{"gene":"FZD9","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":1997,"finding":"FZD9 (originally named FZD3) was identified as a novel seven-transmembrane domain Wnt receptor located in the Williams syndrome deletion region at 7q11.23. Human and Drosophila cells transfected with FZD9 expression constructs bind Drosophila Wingless protein, establishing FZD9 as a functional Wnt-binding receptor. The protein is 591 amino acids and is expressed predominantly in brain, testis, eye, skeletal muscle and kidney.","method":"CpG island cloning, dosage blotting, Wg protein binding assay in transfected cells","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — direct ligand-binding assay in transfected cells, foundational identification paper, highly cited","pmids":["9147651"],"is_preprint":false},{"year":1999,"finding":"Mouse Fzd9, the homolog of human FZD9, is a membrane protein confirmed by immunohistochemistry of transfected cells. It is expressed in the neural tube, myotomes, limb skeletal anlagen, craniofacial regions, nephric ducts, heart, brain, testis, and skeletal muscle during development. The gene maps to the conserved syntenic region on distal mouse chromosome 5, consistent with its role as a Wnt receptor potentially involved in skeletal muscle specification.","method":"RNA in situ hybridization, immunohistochemistry of transfected cells, genetic mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct membrane localization confirmed by immunohistochemistry in transfected cells; expression pattern by in situ hybridization","pmids":["10198163"],"is_preprint":false},{"year":2002,"finding":"Rat Frizzled-9 (Rfz9/FZD9) functions in canonical Wnt/β-catenin signaling. Overexpression of Rfz9 induces hyperphosphorylation and relocalization of Dishevelled-1 (Dvl-1) from cytoplasm to cell membrane, accumulation of cytosolic β-catenin, and TCF-dependent transcription. Among several Wnt members tested, only Wnt-2 activates Rfz9 in TCF-dependent transcription. Rfz9 also relocalizes Axin from cytoplasm to plasma membrane in the presence of Dvl-1. Deletion mutant analysis showed that C-terminal residues required for Dvl-1 modification differ from those required for β-catenin stabilization and TCF transactivation.","method":"Overexpression in 293T cells, TCF-luciferase reporter assay, Western blot, immunofluorescence, deletion mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (reporter assay, co-localization, deletion mutants), identifies specific Wnt-2 as activating ligand","pmids":["12138115"],"is_preprint":false},{"year":2005,"finding":"FZD9 (Fzd-9) is the specific receptor mediating Wnt-7a tumor suppressor activity in non-small cell lung cancer (NSCLC). Wnt-7a and Fzd-9 co-expression reversed cellular transformation, decreased anchorage-independent growth, and induced epithelial differentiation. Wnt-7a was detected in Fzd-9 immunoprecipitates, confirming direct protein interaction. Wnt-7a/Fzd-9 signaling activates the JNK pathway and induces E-cadherin and Sprouty-4 expression but does not activate β-catenin/TCF. Transfection of Fzd-9 into a Wnt-7a-insensitive cell line conferred sensitivity, establishing Fzd-9 as necessary for Wnt-7a response.","method":"Co-immunoprecipitation, soft agar assay, 3D cell culture, stable transfection, Western blot, JNK gain-of-function","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP confirming direct interaction, multiple functional assays, epistasis via transfection rescue, replicated by same group","pmids":["15705594"],"is_preprint":false},{"year":2006,"finding":"The anti-tumorigenic effect of Wnt-7a/Fzd-9 in NSCLC is mediated through ERK5-dependent activation of PPARγ. Wnt-7a and Fzd-9 expression led to increased PPARγ transcriptional activity (without altering PPARγ protein levels) and activated ERK5. Inhibition of PPARγ with SR-202 blocked the increase in PPARγ activity and restored anchorage-independent growth. SR-202 also reversed Wnt-7a/Fzd-9-induced E-cadherin expression, placing ERK5 → PPARγ downstream of FZD9 in this pathway.","method":"PPARγ reporter assay, ERK5 kinase assay, pharmacological inhibition (SR-202), anchorage-independent growth assay, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing pathway order; epistasis via pharmacological inhibition; replicated from prior study","pmids":["16835228"],"is_preprint":false},{"year":2008,"finding":"In human cumulus cells, WNT2 interacts with FZD9 as demonstrated by co-immunoprecipitation: WNT2 antibody precipitated both FZD3 and FZD9, and FZD9 antibody precipitated WNT2. FZD9 co-localizes with DVL and AXIN at the plasma membrane, and β-catenin is highly co-localized with FZD9 and AXIN, suggesting WNT2 acts through FZD9 to regulate the β-catenin pathway in cumulus cells.","method":"Co-immunoprecipitation, immunofluorescence co-localization microscopy","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 3 — reciprocal Co-IP for WNT2/FZD9 interaction; single lab, single method for interaction","pmids":["19038973"],"is_preprint":false},{"year":2009,"finding":"FZD9 (Fz9) siRNA knockdown in hepatocellular carcinoma (HCC) and hepatoblastoma (HB) cell lines significantly suppressed cell proliferation and cell motility, and decreased cyclin D1 expression, without inducing apoptosis (no cleaved caspase-3 detected). This establishes FZD9 as essential for carcinogenesis in liver tumor cells through a mechanism involving cyclin D1.","method":"siRNA knockdown, MTS proliferation assay, wound healing/motility assay, Western blot for cyclin D1 and caspase-3","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype and molecular readout (cyclin D1); single lab","pmids":["19724923"],"is_preprint":false},{"year":2010,"finding":"Sprouty-4 (Spry4) is a downstream transcriptional target of Wnt7A/Fzd9 signaling through PPARγ. The Spry4 promoter activity is increased by Wnt7A/Fzd9 signaling through PPARγ, and Spry4 mediates anti-tumorigenic effects including inhibition of cell growth, migration, invasion, and reversal of epithelial-mesenchymal transition in NSCLC.","method":"Promoter-reporter assay, stable transfection, Transwell migration/invasion assays, Western blot, shRNA knockdown","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — promoter assay establishes transcriptional regulation; pathway placement via genetic epistasis; single lab","pmids":["20501643"],"is_preprint":false},{"year":2016,"finding":"Using iPSC-derived neural progenitor cells from Williams syndrome (WS) patients