{"gene":"WNT7B","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2005,"finding":"WNT7B activates canonical (β-catenin) Wnt signaling by binding to Frizzled-1 (Fzd1) and Frizzled-10 (Fzd10) on the cell surface, and cooperatively activates canonical Wnt signaling with these receptors in the presence of LRP5 co-receptor; it does not activate the noncanonical Wnt pathway in these cell types.","method":"Cell transfection assays, biochemical cell-surface binding studies, canonical vs. non-canonical Wnt pathway reporter assays","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical binding assays combined with pathway reporter assays, multiple receptor-ligand interactions tested, single lab but orthogonal methods","pmids":["15923619"],"is_preprint":false},{"year":2005,"finding":"Macrophage-derived WNT7B acts as a short-range paracrine signal that activates the canonical WNT pathway in vascular endothelial cells of hyaloid vessels, triggering programmed cell death (apoptosis) and vessel regression during eye development.","method":"Conditional genetic deletion of Wnt7b in macrophages in mice, analysis of canonical WNT pathway responses and apoptosis in hyaloid vessel endothelial cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockout with defined molecular and cellular phenotype, published in high-impact journal, replicated across multiple analyses","pmids":["16163358"],"is_preprint":false},{"year":2010,"finding":"Macrophage-derived WNT7B stimulates canonical Wnt pathway responses in kidney epithelial cells to promote tissue repair and regeneration after injury; inducible ablation of macrophages reduces canonical Wnt pathway activity in kidney epithelium, and somatic deletion of Wnt7b in macrophages greatly diminishes kidney repair.","method":"Inducible macrophage ablation, conditional somatic deletion of Wnt7b in macrophages, canonical Wnt pathway reporter analysis in kidney epithelial cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — two complementary conditional genetic loss-of-function approaches with defined pathway and cellular phenotype readouts","pmids":["20160075"],"is_preprint":false},{"year":2002,"finding":"Wnt7b expressed in airway epithelium is required for mesenchymal proliferation and vascular smooth muscle development in the lung; germline deletion causes lung hypoplasia and defects in smooth muscle of major pulmonary vessels leading to hemorrhage.","method":"Germline knockout mouse (replacement of first exon with lacZ), histological and phenotypic analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — germline loss-of-function with clear paracrine signaling phenotype (epithelium to mesenchyme), replicated in conditional model","pmids":["12361974"],"is_preprint":false},{"year":2009,"finding":"Wnt7b expressed in collecting duct epithelium regulates the orientation of epithelial cell division planes (longitudinal vs. radial axis) via paracrine canonical Wnt signaling through β-catenin in the underlying interstitium, thereby establishing the cortico-medullary axis and enabling urine concentration; removal of β-catenin from Wnt-responsive interstitium phenocopies the Wnt7b mutant medullary defect.","method":"Conditional Wnt7b knockout, β-catenin conditional knockout in interstitium, analysis of cell division plane orientation, urine concentration assays, genetic epistasis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with β-catenin plus cell division plane analysis, two complementary loss-of-function models, multiple readouts","pmids":["19060336"],"is_preprint":false},{"year":2008,"finding":"Conditional Wnt7b-null lungs are hypoplastic due to decreased replication of both epithelium and mesenchyme; Wnt7b activates both autocrine and paracrine canonical Wnt signaling cascades and modulates multiple downstream signaling pathways to coordinate proliferation of adjacent cell types.","method":"Conditional Wnt7b knockout mouse, BrdU/proliferation assays, canonical Wnt pathway analysis in epithelium and mesenchyme","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional loss-of-function with autocrine/paracrine signaling dissection and multiple pathway readouts","pmids":["18367557"],"is_preprint":false},{"year":2001,"finding":"Wnt7b expression in the chorion is required for chorion-allantois fusion during placental development; in Wnt7b mutant mice, α4 integrin protein (required for chorioallantoic fusion) is not expressed by cells in the mutant chorion.","method":"Targeted germline mutation of mouse Wnt7b, immunohistochemistry for α4 integrin, histological analysis","journal":"Developmental Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — germline loss-of-function with identification of downstream molecular target (α4 integrin), clear mechanistic