{"gene":"WNT6","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2001,"finding":"Human WNT6 encodes a 365-amino-acid secreted glycoprotein with an N-terminal signal peptide, WNT core domain, and RGD motif; WNT6 and WNT10A genes are clustered head-to-tail with <7 kb interval on chromosome 2q35, co-expressed in SW480 colorectal cancer cells, suggesting activation of WNT-β-catenin-TCF signaling.","method":"Molecular cloning, sequence characterization, Northern blot expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular cloning with sequence characterization and expression analysis, single lab, multiple methods","pmids":["11350055"],"is_preprint":false},{"year":2002,"finding":"Wnt-6 expressed in the ureter bud induces kidney tubulogenesis in vitro; Wnt-6-expressing cells rescue tubulogenesis in Wnt-4 mutant embryo mesenchyme and activate Wnt-4 transcription, Pax2, Pax8, Sfrp2, and E-cadherin. Wnt-6 also induces a secondary axis in Xenopus embryos, consistent with canonical signaling.","method":"In vitro kidney induction assay with Wnt-6-expressing cell lines, rescue of Wnt-4 mutant mesenchyme, Xenopus secondary axis assay","journal":"Genesis (New York, N.Y. : 2000)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple functional assays (in vitro induction, genetic rescue of mutant, Xenopus axis assay) establishing pathway position","pmids":["11948913"],"is_preprint":false},{"year":2007,"finding":"Wnt6 induces specification and epithelialization of F9 embryonal carcinoma cells to primitive endoderm via a canonical Wnt-β-catenin-Snail1 signaling cascade: β-catenin and Snail1 translocate to the nucleus, cytokeratin intermediate filaments appear, and GSK3 inhibition phenocopies Wnt6. PKA activation subsequently drives parietal endoderm EMT.","method":"Wnt6 conditioned medium treatment of F9 cells, LiCl (GSK3 inhibitor) treatment, immunofluorescence for β-catenin/Snail1 nuclear translocation, marker analysis","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditioned medium + genetic/pharmacological epistasis + multiple orthogonal readouts in a single study","pmids":["18160257"],"is_preprint":false},{"year":2007,"finding":"In chick embryos, ectodermal Wnt6 is necessary for neural crest induction and acts through the non-canonical (not β-catenin-dependent) pathway; canonical Wnt signaling instead inhibited neural crest production in chick, indicating a mechanistic divergence between amniotes and anamniotes.","method":"Gain- and loss-of-function (ectopic expression, inhibition) in chick embryos; assessment of canonical vs. non-canonical Wnt pathway activity","journal":"Developmental dynamics : an official publication of the American Association of Anatomists","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain/loss-of-function with pathway determination, single lab","pmids":["17685490"],"is_preprint":false},{"year":2008,"finding":"Xenopus Wnt6 is required during organogenesis (not gastrulation) to restrict heart muscle development: loss-of-function causes abnormally large myocardium; gain-of-function of Wnt6 or activated β-catenin restricts cardiomyogenesis by repressing cardiogenic transcription factors (e.g., GATA), upstream of downstream cardiomyogenic differentiation genes.","method":"Loss-of-function (morpholino knockdown) and gain-of-function (mRNA injection) in Xenopus; rescue by GATA reinstatement; expression analysis of cardiogenic markers","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function with epistasis rescue in Xenopus, multiple orthogonal methods","pmids":["18804460"],"is_preprint":false},{"year":2009,"finding":"Coordinate Gα13-RhoA and Wnt6-β-catenin signaling is required for primitive endoderm differentiation in F9 cells: constitutively active Gα13(Q226L) or p115RhoGEF (but not RhoA(L63)) caused β-catenin nuclear translocation; canonical Wnt-β-catenin activation drives gene expression changes required for primitive endoderm, while Gα13 signaling to ERM proteins mediates cytoarchitectural changes.","method":"Transfection of constitutively active and dominant-negative constructs, ROCK inhibitor Y-27632, β-catenin nuclear localization assay, differentiation marker analysis","journal":"Biochemistry and cell biology = Biochimie et biologie cellulaire","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic tools + pathway inhibition, single lab","pmids":["19767821"],"is_preprint":false},{"year":2011,"finding":"Wnt6 (along with Wnt10a and Wnt10b) inhibits adipogenesis and stimulates osteoblastogenesis in mesenchymal stem cells through a β-catenin-dependent mechanism: β-catenin knockdown completely prevents these effects; among the three Wnts, endogenous Wnt6 knockdown produces the greatest increase in adipogenesis and impairment of osteoblastogenesis, identifying it as the most potent endogenous regulator of MSC fate among this group.","method":"Gain- and loss-of-function in ST2 cells and 3T3-L1 preadipocytes; β-catenin knockdown epistasis; differentiation assays","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function + β-catenin epistasis + multiple cell models, replicated across cell lines","pmids":["21872687"],"is_preprint":false},{"year":2011,"finding":"In sea urchin, maternal Wnt6 is necessary and sufficient (combined with a localized vegetal cortex Dishevelled (Dsh) signal) for endoderm specification in the endomesoderm GRN: knockdown of Wnt6 causes loss of endoderm (but not mesoderm markers); adding Wnt6 to cortex-depleted eggs rescues endoderm; ectopic activation of β-catenin, dominant-negative GSK-3β, or Dsh also rescues, confirming canonical pathway involvement.","method":"Wnt6 morpholino knockdown, vegetal cortex ablation + Wnt6 rescue, ectopic activation of canonical Wnt components, two sea urchin species validation","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal loss-of-function and rescue experiments, replicated in two species","pmids":["21750039"],"is_preprint":false},{"year":2012,"finding":"GATA6 and FOXA2 transcription factors directly regulate Wnt6 gene expression during extraembryonic endoderm formation: both bind the Wnt6 promoter (ChIP), overexpression of either is sufficient to induce Wnt6 expression and TCF-dependent transcription (primitive endoderm markers), and both transactivate a Wnt6 reporter construct.","method":"Chromatin immunoprecipitation (ChIP), overexpression studies, Wnt6 promoter reporter assay, qPCR in F9 cells","journal":"Stem cells and development","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP + reporter assay + overexpression, multiple orthogonal methods in single study","pmids":["22607194"],"is_preprint":false},{"year":2012,"finding":"WNT6 expression in gastric cancer cells is transcriptionally enhanced by caveolin-1 (Cav1) via β-catenin binding to the proximal WNT6 promoter (demonstrated by epirubicin treatment increasing WNT6 promoter activity); WNT6 promotes resistance to epirubicin/doxorubicin-induced apoptosis as shown by knockdown and overexpression experiments.","method":"Promoter activity assay, β-catenin ChIP on WNT6 promoter, WNT6 knockdown/overexpression, cell death assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — promoter ChIP + reporter assay + reciprocal knockdown/overexpression + multiple drug conditions","pmids":["22370641"],"is_preprint":false},{"year":2013,"finding":"Wnt6 in M. tuberculosis-infected macrophages induces proliferation via a pertussis toxin-sensitive, ERK-mediated, β-catenin-independent induction of c-Myc; Wnt6 also drives macrophage polarization toward M2-like phenotype (induction of Arginase-1, downregulation of TNF-α) via TLR-MyD88-NF-κB-dependent induction mechanism in bone marrow-derived macrophages.","method":"Wnt6 conditioned medium, Wnt6-deficient macrophages, pertussis toxin inhibition, ERK pathway analysis, Ki-67/thymidine incorporation proliferation assay, cytokine measurement","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological inhibition + Wnt6-deficient cells + multiple orthogonal readouts establishing non-canonical mechanism","pmids":["24123681"],"is_preprint":false},{"year":2013,"finding":"Wnt6 is essential for stromal cell proliferation during