and an individual with atypical WS, FZD9 was identified as the single gene candidate responsible for the increased doubling time and apoptosis phenotype observed in WS neural progenitor cells. This identifies FZD9 as a regulator of neural progenitor cell proliferation and survival during cortical development.","method":"iPSC differentiation, genetic narrowing using atypical WS patient with smaller deletion, cell doubling time measurement, apoptosis assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — natural genetic experiment with atypical WS narrowing to single gene; functional cellular phenotype in human neuronal model; high-impact journal","pmids":["27509850"],"is_preprint":false},{"year":2017,"finding":"In osteosarcoma, knockdown of c-Fos inhibits the expression of Wnt2 and its receptor Fzd9 at both mRNA and protein levels. Co-immunoprecipitation confirmed a relationship between c-Fos and Wnt2/Fzd9. Knockdown of c-Fos inhibited proliferation, migration, and invasion of OS cells and promoted apoptosis, accompanied by reduced Wnt2/Fzd9 expression, placing FZD9 downstream of c-Fos transcriptional regulation in osteosarcoma.","method":"siRNA knockdown, Western blot, RT-PCR, Co-immunoprecipitation, transwell assay, wound healing, MTS assay, flow cytometry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP; c-Fos regulation of Fzd9 shown by knockdown; single lab","pmids":["28665975"],"is_preprint":false},{"year":2021,"finding":"FZD9 is an essential mediator of Myc-driven tumorigenesis in pancreatic islets. In a mouse model of Myc-driven insulinoma, loss of Fzd9 (a Myc transcriptional target) impaired sustained tumor expansion, prevented β-cell dedifferentiation, and maintained physiological islet structure. Wnt signaling inhibition in Fzd9-competent mice largely recapitulated the suppression of proliferation caused by Fzd9 deficiency, placing FZD9 downstream of Myc and upstream of Wnt signaling in insulinoma.","method":"Genetic knockout in mouse insulinoma model, histology, gene expression profiling, pharmacological Wnt inhibition, epistasis","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic KO with defined tumor phenotype and pathway epistasis via Wnt inhibition; multiple readouts","pmids":["33653688"],"is_preprint":false},{"year":2022,"finding":"miR-520a-5p directly binds the 3'UTR of FZD9 mRNA in lung cell lines and regulates FZD9 expression and the activity of its downstream targets (PPARγ pathway). Cigarette smoke condensate (CSC) increases miR-520a-5p expression (reducing FZD9), while iloprost (a lung cancer chemoprevention prostacyclin analogue) decreases miR-520a-5p expression. Cancer-promoting effects of a miR-520a-5p mimic were rescued by iloprost treatment, establishing miR-520a-5p as a post-transcriptional regulator of FZD9.","method":"3'UTR luciferase reporter assay, miRNA mimic/inhibitor transfection, RT-qPCR, functional cell assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter confirms direct 3'UTR binding; functional rescue experiments; single lab","pmids":["35149732"],"is_preprint":false},{"year":2008,"finding":"Aberrant DNA methylation of the FZD9 locus on chromosome 7 was identified as a mechanism of tumor suppressor gene silencing in MDS progression to AML. In patients with chromosome 7 deletion at the FZD9 locus, aberrant methylation of the remaining allele was associated with the poorest clinical outcome, suggesting biallelic inactivation of FZD9 by deletion plus epigenetic silencing.","method":"DNA methylation microarray, SNP array karyotyping, correlation with clinical outcomes in 184 MDS/AML patients","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 3 — epigenetic mechanism identified by methylation array; clinical correlation supports TSG role; large patient cohort but no functional validation of FZD9 loss","pmids":["18832655"],"is_preprint":false},{"year":2016,"finding":"FZD9 promoter methylation leads to transcriptional silencing of FZD9 in leukemic cell lines. FZD9 expression was absent in leukemic cell lines but restored by the DNA demethylating agent 5-aza-2'-deoxycytidine. Bisulfite sequencing confirmed partial methylation of the FZD9 promoter in non-expressing lines, whereas normal peripheral blood mononuclear cells showed no methylation. FZD9 promoter methylation was found in 52.9% of primary or relapse AML cases.","method":"5-aza-2'-deoxycytidine treatment, bisulfite sequencing, methylation-specific PCR, RT-PCR expression analysis","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 — demethylation rescue directly links promoter methylation to gene silencing; validated in primary patient samples","pmids":["27314612"],"is_preprint":false}],"current_model":"FZD9 is a seven-transmembrane Wnt receptor that binds Wnt-2 (canonical β-catenin pathway, recruiting DVL and Axin to the membrane) and Wnt-7a (non-canonical pathway, activating JNK and ERK5→PPARγ to suppress lung tumor growth and drive epithelial differentiation); it is transcriptionally regulated by Myc and epigenetically silenced by promoter methylation in AML/MDS, and its loss impairs neural progenitor proliferation in Williams syndrome while its presence is required for Myc-driven insulinoma tumorigenesis."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of FZD9 as a functional Wnt-binding receptor within the Williams syndrome critical region resolved the question of whether a Frizzled-family member mapped to 7q11.23 and could bind Wnt ligands.","evidence":"CpG island cloning and Wingless protein binding assay in transfected human and Drosophila cells","pmids":["9147651"],"confidence":"High","gaps":["Specific mammalian Wnt ligand(s) not identified","No downstream signaling characterized","In vivo loss-of-function not tested"]},{"year":2002,"claim":"Demonstration that FZD9 activates canonical β-catenin/TCF signaling specifically through Wnt-2, while recruiting DVL-1 and Axin to the membrane, established the pathway mechanism and ligand specificity.","evidence":"TCF-luciferase reporter, immunofluorescence co-localization, and deletion mutant analysis in 293T cells","pmids":["12138115"],"confidence":"High","gaps":["Structural basis of Wnt-2 selectivity unknown","Endogenous Wnt-2/FZD9 interaction not shown in a physiological tissue at this point"]},{"year":2005,"claim":"Discovery that FZD9 mediates Wnt-7a tumor-suppressor signaling through a non-canonical JNK pathway in NSCLC revealed a second, β-catenin-independent signaling arm and established FZD9 as