link","pmids":["11543617"],"is_preprint":false},{"year":2002,"finding":"WNT7B promoter is directly regulated by the lung-restricted transcription factors TTF-1, GATA6, and Foxa2; TTF-1 and GATA6 physically interact in vivo and synergistically activate the WNT7B promoter, and GATA6/Foxa2 binding site truncations reduce trans-activation.","method":"Electrophoretic mobility shift assays (EMSA), cotransfection reporter assays, promoter truncation analysis, co-immunoprecipitation (TTF-1/GATA6 interaction)","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — EMSA, reporter assay, Co-IP, and mutagenesis in a single study with multiple orthogonal methods","pmids":["11914369"],"is_preprint":false},{"year":2014,"finding":"WNT7B promotes bone formation by activating mTORC1 through the PI3K-AKT signaling pathway; genetic disruption of mTORC1 (by deleting Raptor in the osteoblast lineage) alleviates the WNT7B-induced high-bone-mass phenotype, establishing mTORC1 as a required downstream effector.","method":"Conditional transgenic overexpression of WNT7B in osteoblasts, conditional knockout of Raptor in osteoblasts, bone mass analysis, pathway activity assays","journal":"PLoS Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (Raptor KO rescues WNT7B gain-of-function phenotype), conditional mouse models, rigorous pathway analysis","pmids":["24497849"],"is_preprint":false},{"year":2017,"finding":"Reck (GPI-anchored membrane protein) and Gpr124 (orphan GPCR) function as essential receptor cofactors for WNT7A/WNT7B-specific signaling in CNS vascular endothelial cells; the most N-terminal domain of Reck binds to the LRR and Ig domains of Gpr124; soluble Gpr124(LRR-Ig) probe binds to cells expressing Frizzled, WNT7A or WNT7B, and Reck; soluble Reck(CC1-5) probe binds to cells expressing Frizzled, WNT7A or WNT7B, and Gpr124, indicating a multiprotein complex.","method":"EC-specific conditional knockouts of Reck, targeted mutagenesis of Reck-Gpr124 interface, soluble probe binding assays, CNS angiogenesis and BBB phenotype analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of protein-protein interface validated in cell culture and in vivo, soluble domain binding experiments, multiple orthogonal methods","pmids":["28803732"],"is_preprint":false},{"year":2014,"finding":"Myeloid cell-derived WNT7B mediates the angiogenic switch in breast cancer by activating Wnt/β-catenin signaling specifically in vascular endothelial cells (VECs), increasing VEGFA mRNA and protein expression in VECs; myeloid-specific Wnt7b deletion reduces VEC Wnt/β-catenin target gene expression, reduces tumor-associated VEGFA, impairs angiogenesis, and diminishes macrophage-mediated tumor cell invasion and lung metastasis.","method":"Myeloid-specific conditional Wnt7b knockout in MMTV-PymT breast cancer model, Wnt/β-catenin pathway reporter analysis in VECs, VEGFA expression analysis, tumor angiogenesis and metastasis assays","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with VEC-specific pathway readout, multiple phenotypic endpoints, mechanistic attribution to VEGFA","pmids":["24638982"],"is_preprint":false},{"year":2018,"finding":"Wnt7b signals through the Frizzled-7 (Fz7) receptor in hippocampal neurons to promote dendritic arborization via a non-canonical Wnt pathway; Fz7 loss-of-function impairs dendritic growth both in vitro and in vivo in the mouse hippocampus; Wnt7b-Fz7 signaling induces phosphorylation of CaMKII and JNK, both required for dendritic development.","method":"Fz7 loss-of-function (shRNA and dominant-negative), in vivo dendritic analysis in mouse hippocampus, Western blot for CaMKII and JNK phosphorylation, pharmacological inhibition","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — receptor identified by loss-of-function in vitro and in vivo, downstream kinase signaling validated by phosphorylation assays and pharmacological inhibition, multiple orthogonal methods","pmids":["29898920"],"is_preprint":false},{"year":2013,"finding":"WNT7B drives autocrine Wnt/β-catenin signaling in pancreatic adenocarcinoma (PDAC) cells; WNT7B knockdown reduces Wnt/β-catenin transcriptional activity and anchorage-independent growth, and WLS silencing or IWP-2 (which blocks Wnt ligand processing/secretion) also inhibits Wnt/β-catenin activity, placing WNT7B upstream as the primary ligand.","method":"siRNA knockdown of WNT7B in PDAC cell lines, WLS silencing, IWP-2 treatment, Wnt/β-catenin luciferase reporter assay, anchorage-independent growth assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (genetic knockdown, secretion inhibitor, reporter assay) in multiple cell lines demonstrating autocrine mechanism","pmids":["23416978"],"is_preprint":false},{"year":2013,"finding":"WNT7B is a direct androgen receptor (AR) target gene in castration-resistant prostate cancer (CRPC); WNT7B promotes androgen-independent growth of CRPC cells through activation of protein kinase C (PKC) isozymes (non-canonical Wnt pathway); WNT7B produced by prostate cancer cells induces osteoblast differentiation through direct cell-cell interaction.","method":"AR chromatin immunoprecipitation, WNT7B knockdown in CRPC cells, PKC pathway inhibitors, osteoblast co-culture differentiation assays","journal":"Molecular Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AR ChIP establishes direct transcriptional target, knockdown with PKC pathway analysis, but osteoblast induction relies on co-culture without full mechanistic dissection","pmids":["23386686"],"is_preprint":false},{"year":2013,"finding":"Dkk1 (a Wnt antagonist) inhibits Wnt7b-induced canonical Wnt signaling in kidney collecting duct cells; Dkk1 deficiency in the developing kidney leads to increased expression of canonical Wnt target Lef-1 in stromal cells, and Dkk1 regulates the degree of Wnt7b signaling during kidney papilla development.","method":"Recombinant Dkk1 protein treatment of cultured cells with Wnt7b stimulation, conditional Dkk1 knockout mouse, Lef-1 expression analysis","journal":"Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro antagonism of Wnt7b by Dkk1 plus in vivo genetic analysis, but mechanistic dissection limited to reporter gene readouts","pmids":["21354128"],"is_preprint":false},{"year":2013,"finding":"In aortic endothelial cells, Wnt7b and Msx2 preserve endothelial cell phenotype and maintain expression of EC differentiation markers; endothelial cell-specific deletion of Wnt7b (using Cdh5-Cre) in Wnt7b(fl/fl);LDLR(-/-) mice upregulates aortic osteogenic genes (Osx, Sox9, Runx2, Msx2) and activates Smad1/5 phosphorylation, indicating that EC Wnt7b suppresses endothelial-mesenchymal transition.","method":"Endothelial-specific conditional Wnt7b knockout (Cdh5-Cre), adenoviral Dkk1/Wnt7b/Msx2 overexpression in primary aortic ECs, Western blot, gene expression analysis","journal":"Arteriosclerosis, Thrombosis, and Vascular Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional knockout in mice plus gain-of-function in primary cells, multiple markers measured, two orthogonal experimental systems","pmids":["23685555"],"is_preprint":false},{"year":2019,"finding":"Wnt7b promotes bone formation through stimulation of glucose metabolism (glycolysis) in osteoblast lineage cells; Wnt7b increases GLUT1 expression and glucose consumption, and genetic deletion of GLUT1 (Glut1) essentially abolishes Wnt7b-induced bone formation in vivo, demonstrating GLUT1-dependent glycolysis as a required downstream mechanism.","method":"Compound transgenic mice overexpressing Wnt7b with conditional Glut1 deletion, in vivo bone formation assays (μCT), primary osteoblast culture differentiation, glucose consumption assays","journal":"FASEB Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (Glut1 deletion abolishes Wnt7b effect), in vivo and in vitro orthogonal methods, rigorous compound transgenic model","pmids":["30913395"],"is_preprint":false},{"year":2018,"finding":"Wnt7b acts through Frizzled-7 (Fz7) and the scaffold protein Dvl1 to modulate dendrite arborisation via non-canonical Wnt signaling in hippocampal neurons (β-catenin-independent pathway).","method":"Loss-of-function (Fz7 knockdown), in vitro and in vivo dendritic arborization analysis, reference to Dvl1 scaffold role","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function plus prior mechanistic work cited, single lab, non-canonical pathway dissection","pmids":["29898920"],"is_preprint":false},{"year":2008,"finding":"Wnt7b is a p53 transcriptional target gene in PC12 neuronal cells; NGF signaling stabilizes p53, which induces wnt7b expression in a p53-dependent manner; secreted Wnt7b promotes neurite outgrowth through non-canonical JNK signaling (not β-catenin nuclear translocation); sFRP1 inhibits wnt7b-dependent JNK phosphorylation, confirming that Wnt7b is secreted and acts extracellularly.","method":"Stable shRNA-mediated p53 silencing, wnt7b overexpression rescue of neurite outgrowth in p53-silenced cells, JNK inhibitor (SP600125), sFRP1 treatment, β-catenin nuclear localization assay","journal":"Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic tools, rescue experiment, secretion confirmed by sFRP1 inhibition, single lab","pmids":["18177422"],"is_preprint":false},{"year":2014,"finding":"In hair follicle stem cells (hfSCs), Wnt7b is a direct transcriptional target of canonical BMP signaling; conditional Wnt7b gene targeting disrupts hair follicle cycling (shorter anagen, premature catagen), diminishes HF differentiation markers, and delays HF activation, demonstrating a non-redundant role for Wnt7b in anagen length and catagen entry.","method":"Conditional Wnt7b