uterine decidualization in mice: Wnt6-deficient mice show impaired stromal cell proliferation but normal decidual polyploidization; loss of Wnt6 prolongs cell cycle length by downregulating cyclin B1 expression.","method":"Wnt6-mutant mice, primary stromal cell culture, cell cycle analysis, cyclin B1 expression measurement","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined cellular phenotype + mechanistic readout (cyclin B1) + primary cell model","pmids":["23175771"],"is_preprint":false},{"year":2014,"finding":"WNT6 activates the JNK (c-Jun N-terminal kinase) non-canonical pathway in human dental pulp cells, promoting cell migration and differentiation (mineralization, odontogenic gene expression); JNK pathway inhibition (SP600125) reduces but does not completely abolish WNT6-induced migration and differentiation.","method":"WNT6 conditioned medium, JNK inhibitor SP600125, Western blot for JNK activation, RT-PCR for c-Jun, wound healing/transwell migration assays, ALP and alizarin red staining","journal":"Journal of endodontics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway inhibition + multiple functional readouts, single lab","pmids":["24935540"],"is_preprint":false},{"year":2015,"finding":"Sfrp2 binds Wnt6 and inhibits the Wnt6 canonical signaling pathway in cardiac progenitor cells (CPCs), suppressing CPC proliferation; this inhibition of canonical Wnt6 signaling by Sfrp2 activates the non-canonical Wnt/Planar Cell Polarity (PCP) pathway through JNK, inducing cardiac transcription factor expression and CPC differentiation.","method":"Sfrp2-Wnt6 binding assay, CPC treatment with Sfrp2, canonical/non-canonical pathway reporters, JNK pathway analysis, cardiac differentiation assays","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay + pathway reporter + functional differentiation readout, single lab","pmids":["26071893"],"is_preprint":false},{"year":2016,"finding":"Wnt6 signals through the canonical pathway in renal epithelial cells via FZD7 receptor: Wnt6 increases phosphorylation of GSK3β (Ser9), causes nuclear accumulation of β-catenin, increases TCF/Lef transcriptional activity, induces de novo tubulogenesis in 3D culture, and rescues epithelial dedifferentiation induced by TGF-β. Wnt6 also inhibits TGF-β-mediated p65-NF-κB nuclear translocation.","method":"Wnt6 overexpression in renal epithelial cells, GSK3β phosphorylation assay, β-catenin nuclear localization, TCF/Lef reporter assay, 3D tubulogenesis culture, TGF-β rescue experiments, p65 NF-κB translocation assay","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal canonical pathway readouts + receptor identification + functional rescue in a single study","pmids":["27122540"],"is_preprint":false},{"year":2018,"finding":"In Drosophila ovaries, Wnt6 ligand produced by cap cells is required to maintain anterior escort cells as a niche component: without Wnt6 signaling, anterior escort cells die, leading to loss of germline stem cells. Anterior escort cells promote DE-cadherin anchorage and transiently express the Dpp/BMP ligand to maintain full-strength BMP signaling in germline stem cells.","method":"Drosophila genetic manipulation (Wnt6 loss-of-function, hid-induced escort cell death), lineage analysis, in vivo imaging, BMP reporter assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic loss-of-function with defined cellular phenotype + mechanistic pathway placement, rigorous model system","pmids":["29361569"],"is_preprint":false},{"year":2018,"finding":"PLAGL2 transcriptionally activates Wnt6 in colorectal cancer cells by directly binding to the Wnt6 promoter region, thereby activating the Wnt/β-catenin pathway and promoting colorectal cancer proliferation.","method":"ChIP assay, dual-luciferase reporter assay, PLAGL2 knockdown in HCT116/SW480 cells, xenograft model","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + reporter assay establishing direct transcriptional regulation, single lab","pmids":["30535429"],"is_preprint":false},{"year":2019,"finding":"Secreted Wnt6 binds to FZD4 receptor to activate canonical β-catenin signaling, which is upstream of ROCK1 and 14-3-3σ, mediating diabetes-associated (high glucose/AGE-induced) centrosome amplification; siRNA against Wnt6 or FZD4, and antibodies against Wnt6 or FZD4, all attenuate centrosome amplification.","method":"siRNA knockdown of Wnt6/FZD4/β-catenin, neutralizing antibodies against Wnt6/FZD4, β-catenin nuclear translocation assay, centrosome counting","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic/antibody tools identifying receptor and downstream pathway, single lab","pmids":["31618077"],"is_preprint":false},{"year":2019,"finding":"HBCD (hexabromocyclododecane) promotes adipogenesis by specifically inhibiting Wnt6 gene expression and suppressing the Wnt/β-catenin pathway at an early stage of adipogenesis (upstream of PPARγ induction), without affecting mitotic clonal expansion or C/EBPβ.","method":"RNA sequencing, Wnt6 expression measurement, adipogenic differentiation assays in 3T3-L1 and HPA-V cells, in vivo mouse model","journal":"The Science of the total environment","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA-seq plus in vitro/in vivo validation of Wnt6 suppression, functional adipogenesis assay, single lab","pmids":["31865202"],"is_preprint":false},{"year":2020,"finding":"Wnt6 delivery to the amygdala of MeCP2 T158A (Rett syndrome model) mice ameliorates locomotor and social behavioral deficits; Wnt6 restores GSK-3β phosphorylation, β-catenin phosphorylation levels, and MeCP2 SUMOylation. Wnt6 increases BDNF and IGF-1 promoter activity in a dose-dependent manner.","method":"Lentiviral Wnt6 delivery to amygdala, behavioral assays, Western blot for GSK-3β/β-catenin/MeCP2 SUMOylation, BDNF/IGF-1 promoter reporter assay in HEK293T cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene delivery + multiple molecular readouts + promoter assay, single lab","pmids":["31974426"],"is_preprint":false},{"year":2021,"finding":"WNT6 promotes foam cell formation in M. tuberculosis-infected macrophages by upregulating acetyl-CoA carboxylase 2 (ACC2), a key lipid metabolic gene, leading to increased intracellular triacylglycerol (TAG) storage that supports Mtb survival; genetic or pharmacological loss of WNT6 or ACC2 reduces TAG levels and Mtb survival in macrophages.","method":"Wnt6-deficient macrophages, ACC2 pharmacological inhibition, TAG measurement, Mtb intracellular survival assay, ACC2 inhibitor + isoniazid combination in infected mice","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological loss-of-function, in vitro and in vivo validation, defined molecular target (ACC2)","pmids":["34255743"],"is_preprint":false},{"year":2021,"finding":"In Drosophila testis, Wnt6 is required for GSC differentiation and cyst stem cell (CySC) self-renewal; mechanistically, Wnt6 downregulates Arm (β-catenin), Rac1, and Cdc42 in S2 cells, and Rac1/Cdc42 act downstream of the non-canonical Wnt pathway to regulate stem cell niche homeostasis.","method":"Drosophila genetic manipulation, S2 cell knockdown/overexpression, Western blot for Arm/Rac1/Cdc42, phenotypic analysis of testis niche","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetics + cell-based pathway analysis, single lab","pmids":["33582096"],"is_preprint":false},{"year":2021,"finding":"WNT6 promotes BMP4-driven endothelial differentiation of murine embryonic stem cells: silencing WNT6 in PA6/ES co-cultures partially impairs endothelial differentiation upon BMP4 stimulation, and this dysfunction is recovered by adding recombinant WNT6.","method":"Microarray gene expression, siRNA knockdown, recombinant WNT6 rescue, ES/PA6 co-culture endothelial differentiation assay","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function + rescue experiment, defined functional readout, single lab","pmids":["34478025"],"is_preprint":false},{"year":2022,"finding":"WNT6 activates β-catenin signaling in human dental papilla cells via canonical pathway (β-catenin nuclear accumulation, LEF1 upregulation, enhanced TCF/β-catenin transcriptional activity); Wnt6-induced mineralization in vivo is