a determinant of epithelial differentiation.","evidence":"Co-immunoprecipitation of Wnt-7a/FZD9, soft agar assays, and rescue by FZD9 transfection in NSCLC lines","pmids":["15705594"],"confidence":"High","gaps":["How the same receptor switches between canonical and non-canonical outputs unclear","Co-receptor (LRP5/6 vs. ROR/RYK) involvement not defined"]},{"year":2006,"claim":"Placement of ERK5→PPARγ downstream of Wnt-7a/FZD9 signaling, with Sprouty-4 as a transcriptional effector, delineated the non-canonical pathway from receptor to transcriptional output in NSCLC.","evidence":"ERK5 kinase assay, PPARγ reporter, pharmacological inhibition with SR-202, and anchorage-independent growth rescue","pmids":["16835228","20501643"],"confidence":"High","gaps":["Direct ERK5 activation mechanism by FZD9 not defined","Applicability beyond NSCLC not tested"]},{"year":2008,"claim":"Epigenetic silencing of FZD9 by promoter methylation in MDS/AML—combined with chromosomal deletion of the other allele—provided evidence for FZD9 functioning as a tumor suppressor whose biallelic inactivation drives leukemic progression.","evidence":"Methylation microarray and SNP karyotyping in 184 MDS/AML patients; demethylation rescue in leukemic cell lines","pmids":["18832655","27314612"],"confidence":"Medium","gaps":["Functional consequence of FZD9 re-expression in AML cells not tested","Downstream pathway mediating tumor suppression in hematopoietic cells uncharacterized"]},{"year":2009,"claim":"FZD9 knockdown in hepatocellular carcinoma and hepatoblastoma cells reduced proliferation and cyclin D1 without inducing apoptosis, revealing a pro-proliferative role distinct from its tumor-suppressive function in lung cancer.","evidence":"siRNA knockdown, MTS proliferation assay, wound healing, Western blot for cyclin D1 and caspase-3","pmids":["19724923"],"confidence":"Medium","gaps":["Upstream Wnt ligand not identified in liver tumors","Mechanism linking FZD9 to cyclin D1 not defined"]},{"year":2016,"claim":"Genetic narrowing in iPSC-derived neural progenitors from Williams syndrome patients identified FZD9 as the single gene responsible for impaired proliferation and increased apoptosis, establishing its role in human cortical neurogenesis.","evidence":"iPSC differentiation from WS and atypical WS patients, doubling time and apoptosis measurements","pmids":["27509850"],"confidence":"High","gaps":["Downstream signaling pathway in neural progenitors not characterized","Rescue by FZD9 re-expression not performed"]},{"year":2021,"claim":"Demonstration that FZD9 is a transcriptional target of Myc and is essential for sustained tumor expansion in a mouse insulinoma model revealed FZD9 as a critical node linking oncogenic Myc to Wnt-dependent β-cell dedifferentiation.","evidence":"Genetic Fzd9 knockout in Myc-driven insulinoma mouse model with pharmacological Wnt inhibition epistasis","pmids":["33653688"],"confidence":"High","gaps":["Specific Wnt ligand driving FZD9 in insulinoma not identified","Relevance to human pancreatic endocrine tumors not confirmed"]},{"year":2022,"claim":"Identification of miR-520a-5p as a direct post-transcriptional repressor of FZD9 in lung cells linked cigarette smoke-induced FZD9 downregulation to a specific miRNA mechanism.","evidence":"3ʹUTR luciferase reporter assay, miRNA mimic/inhibitor transfection, functional rescue with iloprost","pmids":["35149732"],"confidence":"Medium","gaps":["In vivo relevance of miR-520a-5p regulation not established","Other miRNAs targeting FZD9 not surveyed"]},{"year":null,"claim":"How FZD9 distinguishes between canonical (Wnt-2/β-catenin) and non-canonical (Wnt-7a/JNK/ERK5) outputs remains mechanistically undefined—specifically the roles of co-receptors, post-translational modifications, and tissue-specific adaptors that dictate pathway choice.","evidence":"","pmids":[],"confidence":"Low","gaps":["Co-receptor identity (LRP5/6, ROR, RYK) for each arm unresolved","Structural basis for ligand selectivity absent","Cell-type determinants of oncogenic vs. tumor-suppressive function unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,10,12,13]}],"complexes":[],"partners":["WNT2","WNT7A","DVL1","AXIN1","CTNNB1","MYC"],"other_free_text":[]},"mechanistic_narrative":"FZD9 is a seven-transmembrane Wnt receptor that transduces both canonical and non-canonical Wnt signals to regulate cell proliferation, differentiation, and survival in neural, epithelial, and endocrine tissues. In the canonical pathway, FZD9 binds Wnt-2, recruits Dishevelled-1 and Axin to the plasma membrane, stabilizes cytosolic β-catenin, and activates TCF-dependent transcription [PMID:12138115, PMID:19038973]; in the non-canonical pathway, FZD9 partners with Wnt-7a to activate JNK and ERK5→PPARγ signaling, suppressing transformation and inducing epithelial differentiation in non-small cell lung cancer [PMID:15705594, PMID:16835228]. Hemizygous loss of FZD9 within the Williams syndrome deletion impairs neural progenitor proliferation and increases apoptosis [PMID:27509850], while FZD9 is a Myc transcriptional target required for sustained tumor expansion in a mouse insulinoma model [PMID:33653688]. FZD9 is epigenetically silenced by promoter methylation in AML/MDS, where biallelic inactivation correlates with disease progression [PMID:18832655, PMID:27314612]."},"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":"31078732","id":"PMC_31078732","title":"A 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vitreoretinopathy in two Japanese families with FZD4 mutations (H69Y and C181R).","date":"2004","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15370539","citation_count":31,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32924931","id":"PMC_32924931","title":"TMEM79/MATTRIN defines a pathway for Frizzled regulation and is required for Xenopus embryogenesis.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32924931","citation_count":17,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35149732","id":"PMC_35149732","title":"miR-520a-5p regulates Frizzled 9 expression and mediates effects of cigarette smoke and iloprost chemoprevention.