-localization\", \"Canonical pathway inference correlative\", \"Not reconciled with non-canonical findings in other tissues\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placing PPARγ between Wnt-7a/FZD9 and Sprouty-4 transcription provided a defined molecular intermediary for the receptor's anti-transformation program.\",\n      \"evidence\": \"Promoter-reporter assays, stable transfection, and siRNA knockdown in NSCLC cells\",\n      \"pmids\": [\"20501643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking FZD9 to PPARγ activation not defined\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Knockout analysis defined FZD9 as a non-canonical driver of osteoblast function and bone formation, with chemokine and interferon-regulated genes including Isg15 as candidate effectors.\",\n      \"evidence\": \"Fzd9-/- mice, primary osteoblast mineralization assays, expression profiling, and β-catenin pathway exclusion\",\n      \"pmids\": [\"21402791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand and proximal signaling in osteoblasts unidentified\", \"Isg15 role causal vs correlative not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extending the bone phenotype to fracture repair confirmed FZD9 is required for new bone formation in regenerative contexts via non-canonical Wnt signaling.\",\n      \"evidence\": \"Fzd9-/- femur osteotomy model with micro-CT, histomorphometry, and biomechanical testing\",\n      \"pmids\": [\"24391920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chemokine reductions (Ccl2, Cxcl5) not mechanistically tied to phenotype\", \"Proximal signaling unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating FZD9 antagonizes agrin-induced AChR clustering revealed a role at the neuromuscular junction linked to cytosolic β-catenin accumulation.\",\n      \"evidence\": \"Gain- and loss-of-function in myotubes, AChR clustering assays, and embryonic NMJ immunolocalization\",\n      \"pmids\": [\"24860427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand driving NMJ effect not identified\", \"Single lab, mechanism of β-catenin accumulation unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolving FZD9 coupling to a precoupled Gαo complex that dissociates on Wnt-5a binding, with Gαo and Gβγ controlling spine density and calcium, provided the receptor's clearest G-protein signaling mechanism.\",\n      \"evidence\": \"Co-IP of FZD9-Gαo, FZD9 knockdown, G-protein inhibitors, and calcium imaging in hippocampal neurons\",\n      \"pmids\": [\"27402827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Gαo precoupling not defined\", \"Downstream effectors of calcium in spinogenesis incompletely mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapping the Williams syndrome neural progenitor phenotype to FZD9 via an atypical deletion established a contributory developmental role in human neurogenesis.\",\n      \"evidence\": \"Patient iPSC-derived neural progenitors, atypical deletion mapping, proliferation and apoptosis assays\",\n      \"pmids\": [\"27509850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway mediating progenitor defect not identified\", \"Contribution relative to other deletion-interval genes in full syndrome unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying miR-31 as a repressor of FZD9 connected tobacco carcinogen exposure and prostacyclin chemoprevention to receptor abundance.\",\n      \"evidence\": \"Mouse models and in vitro carcinogen treatment with miR-31 and FZD9 expression analysis\",\n      \"pmids\": [\"27339092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct 3'UTR binding assay reported\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Lineage tracing established Fzd9 as a marker of a restricted subset of cochlear supporting cells that act as hair cell progenitors.\",\n      \"evidence\": \"Fzd9-CreER lineage tracing, sphere-forming, sorting, and hair cell differentiation assays\",\n      \"pmids\": [\"31427926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional requirement for FZD9 (vs marker status) not tested\", \"Signaling role in progenitor function undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic epistasis placed FZD9 as an essential Wnt-pathway effector downstream of Myc required for sustained pancreatic islet tumor expansion and β-cell dedifferentiation.\",\n      \"evidence\": \"Fzd9 KO in Myc-driven insulinoma mice, pharmacological Wnt inhibition, and expression analysis\",\n      \"pmids\": [\"33653688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand driving the oncogenic FZD9 signal not identified\", \"Branch of Wnt signaling operative in this context unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"In vivo and in vitro studies established a reciprocal FZD9-PPARγ relationship and confirmed FZD9 as the essential receptor for iloprost lung cancer chemoprevention.\",\n      \"evidence\": \"Fzd9-/- urethane lung adenoma model with iloprost, bronchial epithelial knockdown, PPARγ reporter and EMT/invasion assays\",\n      \"pmids\": [\"35707728\", \"35924166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between FZD9 and PPARγ activation not defined\", \"Smoke-induced FZD9 downregulation mechanism only partly explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A 3'UTR reporter assay identified miR-520a-5p as a direct post-transcriptional repressor of FZD9, with iloprost rescuing its pro-tumor effects.\",\n      \"evidence\": \"3'UTR luciferase reporter, miR-520a-5p mimic/inhibitor, and iloprost rescue in lung cell lines\",\n      \"pmids\": [\"35149732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of miR-520a-5p versus miR-31 not weighted\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Under simulated microgravity FZD9 was shown to drive osteogenic mechanotransduction via Akt/ERK phosphorylation, actin remodeling, and YAP nuclear translocation independent of β-catenin.\",\n      \"evidence\": \"Fzd9 overexpression under rotating culture with Western blot, F-actin staining, and YAP localization imaging\",\n      \"pmids\": [\"37585277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based; endogenous requirement not tested\", \"Connection between FZD9 and YAP activation not mechanistically resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single receptor selects among JNK, Gαo/Gβγ, PPARγ, and YAP outputs in different tissues, and which Wnt ligand drives each context, remains unresolved.\",\n      \"evidence\": \"No timeline discovery defines the structural or contextual determinants of FZD9 pathway selection\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural basis for ligand- or tissue-specific coupling\", \"Apparent canonical (β-catenin) versus non-canonical roles not reconciled\", \"Proximal effectors in B cells, cochlea, and islet tumors unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"WNT7A\",\n      \"WNT5A\",\n      \"WNT2\",\n      \"GNAO1\",\n      \"DVL\",\n      \"AXIN\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}