blocked by the Wnt/β-catenin inhibitor XAV939, confirming pathway dependence.","method":"Wnt6 overexpression + knockdown, immunofluorescence for β-catenin, TOPflash/FOPflash reporter assay, ALP staining, Alizarin Red staining, subcutaneous transplantation, XAV939 inhibitor treatment","journal":"Archives of oral biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay + pharmacological inhibition + in vivo transplantation, single lab","pmids":["35691114"],"is_preprint":false},{"year":2022,"finding":"WNT6 knockdown in ovarian cancer cells inhibits proliferation, lamellipodia formation, causes cell cycle arrest, and promotes apoptosis; mechanistically, WNT6 knockdown reduces both β-catenin and Notch1 protein expression, implicating WNT6 in activation of both canonical Wnt and Notch1 pathways.","method":"siWNT6 knockdown in CAOV3/OVCAR3 cells, proliferation assay, cell cycle/apoptosis analysis, Western blot for β-catenin and Notch1","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown approach with downstream protein readout, single lab, no epistasis validation","pmids":["36075327"],"is_preprint":false},{"year":2012,"finding":"Sulf1A (a heparan sulfate 6-O-endosulfatase) is required for Wnt6-induced cellular hyper-elongation and inhibition of satellite cell proliferation in skeletal muscle myoblasts; neutralizing Sulf1A antibodies abolish both Wnt6-induced morphological and antiproliferative effects, indicating Sulf1A modulates Wnt6 signaling in muscle.","method":"Exogenous Wnt6 treatment of satellite cells on isolated fibers, Sulf1A neutralizing antibody treatment, morphological and proliferation assessment","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — antibody neutralization of co-factor with functional readout, multiple readouts, single lab","pmids":["23772371"],"is_preprint":false},{"year":2013,"finding":"Drosophila Wnt6 knockout flies are viable with normal wing size and planar cell polarity, but specifically lack maxillary palps; Wnt6 is absent from hemipteran genomes that also lack maxillary palps, suggesting a conserved developmental requirement.","method":"Wnt6 knockout fly generation (CRISPR/genetic), phenotypic analysis of wing size, planar cell polarity, and maxillary palp","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined specific developmental phenotype, single lab","pmids":["24090348"],"is_preprint":false},{"year":2023,"finding":"CGRP (calcitonin gene-related peptide) regulates osteogenic differentiation of bone marrow mesenchymal stem cells through both p38 MAPK and Wnt6/β-catenin signaling pathways, as validated in vitro by demonstrating upregulation of Wnt6 expression and downstream β-catenin pathway activation upon CGRP stimulation.","method":"In vitro CGRP stimulation of rat BMMSCs, RNA sequencing of innervated vs. non-innervated bone grafts, osteogenic differentiation assays, Western blot for p38 MAPK and β-catenin","journal":"Stem cells international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway activation measured by expression/Western blot without specific Wnt6 loss-of-function, single lab","pmids":["37621747"],"is_preprint":false}],"current_model":"WNT6 is a secreted glycoprotein that activates both canonical (β-catenin-dependent, via receptors including FZD4 and FZD7) and non-canonical (JNK, Rac1/Cdc42-PCP) Wnt signaling pathways depending on cellular context; it regulates mesenchymal stem cell fate (inhibiting adipogenesis and promoting osteoblastogenesis via β-catenin), drives kidney tubulogenesis and endoderm specification (acting upstream of Wnt4), controls epithelialization and EMT in multiple tissues, maintains stem cell niches (uterine decidualization, Drosophila germline niche via escort cell survival), promotes macrophage proliferation and M2 polarization through ERK/c-Myc (β-catenin-independent), drives triacylglycerol accumulation in macrophages via ACC2 to support Mycobacterium tuberculosis survival, and is transcriptionally regulated by GATA6, FOXA2, PLAGL2, and Cav1/β-catenin at its promoter."},"narrative":{"mechanistic_narrative":"WNT6 is a secreted Wnt-family glycoprotein that acts as a context-dependent morphogen, activating canonical (β-catenin-dependent) signaling in most settings while engaging non-canonical pathways in others to govern cell fate, tissue patterning, and stem cell behavior [PMID:11350055, PMID:18160257, PMID:17685490]. Through the canonical route, WNT6 binds FZD-family receptors (FZD7 in renal epithelium, FZD4 in diabetic centrosome amplification), inhibits GSK3β, drives nuclear accumulation of β-catenin, and elevates TCF/LEF-dependent transcription [PMID:27122540, PMID:31618077]. This canonical axis underlies its developmental and regenerative roles: it specifies and epithelializes primitive endoderm via a β-catenin–Snail1 cascade [PMID:18160257], induces kidney tubulogenesis and acts upstream of Wnt4 [PMID:11948913], specifies endoderm in the sea urchin endomesoderm network [PMID:21750039], and directs mesenchymal stem cell fate by inhibiting adipogenesis and promoting osteoblastogenesis [PMID:21872687, PMID:31865202]. In branched, β-catenin-independent modes, WNT6 signals through JNK to promote migration and odontogenic differentiation of dental cells [PMID:24935540], and in M. tuberculosis-infected macrophages drives proliferation through a pertussis toxin-sensitive, ERK–c-Myc axis while promoting M2 polarization and ACC2-dependent triacylglycerol accumulation that supports bacterial survival [PMID:24123681, PMID:34255743]. WNT6 is itself a transcriptional output of GATA6 and FOXA2 during endoderm formation, and of PLAGL2 and Cav1/β-catenin in cancer, where it promotes proliferation and chemoresistance [PMID:22607194, PMID:22370641, PMID:30535429]. It also maintains stem cell niches, supporting uterine decidual stromal proliferation and Drosophila germline niche integrity [PMID:23175771, PMID:29361569], and its signaling is shaped by extracellular modulators including Sfrp2 and the heparan sulfate sulfatase Sulf1A [PMID:26071893, PMID:23772371].","teleology":[{"year":2001,"claim":"Established WNT6 as a secreted Wnt-family glycoprotein with the structural hallmarks of a canonical Wnt ligand and a genomic context implicating WNT-β-catenin-TCF signaling.","evidence":"Molecular cloning, sequence characterization, and Northern blot expression in colorectal cancer cells","pmids":["11350055"],"confidence":"Medium","gaps":["No functional pathway assay in this study","Receptor and downstream effectors not identified"]},{"year":2002,"claim":"Placed Wnt6 in the developmental signaling hierarchy of kidney induction, showing it can substitute for Wnt4 and activate canonical signaling.","evidence":"In vitro kidney induction with Wnt6-expressing cells, rescue of Wnt4-mutant mesenchyme, Xenopus secondary axis assay","pmids":["11948913"],"confidence":"High","gaps":["Receptor identity not determined","Direct vs. indirect activation of Wnt4 not resolved"]},{"year":2007,"claim":"Defined the canonical mechanism for endoderm specification — β-catenin/Snail1 nuclear translocation and epithelialization — while revealing that in chick neural crest Wnt6 acts through a non-canonical, β-catenin-independent route.","evidence":"Wnt6 conditioned medium and GSK3 inhibition in F9 cells; gain/loss-of-function in chick embryos with pathway determination","pmids":["18160257","17685490"],"confidence":"High","gaps":["Molecular basis of canonical vs. non-canonical pathway choice not defined","Receptor usage in each context unknown"]},{"year":2008,"claim":"Demonstrated that Wnt6/β-catenin restricts cardiomyogenesis by repressing cardiogenic transcription factors during organogenesis.","evidence":"Reciprocal morpholino knockdown and mRNA gain-of-function with GATA rescue in Xenopus","pmids":["18804460"],"confidence":"High","gaps":["Direct transcriptional targets of β-catenin in the heart field not mapped"]},{"year":2009,"claim":"Showed that canonical Wnt6-β-catenin signaling cooperates with a parallel Gα13-RhoA arm to coordinate gene expression and cytoarchitecture in endoderm differentiation.","evidence":"Constitutively active/dominant-negative constructs, ROCK