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35149732","citation_count":11,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27314612","id":"PMC_27314612","title":"Methylation status of the promoter region of the human frizzled 9 gene in acute 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India","url":"https://pubmed.ncbi.nlm.nih.gov/914765","citation_count":3,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24107,"output_tokens":1831,"usd":0.049893},"stage2":{"model":"claude-opus-4-6","input_tokens":4528,"output_tokens":1574,"usd":0.092985},"total_usd":0.385278,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":35665,"output_tokens":5446,"usd":0.094342},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7741,"output_tokens":2400,"usd":0.148058}},"stage1_raw":"Looking at the corpus, I need to identify papers about FZD9 (the human gene, also known as the frizzled-9 receptor, located in the Williams-Beuren syndrome deletion region at 7q11.23). I notice significant confusion in this corpus: many papers labeled as being about \"FZD3\" on chromosome 8p21 are actually about a different gene from FZD9. The gene FZD9 was originally called FZD3 in early papers (Wang et al. 1999, PMID:10198163 explicitly states \"we previously identified a novel frizzled gene, FZD3, now renamed FZD9\"). So I need to carefully distinguish:\n\n- Papers about the chromosome 7q11.23 gene (originally FZD3, now FZD9) = relevant\n- Papers about FZD3 on chromosome 8p21 (a different gene) = NOT relevant to FZD9\n\nPapers relevant to FZD9:\n- PMID:10198163 (Wang et al. 1999) - mouse Fzd9, homolog of human FZD9\n- PMID:10874638 (Botta et al. 1999) - WBS deletion, FZD9\n- PMID:10873558 (Sala et al. 2000) - describes \"FZD3\" on chr 8p21 - this is the OTHER FZD3, not FZD9\n- PMID:28665975 (Wang et al. 2017) - Fzd9 as Wnt2 receptor in osteosarcoma\n- PMID:33653688 (Zacarías-Fluck et al. 2021) - Fzd9 in Myc-driven insulinoma\n- PMID:19024982 (Abdul Rahman et al. 2008) - FZD9 upregulation in stem cells\n\nNow examining Fzd3/axon guidance papers - these are about chromosome 8p21 FZD3 (mouse Fzd3), not FZD9. The mouse Fzd3 is the ortholog of human FZD3 (chr 8p21), not FZD9.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Mouse Fzd9 (homolog of human FZD9, originally named FZD3 then renamed FZD9) encodes a 592-amino-acid seven-transmembrane membrane protein with a cysteine-rich extracellular domain that localizes to the cell membrane, as confirmed by immunohistochemistry of transfected cells; its product can interact with the Drosophila wingless (Wnt) protein, identifying it as a putative Wnt receptor.\",\n      \"method\": \"Immunohistochemistry of transfected cells; protein interaction with Wingless; RNA in situ hybridization for expression mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — membrane localization confirmed by transfection/IHC; Wnt interaction established; single lab but multiple methods\",\n      \"pmids\": [\"10198163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FZD9 (within the Williams-Beuren syndrome deletion at 7q11.23) is not responsible for the major features of Williams syndrome, as patients carrying a smaller deletion that excludes both STX1A and FZD9 still present the full WBS phenotype.\",\n      \"method\": \"Genetic deletion mapping in WBS patients with atypical smaller deletions\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via natural human deletion, two patients characterized\",\n      \"pmids\": [\"10874638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In osteosarcoma cells, Fzd9 protein co-immunoprecipitates with c-Fos and Wnt2, and knockdown of c-Fos reduces Fzd9 and Wnt2 expression, inhibiting OS cell proliferation, migration, and invasion, indicating that c-Fos transcriptionally regulates Fzd9 as part of a Wnt2/Fzd9 signaling axis promoting OS malignancy.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown of c-Fos; cell proliferation (MTS, EdU), migration (wound healing, Transwell), and apoptosis (flow cytometry) assays; Western blot and RT-PCR\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus KD with multiple functional readouts, single lab\",\n      \"pmids\": [\"28665975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets: genetic deletion of Fzd9 in a mouse model of Myc-induced insulinoma impairs sustained tumor expansion and β-cell dedifferentiation, and pharmacological Wnt signaling inhibition in Fzd9-competent mice recapitulates the suppression of proliferation caused by Fzd9 deficiency, placing Fzd9 downstream of Myc as a critical Wnt receptor effector.\",\n      \"method\": \"Genetic knockout (Fzd9-null mice) in Myc-driven insulinoma mouse model; pharmacological Wnt inhibition; global gene expression analysis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo genetic KO with defined tumor phenotype, pharmacological rescue, and transcriptomic validation; multiple orthogonal methods\",\n      \"pmids\": [\"33653688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FZD9 mRNA is significantly upregulated in human chorion-derived stem cells after angiogenic induction (culture in EDM50 with bFGF and VEGF), co-expressed with stemness markers SOX-2, Nestin, OCT-4, and FGF-4, suggesting FZD9 is associated with stem cell identity in this context.\",\n      \"method\": \"RT-qPCR expression analysis of stem cells after angiogenic induction\",\n      \"journal\": \"The Medical journal of Malaysia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — expression correlation only, no functional mechanistic validation\",\n      \"pmids\": [\"19024982\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD9 (originally named FZD3, renamed FZD9) is a seven-transmembrane Wnt receptor localized to the cell membrane that binds Wnt ligands (including Wingless/Wnt2), is transcriptionally regulated by c-Fos in osteosarcoma, and functions as an essential downstream effector of Myc-driven Wnt signaling required for pancreatic islet tumorigenesis and β-cell dedifferentiation in mice.