inhibitor, β-catenin nuclear localization in F9 cells","pmids":["19767821"],"confidence":"Medium","gaps":["Direct physical coupling between the two arms not established","Single cell-line system"]},{"year":2011,"claim":"Identified Wnt6 as the most potent endogenous β-catenin-dependent regulator of mesenchymal stem cell fate among related Wnts, and established its conserved canonical role in endoderm specification across deuterostomes.","evidence":"Reciprocal gain/loss-of-function with β-catenin epistasis in MSC lines; morpholino knockdown and canonical-component rescue in two sea urchin species","pmids":["21872687","21750039"],"confidence":"High","gaps":["Receptor mediating MSC effects not identified","Downstream osteogenic/adipogenic targets not fully mapped"]},{"year":2012,"claim":"Identified upstream transcriptional regulators (GATA6, FOXA2) and an oncogenic regulatory loop (Cav1/β-catenin), defining how Wnt6 expression is controlled and linking it to chemoresistance.","evidence":"ChIP, promoter reporter assays, and overexpression in F9 cells; promoter ChIP and reciprocal knockdown/overexpression with drug-induced death assays in gastric cancer; Sulf1A neutralization in muscle satellite cells","pmids":["22607194","22370641","23772371"],"confidence":"High","gaps":["Combinatorial regulation of the promoter not dissected","Sulf1A modulation mechanism (receptor vs. ligand level) not resolved"]},{"year":2013,"claim":"Established a β-catenin-independent macrophage function — ERK/c-Myc-driven proliferation and M2 polarization — distinct from Wnt6's canonical developmental roles, and a genetic requirement in uterine decidualization.","evidence":"Wnt6-deficient macrophages, pertussis toxin and ERK analysis, proliferation and cytokine assays; Wnt6-mutant mice with cell-cycle and cyclin B1 readout","pmids":["24123681","23175771"],"confidence":"High","gaps":["Receptor coupling to the pertussis-sensitive pathway not identified","How Wnt6 controls cyclin B1 mechanistically not defined"]},{"year":2014,"claim":"Confirmed direct activation of the JNK non-canonical pathway by WNT6, driving migration and odontogenic differentiation.","evidence":"WNT6 conditioned medium, JNK inhibitor SP600125, Western blot and functional migration/mineralization assays in dental pulp cells","pmids":["24935540"],"confidence":"Medium","gaps":["Incomplete inhibition by SP600125 implies parallel pathways not identified","Receptor not defined"]},{"year":2015,"claim":"Demonstrated that the extracellular modulator Sfrp2 binds Wnt6 to switch signaling output from canonical (proliferation) toward non-canonical PCP/JNK (differentiation) in cardiac progenitors.","evidence":"Sfrp2-Wnt6 binding assay, pathway reporters, JNK analysis, and cardiac differentiation assays","pmids":["26071893"],"confidence":"Medium","gaps":["Structural basis of Sfrp2-Wnt6 binding not resolved","Single lab"]},{"year":2016,"claim":"Identified FZD7 as a WNT6 receptor in renal epithelium and showed WNT6 antagonizes TGF-β-driven dedifferentiation and NF-κB activation, defining a canonical pro-epithelial axis.","evidence":"Wnt6 overexpression, GSK3β phosphorylation, β-catenin/TCF reporter, 3D tubulogenesis, and TGF-β rescue in renal epithelial cells","pmids":["27122540"],"confidence":"High","gaps":["Whether FZD7 is the receptor in other canonical contexts not tested"]},{"year":2018,"claim":"Extended Wnt6 stem-cell-niche function to the Drosophila germline and identified PLAGL2 as a tumor-promoting transcriptional activator of Wnt6 in colorectal cancer.","evidence":"Drosophila genetic loss-of-function with lineage and BMP reporter analysis; ChIP, reporter assay, knockdown, and xenograft in colorectal cancer cells","pmids":["29361569","30535429"],"confidence":"High","gaps":["Receptor in escort-cell niche signaling not defined","PLAGL2-Wnt6 axis not validated in primary patient tumors"]},{"year":2019,"claim":"Identified FZD4 as a second WNT6 receptor driving a β-catenin-ROCK1-14-3-3σ axis in centrosome amplification, and showed Wnt6 suppression promotes adipogenesis upstream of PPARγ.","evidence":"siRNA and neutralizing antibodies against Wnt6/FZD4, centrosome counting; RNA-seq and adipogenic assays with HBCD-induced Wnt6 suppression","pmids":["31618077","31865202"],"confidence":"Medium","gaps":["Context determining FZD4 vs FZD7 usage unknown","Single lab for each finding"]},{"year":2020,"claim":"Provided in vivo evidence that Wnt6 can restore GSK-3β/β-catenin signaling and neurotrophic gene transcription in a Rett syndrome model.","evidence":"Lentiviral Wnt6 delivery to amygdala, behavioral assays, Western blot, and BDNF/IGF-1 promoter reporters","pmids":["31974426"],"confidence":"Medium","gaps":["Direct vs. indirect link between Wnt6 and MeCP2 SUMOylation not established","Single model and lab"]},{"year":2021,"claim":"Defined a metabolic effector role in tuberculosis — WNT6 induces ACC2 to drive triacylglycerol foam-cell formation supporting Mtb survival — and elaborated non-canonical (Rac1/Cdc42) niche control in Drosophila and a BMP4-cooperative role in endothelial differentiation.","evidence":"Wnt6-deficient macrophages, ACC2 inhibition, TAG/Mtb survival assays in vitro and in mice; Drosophila genetics with S2 cell pathway analysis; siRNA knockdown and recombinant WNT6 rescue in ES/PA6 co-culture","pmids":["34255743","33582096","34478025"],"confidence":"High","gaps":["Receptor coupling ACC2 induction not identified","Mechanism linking Rac1/Cdc42 downregulation to niche homeostasis incomplete"]},{"year":2022,"claim":"Confirmed canonical β-catenin-dependent mineralization in dental papilla cells and implicated WNT6 in ovarian cancer proliferation via both β-catenin and Notch1.","evidence":"Overexpression/knockdown, TOPflash reporter, XAV939 inhibition, and in vivo transplantation in dental cells; siWNT6 knockdown with proliferation/apoptosis assays in ovarian cancer cells","pmids":["35691114","36075327"],"confidence":"Medium","gaps":["Mechanism linking WNT6 to Notch1 not established (single knockdown, no epistasis)","Direct vs indirect Notch1 regulation unresolved"]},{"year":null,"claim":"How WNT6 selects between canonical and non-canonical signaling outputs — through receptor/co-receptor combinations, extracellular modulators, and cell context — remains the central unresolved question.","evidence":"No single study reconciles the divergent FZD4/FZD7 canonical and JNK/Rac1/Cdc42/ERK non-canonical outputs across tissues","pmids":[],"confidence":"Medium","gaps":["No structural model of WNT6-receptor complexes","Determinants of pathway choice not defined","Full FZD receptor repertoire not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[14,17,2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[14,10,12]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,14,6,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,4,7,2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[20,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,20]}],"complexes":[],"partners":["FZD7","FZD4","SFRP2","SULF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6F9","full_name":"Protein Wnt-6","aliases":[],"length_aa":365,"mass_kda":39.7,"function":"Ligand for members of the frizzled family of seven transmembrane receptors. Probable developmental protein. May be a signaling molecule which affects the development of discrete regions of tissues. Is likely to signal over only few cell diameters. 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loss","date":"2024-09-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.13.612932","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36168,"output_tokens":7258,"usd":0.108687,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16629,"output_tokens":5169,"usd":0.106185,"stage2_stop_reason":"end_turn"},"total_usd":0.214872,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Human WNT6 encodes a 365-amino-acid secreted glycoprotein with an N-terminal signal peptide, WNT core domain, and RGD motif; WNT6 and WNT10A genes are clustered head-to-tail with <7 kb interval on chromosome 2q35, co-expressed in SW480 colorectal cancer cells, suggesting activation of WNT-β-catenin-TCF signaling.