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\n**Retrieved Papers (FZD9 corpus):**\n- Papers 1-4, 6-9, 11-13, 16-23, 25-29, 32-36, 38-39, 41, 43-44, 47: About FZD3 (chromosome 8p21), not FZD9 — EXCLUDE (alias collision: FZD9 was originally named FZD3 in 1997 but then renamed; the current FZD3 on chr8p21 is a different gene)\n- Paper 5 (PMID:10198163): About mouse Fzd9 (homolog of human FZD9, in WBS deletion region) — KEEP\n- Paper 10 (PMID:28665975): About c-Fos/Wnt2/Fzd9 in osteosarcoma — KEEP\n- Paper 14 (PMID:26939553): About Celsr3/Fzd3 forebrain — this is FZD3 (chr8), not FZD9 — EXCLUDE\n- Paper 15 (PMID:27170656): Celsr3/Fzd3 — EXCLUDE\n- Paper 18 (PMID:25813877): Celsr3/Fzd3 — EXCLUDE\n- Paper 24 (PMID:31311957): Fzd3 in inner ear — EXCLUDE\n- Paper 25 (PMID:1713994): CD-349 pharmacology — EXCLUDE (unrelated)\n- Paper 28 (PMID:2854176): CD-349 — EXCLUDE\n- Paper 30 (PMID:39094673): WNT5B/FZD3/DVL3 — EXCLUDE (FZD3 not FZD9)\n- Paper 31 (PMID:33653688): Fzd9 in Myc-driven insulinoma — KEEP\n- Paper 37 (PMID:38348712): FZD3 in pelvic organ prolapse — EXCLUDE\n- Paper 40 (PMID:35153658): Fzd3 in inner ear — EXCLUDE\n- Paper 42 (PMID:19024982): FZD9 expression in stem cells — KEEP\n- Paper 44 (PMID:2167684): CD-349/calmodulin — EXCLUDE\n- Paper 45 (PMID:39796015): FZD3 in buffalo — EXCLUDE\n- Paper 46 (PMID:41250128): METTL3/FZD3 — EXCLUDE (FZD3)\n- Paper 47 (PMID:2795432): CD-349 — EXCLUDE\n- Paper 48 (PMID:41862898): FZD3 in SCLC — EXCLUDE\n\n**gene2pubmed curated papers:**\n- PMID:16189514: Proteome PPI map — mentions FZD9 interactions — KEEP\n- PMID:12477932: cDNA sequences — EXCLUDE (no mechanism)\n- PMID:25416956: Proteome interactome map — KEEP (binary PPI)\n- PMID:21873635: GO annotations — EXCLUDE\n- PMID:9192640: FRP/SFRP — not FZD9 — EXCLUDE\n- PMID:18832655: MDS/AML methylation, FZD9 as TSG candidate — KEEP\n- PMID:12853948: Chr7 sequence — EXCLUDE\n- PMID:14688793: Mutant FZD4 oligomerization — EXCLUDE (FZD4)\n- PMID:27509850: Williams syndrome iPSC model, FZD9 — KEEP\n- PMID:9147651: Original FZD9 identification (called FZD3 then) — KEEP\n- PMID:15705594: Wnt-7a/Fzd-9 in NSCLC — KEEP\n- PMID:9707618: FzE3 (FZD7?) in esophageal carcinoma — need to check: \"FzE3\" later identified as FZD7, not FZD9 — EXCLUDE\n- PMID:16835228: Wnt7a/Fzd9/ERK5/PPARγ in NSCLC — KEEP\n- PMID:12138115: Rat Frizzled-9 (Rfz9) — KEEP\n- PMID:20501643: Spry4/Wnt7A/Fzd9 in NSCLC — KEEP\n- PMID:19038973: WNT/beta-CATENIN in cumulus cells, FZD9 — KEEP\n- PMID:20398908: CNV in psychiatric disorders — EXCLUDE (no mechanism)\n- PMID:19724923: Fz9 siRNA in hepatoma — KEEP\n- PMID:15370539: FZD4 mutations — EXCLUDE\n- PMID:32924931: TMEM79/FZD regulation — KEEP (covers FZD family including FZD9 context)\n- PMID:35149732: miR-520a-5p/FZD9 — KEEP\n- PMID:27314612: FZD9 promoter methylation in AML — KEEP\n- PMID:19543507: FZD SNPs — EXCLUDE (no mechanism)\n- PMID:40437099: EndoMAP — EXCLUDE (no specific FZD9 mechanism)\n- PMID:914765: Viral hepatitis — EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"FZD9 (originally named FZD3) was identified as a novel seven-transmembrane domain Wnt receptor located in the Williams syndrome deletion region at 7q11.23. Human and Drosophila cells transfected with FZD9 expression constructs bind Drosophila Wingless protein, establishing FZD9 as a functional Wnt-binding receptor. The protein is 591 amino acids and is expressed predominantly in brain, testis, eye, skeletal muscle and kidney.\",\n      \"method\": \"CpG island cloning, dosage blotting, Wg protein binding assay in transfected cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct ligand-binding assay in transfected cells, foundational identification paper, highly cited\",\n      \"pmids\": [\"9147651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mouse Fzd9, the homolog of human FZD9, is a membrane protein confirmed by immunohistochemistry of transfected cells. It is expressed in the neural tube, myotomes, limb skeletal anlagen, craniofacial regions, nephric ducts, heart, brain, testis, and skeletal muscle during development. The gene maps to the conserved syntenic region on distal mouse chromosome 5, consistent with its role as a Wnt receptor potentially involved in skeletal muscle specification.\",\n      \"method\": \"RNA in situ hybridization, immunohistochemistry of transfected cells, genetic mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct membrane localization confirmed by immunohistochemistry in transfected cells; expression pattern by in situ hybridization\",\n      \"pmids\": [\"10198163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Rat Frizzled-9 (Rfz9/FZD9) functions in canonical Wnt/β-catenin signaling. Overexpression of Rfz9 induces hyperphosphorylation and relocalization of Dishevelled-1 (Dvl-1) from cytoplasm to cell membrane, accumulation of cytosolic β-catenin, and TCF-dependent transcription. Among several Wnt members tested, only Wnt-2 activates Rfz9 in TCF-dependent transcription. Rfz9 also relocalizes Axin from cytoplasm to plasma membrane in the presence of Dvl-1. Deletion mutant analysis showed that C-terminal residues required for Dvl-1 modification differ from those required for β-catenin stabilization and TCF transactivation.\",\n      \"method\": \"Overexpression in 293T cells, TCF-luciferase reporter assay, Western blot, immunofluorescence, deletion mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter assay, co-localization, deletion mutants), identifies specific Wnt-2 as activating ligand\",\n      \"pmids\": [\"12138115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FZD9 (Fzd-9) is the specific receptor mediating Wnt-7a tumor suppressor activity in non-small cell lung cancer (NSCLC). Wnt-7a and Fzd-9 co-expression reversed cellular transformation, decreased anchorage-independent growth, and induced epithelial differentiation. Wnt-7a was detected in Fzd-9 immunoprecipitates, confirming direct protein interaction. Wnt-7a/Fzd-9 signaling activates the JNK pathway and induces E-cadherin and Sprouty-4 expression but does not activate β-catenin/TCF. Transfection of Fzd-9 into a Wnt-7a-insensitive cell line conferred sensitivity, establishing Fzd-9 as necessary for Wnt-7a response.\",\n      \"method\": \"Co-immunoprecipitation, soft agar assay, 3D cell culture, stable transfection, Western blot, JNK gain-of-function\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP confirming direct interaction, multiple functional assays, epistasis via transfection rescue, replicated by same group\",\n      \"pmids\": [\"15705594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The anti-tumorigenic effect of Wnt-7a/Fzd-9 in NSCLC is mediated through ERK5-dependent activation of PPARγ. Wnt-7a and Fzd-9 expression led to increased PPARγ transcriptional activity (without altering PPARγ protein levels) and activated ERK5. Inhibition of PPARγ with SR-202 blocked the increase in PPARγ activity and restored anchorage-independent growth. SR-202 also reversed Wnt-7a/Fzd-9-induced E-cadherin expression, placing ERK5 → PPARγ downstream of FZD9 in this pathway.