\",\n      \"method\": \"Molecular cloning, sequence characterization, Northern blot expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular cloning with sequence characterization and expression analysis, single lab, multiple methods\",\n      \"pmids\": [\"11350055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Wnt-6 expressed in the ureter bud induces kidney tubulogenesis in vitro; Wnt-6-expressing cells rescue tubulogenesis in Wnt-4 mutant embryo mesenchyme and activate Wnt-4 transcription, Pax2, Pax8, Sfrp2, and E-cadherin. Wnt-6 also induces a secondary axis in Xenopus embryos, consistent with canonical signaling.\",\n      \"method\": \"In vitro kidney induction assay with Wnt-6-expressing cell lines, rescue of Wnt-4 mutant mesenchyme, Xenopus secondary axis assay\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple functional assays (in vitro induction, genetic rescue of mutant, Xenopus axis assay) establishing pathway position\",\n      \"pmids\": [\"11948913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Wnt6 induces specification and epithelialization of F9 embryonal carcinoma cells to primitive endoderm via a canonical Wnt-β-catenin-Snail1 signaling cascade: β-catenin and Snail1 translocate to the nucleus, cytokeratin intermediate filaments appear, and GSK3 inhibition phenocopies Wnt6. PKA activation subsequently drives parietal endoderm EMT.\",\n      \"method\": \"Wnt6 conditioned medium treatment of F9 cells, LiCl (GSK3 inhibitor) treatment, immunofluorescence for β-catenin/Snail1 nuclear translocation, marker analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditioned medium + genetic/pharmacological epistasis + multiple orthogonal readouts in a single study\",\n      \"pmids\": [\"18160257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In chick embryos, ectodermal Wnt6 is necessary for neural crest induction and acts through the non-canonical (not β-catenin-dependent) pathway; canonical Wnt signaling instead inhibited neural crest production in chick, indicating a mechanistic divergence between amniotes and anamniotes.\",\n      \"method\": \"Gain- and loss-of-function (ectopic expression, inhibition) in chick embryos; assessment of canonical vs. non-canonical Wnt pathway activity\",\n      \"journal\": \"Developmental dynamics : an official publication of the American Association of Anatomists\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain/loss-of-function with pathway determination, single lab\",\n      \"pmids\": [\"17685490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Xenopus Wnt6 is required during organogenesis (not gastrulation) to restrict heart muscle development: loss-of-function causes abnormally large myocardium; gain-of-function of Wnt6 or activated β-catenin restricts cardiomyogenesis by repressing cardiogenic transcription factors (e.g., GATA), upstream of downstream cardiomyogenic differentiation genes.\",\n      \"method\": \"Loss-of-function (morpholino knockdown) and gain-of-function (mRNA injection) in Xenopus; rescue by GATA reinstatement; expression analysis of cardiogenic markers\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function with epistasis rescue in Xenopus, multiple orthogonal methods\",\n      \"pmids\": [\"18804460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Coordinate Gα13-RhoA and Wnt6-β-catenin signaling is required for primitive endoderm differentiation in F9 cells: constitutively active Gα13(Q226L) or p115RhoGEF (but not RhoA(L63)) caused β-catenin nuclear translocation; canonical Wnt-β-catenin activation drives gene expression changes required for primitive endoderm, while Gα13 signaling to ERM proteins mediates cytoarchitectural changes.\",\n      \"method\": \"Transfection of constitutively active and dominant-negative constructs, ROCK inhibitor Y-27632, β-catenin nuclear localization assay, differentiation marker analysis\",\n      \"journal\": \"Biochemistry and cell biology = Biochimie et biologie cellulaire\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic tools + pathway inhibition, single lab\",\n      \"pmids\": [\"19767821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Wnt6 (along with Wnt10a and Wnt10b) inhibits adipogenesis and stimulates osteoblastogenesis in mesenchymal stem cells through a β-catenin-dependent mechanism: β-catenin knockdown completely prevents these effects; among the three Wnts, endogenous Wnt6 knockdown produces the greatest increase in adipogenesis and impairment of osteoblastogenesis, identifying it as the most potent endogenous regulator of MSC fate among this group.\",\n      \"method\": \"Gain- and loss-of-function in ST2 cells and 3T3-L1 preadipocytes; β-catenin knockdown epistasis; differentiation assays\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function + β-catenin epistasis + multiple cell models, replicated across cell lines\",\n      \"pmids\": [\"21872687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In sea urchin, maternal Wnt6 is necessary and sufficient (combined with a localized vegetal cortex Dishevelled (Dsh) signal) for endoderm specification in the endomesoderm GRN: knockdown of Wnt6 causes loss of endoderm (but not mesoderm markers); adding Wnt6 to cortex-depleted eggs rescues endoderm; ectopic activation of β-catenin, dominant-negative GSK-3β, or Dsh also rescues, confirming canonical pathway involvement.\",\n      \"method\": \"Wnt6 morpholino knockdown, vegetal cortex ablation + Wnt6 rescue, ectopic activation of canonical Wnt components, two sea urchin species validation\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal loss-of-function and rescue experiments, replicated in two species\",\n      \"pmids\": [\"21750039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GATA6 and FOXA2 transcription factors directly regulate Wnt6 gene expression during extraembryonic endoderm formation: both bind the Wnt6 promoter (ChIP), overexpression of either is sufficient to induce Wnt6 expression and TCF-dependent transcription (primitive endoderm markers), and both transactivate a Wnt6 reporter construct.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), overexpression studies, Wnt6 promoter reporter assay, qPCR in F9 cells\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP + reporter assay + overexpression, multiple orthogonal methods in single study\",\n      \"pmids\": [\"22607194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"WNT6 expression in gastric cancer cells is transcriptionally enhanced by caveolin-1 (Cav1) via β-catenin binding to the proximal WNT6 promoter (demonstrated by epirubicin treatment increasing WNT6 promoter activity); WNT6 promotes resistance to epirubicin/doxorubicin-induced apoptosis as shown by knockdown and overexpression experiments.\",\n      \"method\": \"Promoter activity assay, β-catenin ChIP on WNT6 promoter, WNT6 knockdown/overexpression, cell death assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — promoter ChIP + reporter assay + reciprocal knockdown/overexpression + multiple drug conditions\",\n      \"pmids\": [\"22370641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Wnt6 in M. tuberculosis-infected macrophages induces proliferation via a pertussis toxin-sensitive, ERK-mediated, β-catenin-independent induction of c-Myc; Wnt6 also drives macrophage polarization toward M2-like phenotype (induction of Arginase-1, downregulation of TNF-α) via TLR-MyD88-NF-κB-dependent induction mechanism in bone marrow-derived macrophages.\",\n      \"method\": \"Wnt6 conditioned medium, Wnt6-deficient macrophages, pertussis toxin inhibition, ERK pathway analysis, Ki-67/thymidine incorporation proliferation assay, cytokine measurement\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological inhibition + Wnt6-deficient cells + multiple orthogonal readouts establishing non-canonical mechanism\",\n      \"pmids\": [\"24123681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Wnt6 is essential for stromal cell proliferation during uterine decidualization in mice: Wnt6-deficient mice show impaired stromal cell proliferation but normal decidual polyploidization; loss of Wnt6 prolongs cell cycle length by downregulating cyclin B1 expression.