\",\n      \"method\": \"PPARγ reporter assay, ERK5 kinase assay, pharmacological inhibition (SR-202), anchorage-independent growth assay, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing pathway order; epistasis via pharmacological inhibition; replicated from prior study\",\n      \"pmids\": [\"16835228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In human cumulus cells, WNT2 interacts with FZD9 as demonstrated by co-immunoprecipitation: WNT2 antibody precipitated both FZD3 and FZD9, and FZD9 antibody precipitated WNT2. FZD9 co-localizes with DVL and AXIN at the plasma membrane, and β-catenin is highly co-localized with FZD9 and AXIN, suggesting WNT2 acts through FZD9 to regulate the β-catenin pathway in cumulus cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization microscopy\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reciprocal Co-IP for WNT2/FZD9 interaction; single lab, single method for interaction\",\n      \"pmids\": [\"19038973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FZD9 (Fz9) siRNA knockdown in hepatocellular carcinoma (HCC) and hepatoblastoma (HB) cell lines significantly suppressed cell proliferation and cell motility, and decreased cyclin D1 expression, without inducing apoptosis (no cleaved caspase-3 detected). This establishes FZD9 as essential for carcinogenesis in liver tumor cells through a mechanism involving cyclin D1.\",\n      \"method\": \"siRNA knockdown, MTS proliferation assay, wound healing/motility assay, Western blot for cyclin D1 and caspase-3\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype and molecular readout (cyclin D1); single lab\",\n      \"pmids\": [\"19724923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sprouty-4 (Spry4) is a downstream transcriptional target of Wnt7A/Fzd9 signaling through PPARγ. The Spry4 promoter activity is increased by Wnt7A/Fzd9 signaling through PPARγ, and Spry4 mediates anti-tumorigenic effects including inhibition of cell growth, migration, invasion, and reversal of epithelial-mesenchymal transition in NSCLC.\",\n      \"method\": \"Promoter-reporter assay, stable transfection, Transwell migration/invasion assays, Western blot, shRNA knockdown\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter assay establishes transcriptional regulation; pathway placement via genetic epistasis; single lab\",\n      \"pmids\": [\"20501643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Using iPSC-derived neural progenitor cells from Williams syndrome (WS) patients and an individual with atypical WS, FZD9 was identified as the single gene candidate responsible for the increased doubling time and apoptosis phenotype observed in WS neural progenitor cells. This identifies FZD9 as a regulator of neural progenitor cell proliferation and survival during cortical development.\",\n      \"method\": \"iPSC differentiation, genetic narrowing using atypical WS patient with smaller deletion, cell doubling time measurement, apoptosis assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — natural genetic experiment with atypical WS narrowing to single gene; functional cellular phenotype in human neuronal model; high-impact journal\",\n      \"pmids\": [\"27509850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In osteosarcoma, knockdown of c-Fos inhibits the expression of Wnt2 and its receptor Fzd9 at both mRNA and protein levels. Co-immunoprecipitation confirmed a relationship between c-Fos and Wnt2/Fzd9. Knockdown of c-Fos inhibited proliferation, migration, and invasion of OS cells and promoted apoptosis, accompanied by reduced Wnt2/Fzd9 expression, placing FZD9 downstream of c-Fos transcriptional regulation in osteosarcoma.\",\n      \"method\": \"siRNA knockdown, Western blot, RT-PCR, Co-immunoprecipitation, transwell assay, wound healing, MTS assay, flow cytometry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP; c-Fos regulation of Fzd9 shown by knockdown; single lab\",\n      \"pmids\": [\"28665975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FZD9 is an essential mediator of Myc-driven tumorigenesis in pancreatic islets. In a mouse model of Myc-driven insulinoma, loss of Fzd9 (a Myc transcriptional target) impaired sustained tumor expansion, prevented β-cell dedifferentiation, and maintained physiological islet structure. Wnt signaling inhibition in Fzd9-competent mice largely recapitulated the suppression of proliferation caused by Fzd9 deficiency, placing FZD9 downstream of Myc and upstream of Wnt signaling in insulinoma.\",\n      \"method\": \"Genetic knockout in mouse insulinoma model, histology, gene expression profiling, pharmacological Wnt inhibition, epistasis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic KO with defined tumor phenotype and pathway epistasis via Wnt inhibition; multiple readouts\",\n      \"pmids\": [\"33653688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-520a-5p directly binds the 3'UTR of FZD9 mRNA in lung cell lines and regulates FZD9 expression and the activity of its downstream targets (PPARγ pathway). Cigarette smoke condensate (CSC) increases miR-520a-5p expression (reducing FZD9), while iloprost (a lung cancer chemoprevention prostacyclin analogue) decreases miR-520a-5p expression. Cancer-promoting effects of a miR-520a-5p mimic were rescued by iloprost treatment, establishing miR-520a-5p as a post-transcriptional regulator of FZD9.\",\n      \"method\": \"3'UTR luciferase reporter assay, miRNA mimic/inhibitor transfection, RT-qPCR, functional cell assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter confirms direct 3'UTR binding; functional rescue experiments; single lab\",\n      \"pmids\": [\"35149732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Aberrant DNA methylation of the FZD9 locus on chromosome 7 was identified as a mechanism of tumor suppressor gene silencing in MDS progression to AML. In patients with chromosome 7 deletion at the FZD9 locus, aberrant methylation of the remaining allele was associated with the poorest clinical outcome, suggesting biallelic inactivation of FZD9 by deletion plus epigenetic silencing.\",\n      \"method\": \"DNA methylation microarray, SNP array karyotyping, correlation with clinical outcomes in 184 MDS/AML patients\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — epigenetic mechanism identified by methylation array; clinical correlation supports TSG role; large patient cohort but no functional validation of FZD9 loss\",\n      \"pmids\": [\"18832655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FZD9 promoter methylation leads to transcriptional silencing of FZD9 in leukemic cell lines. FZD9 expression was absent in leukemic cell lines but restored by the DNA demethylating agent 5-aza-2'-deoxycytidine. Bisulfite sequencing confirmed partial methylation of the FZD9 promoter in non-expressing lines, whereas normal peripheral blood mononuclear cells showed no methylation. FZD9 promoter methylation was found in 52.9% of primary or relapse AML cases.\",\n      \"method\": \"5-aza-2'-deoxycytidine treatment, bisulfite sequencing, methylation-specific PCR, RT-PCR expression analysis\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — demethylation rescue directly links promoter methylation to gene silencing; validated in primary patient samples\",\n      \"pmids\": [\"27314612\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD9 is a seven-transmembrane Wnt receptor that binds Wnt-2 (canonical β-catenin pathway, recruiting DVL and Axin to the membrane) and Wnt-7a (non-canonical pathway, activating JNK and ERK5→PPARγ to suppress lung tumor growth and drive epithelial differentiation); it is transcriptionally regulated by Myc and epigenetically silenced by promoter methylation in AML/MDS, and its loss impairs neural progenitor proliferation in Williams syndrome while its presence is required for Myc-driven insulinoma tumorigenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FZD9 is a seven-transmembrane Wnt receptor with an extracellular cysteine-rich domain that localizes to the cell membrane and binds Wnt ligands, functioning as a signal-transducing component of the Wnt pathway [PMID:10198163]. In osteosarcoma cells, FZD9 participates in a Wnt2/FZD9 signaling axis transcriptionally regulated by c-Fos that promotes proliferation, migration, and invasion [PMID:28665975]. Genetic deletion of Fzd9 in a mouse model of Myc-driven pancreatic insulinoma impairs sustained tumor expansion and β-cell dedifferentiation, establishing FZD9 as an essential downstream effector of Myc-activated Wnt signaling in tumorigenesis [PMID:33653688].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing FZD9 as a Wnt receptor: cloning revealed a seven-transmembrane protein with a cysteine-rich domain that localizes to the plasma membrane and interacts with the Drosophila Wingless (Wnt) ligand, identifying it as a candidate Wnt receptor.\",\n      \"evidence\": \"Immunohistochemistry of transfected cells, protein interaction assay with Wingless, and RNA in situ hybridization in mouse\",\n      \"pmids\": [\"10198163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling pathways activated by FZD9 upon Wnt binding were not characterized\",\n        \"Binding specificity for individual mammalian Wnt ligands was not determined\",\n        \"No loss-of-function data to establish in vivo requirement\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Ruling out FZD9 as the driver of Williams-Beuren syndrome: genetic mapping of atypical WBS deletions showed that patients lacking FZD9 still present the full phenotype, demonstrating FZD9 hemizygosity is not responsible for the major features of WBS.\",\n      \"evidence\": \"Deletion mapping in WBS patients with smaller atypical deletions excluding FZD9\",\n      \"pmids\": [\"10874638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only two patients with atypical deletions were characterized\",\n        \"Subtle neurodevelopmental contributions of FZD9 haploinsufficiency were not assessed\",\n        \"No functional rescue experiments were performed\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placing FZD9 in a c-Fos–Wnt2 oncogenic axis: co-immunoprecipitation showed FZD9 associates with c-Fos and Wnt2, and c-Fos knockdown reduced FZD9/Wnt2 expression and suppressed osteosarcoma cell proliferation, migration, and invasion, linking FZD9 to a transcriptionally regulated Wnt signaling module in cancer.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown of c-Fos, proliferation/migration/apoptosis assays, and Western blot/RT-PCR in osteosarcoma cells\",\n      \"pmids\": [\"28665975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reciprocal co-IP (FZD9 as bait) was not reported\",\n        \"Direct transcriptional regulation of FZD9 by c-Fos (e.g., promoter binding) was not demonstrated\",\n        \"Whether FZD9 signals through canonical (β-catenin) or non-canonical Wnt pathways in OS was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating in vivo essentiality: genetic ablation of Fzd9 in a Myc-driven pancreatic insulinoma model blocked sustained tumor expansion and β-cell dedifferentiation, and pharmacological Wnt inhibition phenocopied this effect, establishing FZD9 as a critical Wnt receptor downstream of Myc in tumorigenesis.\",\n      \"evidence\": \"Fzd9-null knockout mice crossed into Myc-driven insulinoma model; pharmacological Wnt inhibition; global transcriptomic analysis\",\n      \"pmids\": [\"33653688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific Wnt ligand(s) engaging FZD9 in islet tumors were not identified\",\n        \"Whether FZD9 signals through Dishevelled/β-catenin or alternative pathways in this context is unknown\",\n        \"Relevance to human pancreatic neuroendocrine tumors was not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific Wnt ligand selectivity of FZD9, its intracellular signaling cascade (canonical vs. non-canonical), co-receptor requirements, and structural basis for ligand engagement remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of FZD9 bound to a Wnt ligand exists\",\n        \"Downstream effectors (Dishevelled isoforms, β-catenin stabilization) have not been mapped for FZD9 specifically\",\n        \"In vivo requirement in normal adult tissues beyond pancreatic islets has not been characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"WNT2\",\n      \"FOS\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"FZD9 is a seven-transmembrane Wnt receptor that transduces both canonical and non-canonical Wnt signals to regulate cell proliferation, differentiation, and survival in neural, epithelial, and endocrine tissues. In the canonical pathway, FZD9 binds Wnt-2, recruits Dishevelled-1 and Axin to the plasma membrane, stabilizes cytosolic β-catenin, and activates TCF-dependent transcription [PMID:12138115, PMID:19038973]; in the non-canonical pathway, FZD9 partners with Wnt-7a to activate JNK and ERK5→PPARγ signaling, suppressing transformation and inducing epithelial differentiation in non-small cell lung cancer [PMID:15705594, PMID:16835228]. Hemizygous loss of FZD9 within the Williams syndrome deletion impairs neural progenitor proliferation and increases apoptosis [PMID:27509850], while FZD9 is a Myc transcriptional target required for sustained tumor expansion in a mouse insulinoma model [PMID:33653688]. FZD9 is epigenetically silenced by promoter methylation in AML/MDS, where biallelic inactivation correlates with disease progression [PMID:18832655, PMID:27314612].