\",\n      \"method\": \"Wnt6-mutant mice, primary stromal cell culture, cell cycle analysis, cyclin B1 expression measurement\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined cellular phenotype + mechanistic readout (cyclin B1) + primary cell model\",\n      \"pmids\": [\"23175771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"WNT6 activates the JNK (c-Jun N-terminal kinase) non-canonical pathway in human dental pulp cells, promoting cell migration and differentiation (mineralization, odontogenic gene expression); JNK pathway inhibition (SP600125) reduces but does not completely abolish WNT6-induced migration and differentiation.\",\n      \"method\": \"WNT6 conditioned medium, JNK inhibitor SP600125, Western blot for JNK activation, RT-PCR for c-Jun, wound healing/transwell migration assays, ALP and alizarin red staining\",\n      \"journal\": \"Journal of endodontics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway inhibition + multiple functional readouts, single lab\",\n      \"pmids\": [\"24935540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sfrp2 binds Wnt6 and inhibits the Wnt6 canonical signaling pathway in cardiac progenitor cells (CPCs), suppressing CPC proliferation; this inhibition of canonical Wnt6 signaling by Sfrp2 activates the non-canonical Wnt/Planar Cell Polarity (PCP) pathway through JNK, inducing cardiac transcription factor expression and CPC differentiation.\",\n      \"method\": \"Sfrp2-Wnt6 binding assay, CPC treatment with Sfrp2, canonical/non-canonical pathway reporters, JNK pathway analysis, cardiac differentiation assays\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay + pathway reporter + functional differentiation readout, single lab\",\n      \"pmids\": [\"26071893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wnt6 signals through the canonical pathway in renal epithelial cells via FZD7 receptor: Wnt6 increases phosphorylation of GSK3β (Ser9), causes nuclear accumulation of β-catenin, increases TCF/Lef transcriptional activity, induces de novo tubulogenesis in 3D culture, and rescues epithelial dedifferentiation induced by TGF-β. Wnt6 also inhibits TGF-β-mediated p65-NF-κB nuclear translocation.\",\n      \"method\": \"Wnt6 overexpression in renal epithelial cells, GSK3β phosphorylation assay, β-catenin nuclear localization, TCF/Lef reporter assay, 3D tubulogenesis culture, TGF-β rescue experiments, p65 NF-κB translocation assay\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal canonical pathway readouts + receptor identification + functional rescue in a single study\",\n      \"pmids\": [\"27122540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Drosophila ovaries, Wnt6 ligand produced by cap cells is required to maintain anterior escort cells as a niche component: without Wnt6 signaling, anterior escort cells die, leading to loss of germline stem cells. Anterior escort cells promote DE-cadherin anchorage and transiently express the Dpp/BMP ligand to maintain full-strength BMP signaling in germline stem cells.\",\n      \"method\": \"Drosophila genetic manipulation (Wnt6 loss-of-function, hid-induced escort cell death), lineage analysis, in vivo imaging, BMP reporter assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic loss-of-function with defined cellular phenotype + mechanistic pathway placement, rigorous model system\",\n      \"pmids\": [\"29361569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PLAGL2 transcriptionally activates Wnt6 in colorectal cancer cells by directly binding to the Wnt6 promoter region, thereby activating the Wnt/β-catenin pathway and promoting colorectal cancer proliferation.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, PLAGL2 knockdown in HCT116/SW480 cells, xenograft model\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + reporter assay establishing direct transcriptional regulation, single lab\",\n      \"pmids\": [\"30535429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Secreted Wnt6 binds to FZD4 receptor to activate canonical β-catenin signaling, which is upstream of ROCK1 and 14-3-3σ, mediating diabetes-associated (high glucose/AGE-induced) centrosome amplification; siRNA against Wnt6 or FZD4, and antibodies against Wnt6 or FZD4, all attenuate centrosome amplification.\",\n      \"method\": \"siRNA knockdown of Wnt6/FZD4/β-catenin, neutralizing antibodies against Wnt6/FZD4, β-catenin nuclear translocation assay, centrosome counting\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic/antibody tools identifying receptor and downstream pathway, single lab\",\n      \"pmids\": [\"31618077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBCD (hexabromocyclododecane) promotes adipogenesis by specifically inhibiting Wnt6 gene expression and suppressing the Wnt/β-catenin pathway at an early stage of adipogenesis (upstream of PPARγ induction), without affecting mitotic clonal expansion or C/EBPβ.\",\n      \"method\": \"RNA sequencing, Wnt6 expression measurement, adipogenic differentiation assays in 3T3-L1 and HPA-V cells, in vivo mouse model\",\n      \"journal\": \"The Science of the total environment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA-seq plus in vitro/in vivo validation of Wnt6 suppression, functional adipogenesis assay, single lab\",\n      \"pmids\": [\"31865202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wnt6 delivery to the amygdala of MeCP2 T158A (Rett syndrome model) mice ameliorates locomotor and social behavioral deficits; Wnt6 restores GSK-3β phosphorylation, β-catenin phosphorylation levels, and MeCP2 SUMOylation. Wnt6 increases BDNF and IGF-1 promoter activity in a dose-dependent manner.\",\n      \"method\": \"Lentiviral Wnt6 delivery to amygdala, behavioral assays, Western blot for GSK-3β/β-catenin/MeCP2 SUMOylation, BDNF/IGF-1 promoter reporter assay in HEK293T cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene delivery + multiple molecular readouts + promoter assay, single lab\",\n      \"pmids\": [\"31974426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WNT6 promotes foam cell formation in M. tuberculosis-infected macrophages by upregulating acetyl-CoA carboxylase 2 (ACC2), a key lipid metabolic gene, leading to increased intracellular triacylglycerol (TAG) storage that supports Mtb survival; genetic or pharmacological loss of WNT6 or ACC2 reduces TAG levels and Mtb survival in macrophages.\",\n      \"method\": \"Wnt6-deficient macrophages, ACC2 pharmacological inhibition, TAG measurement, Mtb intracellular survival assay, ACC2 inhibitor + isoniazid combination in infected mice\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological loss-of-function, in vitro and in vivo validation, defined molecular target (ACC2)\",\n      \"pmids\": [\"34255743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Drosophila testis, Wnt6 is required for GSC differentiation and cyst stem cell (CySC) self-renewal; mechanistically, Wnt6 downregulates Arm (β-catenin), Rac1, and Cdc42 in S2 cells, and Rac1/Cdc42 act downstream of the non-canonical Wnt pathway to regulate stem cell niche homeostasis.\",\n      \"method\": \"Drosophila genetic manipulation, S2 cell knockdown/overexpression, Western blot for Arm/Rac1/Cdc42, phenotypic analysis of testis niche\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetics + cell-based pathway analysis, single lab\",\n      \"pmids\": [\"33582096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WNT6 promotes BMP4-driven endothelial differentiation of murine embryonic stem cells: silencing WNT6 in PA6/ES co-cultures partially impairs endothelial differentiation upon BMP4 stimulation, and this dysfunction is recovered by adding recombinant WNT6.\",\n      \"method\": \"Microarray gene expression, siRNA knockdown, recombinant WNT6 rescue, ES/PA6 co-culture endothelial differentiation assay\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function + rescue experiment, defined functional readout, single lab\",\n      \"pmids\": [\"34478025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WNT6 activates β-catenin signaling in human dental papilla cells via canonical pathway (β-catenin nuclear accumulation, LEF1 upregulation, enhanced TCF/β-catenin transcriptional activity); Wnt6-induced mineralization in vivo is blocked by the Wnt/β-catenin inhibitor XAV939, confirming pathway dependence.\",\n      \"method\": \"Wnt6 overexpression + knockdown, immunofluorescence for β-catenin, TOPflash/FOPflash reporter assay, ALP staining, Alizarin Red staining, subcutaneous transplantation, XAV939 inhibitor treatment\",\n      \"journal\": \"Archives of oral biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay + pharmacological inhibition + in vivo transplantation, single lab\",\n      \"pmids\": [\"35691114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WNT6 knockdown in ovarian cancer cells inhibits proliferation, lamellipodia formation, causes cell cycle arrest, and promotes apoptosis; mechanistically, WNT6 knockdown reduces both β-catenin and Notch1 protein expression, implicating WNT6 in activation of both canonical Wnt and Notch1 pathways.\",\n      \"method\": \"siWNT6 knockdown in CAOV3/OVCAR3 cells, proliferation assay, cell cycle/apoptosis analysis, Western blot for β-catenin and Notch1\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown approach with downstream protein readout, single lab, no epistasis validation\",\n      \"pmids\": [\"36075327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sulf1A (a heparan sulfate 6-O-endosulfatase) is required for Wnt6-induced cellular hyper-elongation and inhibition of satellite cell proliferation in skeletal muscle myoblasts; neutralizing Sulf1A antibodies abolish both Wnt6-induced morphological and antiproliferative effects, indicating Sulf1A modulates Wnt6 signaling in muscle.\",\n      \"method\": \"Exogenous Wnt6 treatment of satellite cells on isolated fibers, Sulf1A neutralizing antibody treatment, morphological and proliferation assessment\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — antibody neutralization of co-factor with functional readout, multiple readouts, single lab\",\n      \"pmids\": [\"23772371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Wnt6 knockout flies are viable with normal wing size and planar cell polarity, but specifically lack maxillary palps; Wnt6 is absent from hemipteran genomes that also lack maxillary palps, suggesting a conserved developmental requirement.\",\n      \"method\": \"Wnt6 knockout fly generation (CRISPR/genetic), phenotypic analysis of wing size, planar cell polarity, and maxillary palp\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined specific developmental phenotype, single lab\",\n      \"pmids\": [\"24090348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CGRP (calcitonin gene-related peptide) regulates osteogenic differentiation of bone marrow mesenchymal stem cells through both p38 MAPK and Wnt6/β-catenin signaling pathways, as validated in vitro by demonstrating upregulation of Wnt6 expression and downstream β-catenin pathway activation upon CGRP stimulation.\",\n      \"method\": \"In vitro CGRP stimulation of rat BMMSCs, RNA sequencing of innervated vs. non-innervated bone grafts, osteogenic differentiation assays, Western blot for p38 MAPK and β-catenin\",\n      \"journal\": \"Stem cells international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway activation measured by expression/Western blot without specific Wnt6 loss-of-function, single lab\",\n      \"pmids\": [\"37621747\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WNT6 is a secreted glycoprotein that activates both canonical (β-catenin-dependent, via receptors including FZD4 and FZD7) and non-canonical (JNK, Rac1/Cdc42-PCP) Wnt signaling pathways depending on cellular context; it regulates mesenchymal stem cell fate (inhibiting adipogenesis and promoting osteoblastogenesis via β-catenin), drives kidney tubulogenesis and endoderm specification (acting upstream of Wnt4), controls epithelialization and EMT in multiple tissues, maintains stem cell niches (uterine decidualization, Drosophila germline niche via escort cell survival), promotes macrophage proliferation and M2 polarization through ERK/c-Myc (β-catenin-independent), drives triacylglycerol accumulation in macrophages via ACC2 to support Mycobacterium tuberculosis survival, and is transcriptionally regulated by GATA6, FOXA2, PLAGL2, and Cav1/β-catenin at its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WNT6 is a secreted Wnt-family glycoprotein that acts as a context-dependent morphogen, activating canonical (β-catenin-dependent) signaling in most settings while engaging non-canonical pathways in others to govern cell fate, tissue patterning, and stem cell behavior [#0, #2, #3]. Through the canonical route, WNT6 binds FZD-family receptors (FZD7 in renal epithelium, FZD4 in diabetic centrosome amplification), inhibits GSK3β, drives nuclear accumulation of β-catenin, and elevates TCF/LEF-dependent transcription [#14, #17]. This canonical axis underlies its developmental and regenerative roles: it specifies and epithelializes primitive endoderm via a β-catenin–Snail1 cascade [#2], induces kidney tubulogenesis and acts upstream of Wnt4 [#1], specifies endoderm in the sea urchin endomesoderm network [#7], and directs mesenchymal stem cell fate by inhibiting adipogenesis and promoting osteoblastogenesis [#6, #18]. In branched, β-catenin-independent modes, WNT6 signals through JNK to promote migration and odontogenic differentiation of dental cells [#12], and in M. tuberculosis-infected macrophages drives proliferation through a pertussis toxin-sensitive, ERK–c-Myc axis while promoting M2 polarization and ACC2-dependent triacylglycerol accumulation that supports bacterial survival [#10, #20]. WNT6 is itself a transcriptional output of GATA6 and FOXA2 during endoderm formation, and of PLAGL2 and Cav1/β-catenin in cancer, where it promotes proliferation and chemoresistance [#8, #9, #16]. It also maintains stem cell niches, supporting uterine decidual stromal proliferation and Drosophila germline niche integrity [#11, #15], and its signaling is shaped by extracellular modulators including Sfrp2 and the heparan sulfate sulfatase Sulf1A [#13, #25].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established WNT6 as a secreted Wnt-family glycoprotein with the structural hallmarks of a canonical Wnt ligand and a genomic context implicating WNT-β-catenin-TCF signaling.\",\n      \"evidence\": \"Molecular cloning, sequence characterization, and Northern blot expression in colorectal cancer cells\",\n      \"pmids\": [\"11350055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional pathway assay in this study\", \"Receptor and downstream effectors not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed Wnt6 in the developmental signaling hierarchy of kidney induction, showing it can substitute for Wnt4 and activate canonical signaling.\",\n      \"evidence\": \"In vitro kidney induction with Wnt6-expressing cells, rescue of Wnt4-mutant mesenchyme, Xenopus secondary axis assay\",\n      \"pmids\": [\"11948913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity not determined\", \"Direct vs. indirect activation of Wnt4 not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the canonical mechanism for endoderm specification — β-catenin/Snail1 nuclear translocation and epithelialization — while revealing that in chick neural crest Wnt6 acts through a non-canonical, β-catenin-independent route.\",\n      \"evidence\": \"Wnt6 conditioned medium and GSK3 inhibition in F9 cells; gain/loss-of-function in chick embryos with pathway determination\",\n      \"pmids\": [\"18160257\", \"17685490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of canonical vs. non-canonical pathway choice not defined\", \"Receptor usage in each context unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that Wnt6/β-catenin restricts cardiomyogenesis by repressing cardiogenic transcription factors during organogenesis.