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of FZD9 as a functional Wnt-binding receptor within the Williams syndrome critical region resolved the question of whether a Frizzled-family member mapped to 7q11.23 and could bind Wnt ligands.\",\n      \"evidence\": \"CpG island cloning and Wingless protein binding assay in transfected human and Drosophila cells\",\n      \"pmids\": [\"9147651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific mammalian Wnt ligand(s) not identified\", \"No downstream signaling characterized\", \"In vivo loss-of-function not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstration that FZD9 activates canonical β-catenin/TCF signaling specifically through Wnt-2, while recruiting DVL-1 and Axin to the membrane, established the pathway mechanism and ligand specificity.\",\n      \"evidence\": \"TCF-luciferase reporter, immunofluorescence co-localization, and deletion mutant analysis in 293T cells\",\n      \"pmids\": [\"12138115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Wnt-2 selectivity unknown\", \"Endogenous Wnt-2/FZD9 interaction not shown in a physiological tissue at this point\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that FZD9 mediates Wnt-7a tumor-suppressor signaling through a non-canonical JNK pathway in NSCLC revealed a second, β-catenin-independent signaling arm and established FZD9 as a determinant of epithelial differentiation.\",\n      \"evidence\": \"Co-immunoprecipitation of Wnt-7a/FZD9, soft agar assays, and rescue by FZD9 transfection in NSCLC lines\",\n      \"pmids\": [\"15705594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same receptor switches between canonical and non-canonical outputs unclear\", \"Co-receptor (LRP5/6 vs. ROR/RYK) involvement not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placement of ERK5→PPARγ downstream of Wnt-7a/FZD9 signaling, with Sprouty-4 as a transcriptional effector, delineated the non-canonical pathway from receptor to transcriptional output in NSCLC.\",\n      \"evidence\": \"ERK5 kinase assay, PPARγ reporter, pharmacological inhibition with SR-202, and anchorage-independent growth rescue\",\n      \"pmids\": [\"16835228\", \"20501643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ERK5 activation mechanism by FZD9 not defined\", \"Applicability beyond NSCLC not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Epigenetic silencing of FZD9 by promoter methylation in MDS/AML—combined with chromosomal deletion of the other allele—provided evidence for FZD9 functioning as a tumor suppressor whose biallelic inactivation drives leukemic progression.\",\n      \"evidence\": \"Methylation microarray and SNP karyotyping in 184 MDS/AML patients; demethylation rescue in leukemic cell lines\",\n      \"pmids\": [\"18832655\", \"27314612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of FZD9 re-expression in AML cells not tested\", \"Downstream pathway mediating tumor suppression in hematopoietic cells uncharacterized\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"FZD9 knockdown in hepatocellular carcinoma and hepatoblastoma cells reduced proliferation and cyclin D1 without inducing apoptosis, revealing a pro-proliferative role distinct from its tumor-suppressive function in lung cancer.\",\n      \"evidence\": \"siRNA knockdown, MTS proliferation assay, wound healing, Western blot for cyclin D1 and caspase-3\",\n      \"pmids\": [\"19724923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream Wnt ligand not identified in liver tumors\", \"Mechanism linking FZD9 to cyclin D1 not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic narrowing in iPSC-derived neural progenitors from Williams syndrome patients identified FZD9 as the single gene responsible for impaired proliferation and increased apoptosis, establishing its role in human cortical neurogenesis.\",\n      \"evidence\": \"iPSC differentiation from WS and atypical WS patients, doubling time and apoptosis measurements\",\n      \"pmids\": [\"27509850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathway in neural progenitors not characterized\", \"Rescue by FZD9 re-expression not performed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstration that FZD9 is a transcriptional target of Myc and is essential for sustained tumor expansion in a mouse insulinoma model revealed FZD9 as a critical node linking oncogenic Myc to Wnt-dependent β-cell dedifferentiation.\",\n      \"evidence\": \"Genetic Fzd9 knockout in Myc-driven insulinoma mouse model with pharmacological Wnt inhibition epistasis\",\n      \"pmids\": [\"33653688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific Wnt ligand driving FZD9 in insulinoma not identified\", \"Relevance to human pancreatic endocrine tumors not confirmed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of miR-520a-5p as a direct post-transcriptional repressor of FZD9 in lung cells linked cigarette smoke-induced FZD9 downregulation to a specific miRNA mechanism.\",\n      \"evidence\": \"3ʹUTR luciferase reporter assay, miRNA mimic/inhibitor transfection, functional rescue with iloprost\",\n      \"pmids\": [\"35149732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of miR-520a-5p regulation not established\", \"Other miRNAs targeting FZD9 not surveyed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FZD9 distinguishes between canonical (Wnt-2/β-catenin) and non-canonical (Wnt-7a/JNK/ERK5) outputs remains mechanistically undefined—specifically the roles of co-receptors, post-translational modifications, and tissue-specific adaptors that dictate pathway choice.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Co-receptor identity (LRP5/6, ROR, RYK) for each arm unresolved\", \"Structural basis for ligand selectivity absent\", \"Cell-type determinants of oncogenic vs. tumor-suppressive function unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 10, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WNT2\", \"WNT7A\", \"DVL1\", \"AXIN1\", \"CTNNB1\", \"MYC\"],\n    \"other_free_text\": []\n  }\n}\n```"}