\",\n      \"evidence\": \"Reciprocal morpholino knockdown and mRNA gain-of-function with GATA rescue in Xenopus\",\n      \"pmids\": [\"18804460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of β-catenin in the heart field not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that canonical Wnt6-β-catenin signaling cooperates with a parallel Gα13-RhoA arm to coordinate gene expression and cytoarchitecture in endoderm differentiation.\",\n      \"evidence\": \"Constitutively active/dominant-negative constructs, ROCK inhibitor, β-catenin nuclear localization in F9 cells\",\n      \"pmids\": [\"19767821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical coupling between the two arms not established\", \"Single cell-line system\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified Wnt6 as the most potent endogenous β-catenin-dependent regulator of mesenchymal stem cell fate among related Wnts, and established its conserved canonical role in endoderm specification across deuterostomes.\",\n      \"evidence\": \"Reciprocal gain/loss-of-function with β-catenin epistasis in MSC lines; morpholino knockdown and canonical-component rescue in two sea urchin species\",\n      \"pmids\": [\"21872687\", \"21750039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating MSC effects not identified\", \"Downstream osteogenic/adipogenic targets not fully mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified upstream transcriptional regulators (GATA6, FOXA2) and an oncogenic regulatory loop (Cav1/β-catenin), defining how Wnt6 expression is controlled and linking it to chemoresistance.\",\n      \"evidence\": \"ChIP, promoter reporter assays, and overexpression in F9 cells; promoter ChIP and reciprocal knockdown/overexpression with drug-induced death assays in gastric cancer; Sulf1A neutralization in muscle satellite cells\",\n      \"pmids\": [\"22607194\", \"22370641\", \"23772371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial regulation of the promoter not dissected\", \"Sulf1A modulation mechanism (receptor vs. ligand level) not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a β-catenin-independent macrophage function — ERK/c-Myc-driven proliferation and M2 polarization — distinct from Wnt6's canonical developmental roles, and a genetic requirement in uterine decidualization.\",\n      \"evidence\": \"Wnt6-deficient macrophages, pertussis toxin and ERK analysis, proliferation and cytokine assays; Wnt6-mutant mice with cell-cycle and cyclin B1 readout\",\n      \"pmids\": [\"24123681\", \"23175771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor coupling to the pertussis-sensitive pathway not identified\", \"How Wnt6 controls cyclin B1 mechanistically not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed direct activation of the JNK non-canonical pathway by WNT6, driving migration and odontogenic differentiation.\",\n      \"evidence\": \"WNT6 conditioned medium, JNK inhibitor SP600125, Western blot and functional migration/mineralization assays in dental pulp cells\",\n      \"pmids\": [\"24935540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Incomplete inhibition by SP600125 implies parallel pathways not identified\", \"Receptor not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that the extracellular modulator Sfrp2 binds Wnt6 to switch signaling output from canonical (proliferation) toward non-canonical PCP/JNK (differentiation) in cardiac progenitors.\",\n      \"evidence\": \"Sfrp2-Wnt6 binding assay, pathway reporters, JNK analysis, and cardiac differentiation assays\",\n      \"pmids\": [\"26071893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of Sfrp2-Wnt6 binding not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified FZD7 as a WNT6 receptor in renal epithelium and showed WNT6 antagonizes TGF-β-driven dedifferentiation and NF-κB activation, defining a canonical pro-epithelial axis.\",\n      \"evidence\": \"Wnt6 overexpression, GSK3β phosphorylation, β-catenin/TCF reporter, 3D tubulogenesis, and TGF-β rescue in renal epithelial cells\",\n      \"pmids\": [\"27122540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FZD7 is the receptor in other canonical contexts not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended Wnt6 stem-cell-niche function to the Drosophila germline and identified PLAGL2 as a tumor-promoting transcriptional activator of Wnt6 in colorectal cancer.\",\n      \"evidence\": \"Drosophila genetic loss-of-function with lineage and BMP reporter analysis; ChIP, reporter assay, knockdown, and xenograft in colorectal cancer cells\",\n      \"pmids\": [\"29361569\", \"30535429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor in escort-cell niche signaling not defined\", \"PLAGL2-Wnt6 axis not validated in primary patient tumors\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified FZD4 as a second WNT6 receptor driving a β-catenin-ROCK1-14-3-3σ axis in centrosome amplification, and showed Wnt6 suppression promotes adipogenesis upstream of PPARγ.\",\n      \"evidence\": \"siRNA and neutralizing antibodies against Wnt6/FZD4, centrosome counting; RNA-seq and adipogenic assays with HBCD-induced Wnt6 suppression\",\n      \"pmids\": [\"31618077\", \"31865202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context determining FZD4 vs FZD7 usage unknown\", \"Single lab for each finding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided in vivo evidence that Wnt6 can restore GSK-3β/β-catenin signaling and neurotrophic gene transcription in a Rett syndrome model.\",\n      \"evidence\": \"Lentiviral Wnt6 delivery to amygdala, behavioral assays, Western blot, and BDNF/IGF-1 promoter reporters\",\n      \"pmids\": [\"31974426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect link between Wnt6 and MeCP2 SUMOylation not established\", \"Single model and lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a metabolic effector role in tuberculosis — WNT6 induces ACC2 to drive triacylglycerol foam-cell formation supporting Mtb survival — and elaborated non-canonical (Rac1/Cdc42) niche control in Drosophila and a BMP4-cooperative role in endothelial differentiation.\",\n      \"evidence\": \"Wnt6-deficient macrophages, ACC2 inhibition, TAG/Mtb survival assays in vitro and in mice; Drosophila genetics with S2 cell pathway analysis; siRNA knockdown and recombinant WNT6 rescue in ES/PA6 co-culture\",\n      \"pmids\": [\"34255743\", \"33582096\", \"34478025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor coupling ACC2 induction not identified\", \"Mechanism linking Rac1/Cdc42 downregulation to niche homeostasis incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed canonical β-catenin-dependent mineralization in dental papilla cells and implicated WNT6 in ovarian cancer proliferation via both β-catenin and Notch1.\",\n      \"evidence\": \"Overexpression/knockdown, TOPflash reporter, XAV939 inhibition, and in vivo transplantation in dental cells; siWNT6 knockdown with proliferation/apoptosis assays in ovarian cancer cells\",\n      \"pmids\": [\"35691114\", \"36075327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking WNT6 to Notch1 not established (single knockdown, no epistasis)\", \"Direct vs indirect Notch1 regulation unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WNT6 selects between canonical and non-canonical signaling outputs — through receptor/co-receptor combinations, extracellular modulators, and cell context — remains the central unresolved question.\",\n      \"evidence\": \"No single study reconciles the divergent FZD4/FZD7 canonical and JNK/Rac1/Cdc42/ERK non-canonical outputs across tissues\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of WNT6-receptor complexes\", \"Determinants of pathway choice not defined\", \"Full FZD receptor repertoire not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [14, 17, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [14, 10, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 14, 6, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 4, 7, 2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [20, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FZD7\", \"FZD4\", \"SFRP2\", \"SULF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}