knockout (morphogenesis and postnatal), BMP signaling manipulation, flow cytometry, BrdU labeling, marker expression analysis","journal":"Stem Cells","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional knockout with molecular mechanism (BMP target) and multiple defined phenotypic readouts, single lab but orthogonal methods","pmids":["24222445"],"is_preprint":false},{"year":2021,"finding":"The lncRNA Lnc-Rewind acts as an epigenetic regulator that represses Wnt7b expression in muscle stem cells (MuSCs) in cis; Lnc-Rewind interacts with the G9a histone lysine methyltransferase and mediates repression of Wnt7b by H3K9me2 deposition at the Wnt7b locus.","method":"RNA immunoprecipitation (RIP) for G9a interaction, ChIP for H3K9me2 at Wnt7b locus, lncRNA loss-of-function, RNA-seq in MuSCs","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and ChIP establish the epigenetic mechanism, loss-of-function confirms functional relevance, single lab","pmids":["33432928"],"is_preprint":false},{"year":2018,"finding":"The histone demethylase LSD1 (KDM1A) epigenetically represses WNT7B expression in osteoblasts; LSD1 deficiency results in increased WNT7B expression, enhanced osteoblast differentiation, and increased bone mass; genetic downregulation of WNT7B-related signaling attenuates the bone phenotype in LSD1-deficient mice.","method":"LSD1 knockdown in human MSCs, conditional LSD1 knockout mice, WNT7B expression analysis, genetic inhibition of WNT7B signaling, small-molecule inhibitor studies","journal":"Bone Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO plus genetic epistasis with WNT7B, single lab, multiple readouts","pmids":["29707403"],"is_preprint":false},{"year":2016,"finding":"Wnt7b expressed in ureteric bud epithelium activates canonical Wnt signaling in mural cells of periureteric bud capillaries in the renal medulla; Wnt7b loss enhances proliferation of target mural cells (associated with decreased PDGFRβ and p57kip2 expression) and impairs capillary lumen formation by reducing VE-cadherin at the cell surface of medullary capillary endothelium.","method":"Conditional Wnt7b knockout, immunofluorescence for mural cell markers, VE-cadherin localization analysis, proliferation assays","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with cell-type-specific molecular pathway readouts and VE-cadherin mechanistic attribution, single lab","pmids":["27432740"],"is_preprint":false},{"year":2022,"finding":"EZH2 interacts with HP1BP3 in glioma stem cells, impairing H3K9 methylation, and this EZH2-HP1BP3 complex co-activates WNT7B expression; autocrine WNT7B/β-catenin signaling promotes TMZ resistance and stemness in GBM, and WNT7B inhibition (LGK974) reverses TMZ resistance.","method":"Co-immunoprecipitation plus mass spectrometry, ChIP, WNT7B overexpression/knockdown, LGK974 WNT secretion inhibitor, TMZ resistance assays, glioma stem cell self-renewal assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identifies complex, ChIP links complex to WNT7B locus, pharmacological inhibition confirms pathway dependence, single lab","pmids":["36517590"],"is_preprint":false},{"year":2020,"finding":"Wnt7b-induced Sox11 expression in bone marrow mesenchymal stem cells (BMSCs) enhances self-renewal and osteogenic differentiation; this signaling is β-catenin-independent and instead activates Ca2+-dependent Nfatc1 signaling to directly induce Sox11 transcription; Sox11 in turn activates transcription of proliferation-related (Ccnb1, Sox2) and osteogenesis-related (Runx2, Sp7) factors.","method":"Transgenic mouse overexpression, RNA-seq, ChIP-qPCR (Sox11 binding to target promoters), shRNA knockdown, colony formation and osteogenic differentiation assays, Nfatc1 pathway analysis","journal":"Stem Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes direct transcriptional target, Ca2+/Nfatc1 pathway dissected, β-catenin independence shown, single lab with multiple orthogonal methods","pmids":["32346881"],"is_preprint":false},{"year":2017,"finding":"WNT7B promotes migration and differentiation (odontogenic/osteogenic) of human dental pulp cells partly through activation of both the canonical WNT/β-catenin pathway and the non-canonical JNK pathway; pharmacological inhibition of either pathway (XAV939 or SP600125) partly offsets WNT7B-induced differentiation.","method":"Recombinant WNT7B protein treatment, WNT/β-catenin luciferase reporter, Western blot for pathway activation, pathway inhibitors (XAV939, SP600125), ALP activity, alizarin red staining, scratch assay","journal":"Archives of Oral Biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple pathway readouts and orthogonal pharmacological inhibitors, recombinant protein approach, single lab","pmids":["29268145"],"is_preprint":false},{"year":2024,"finding":"Wnt7b acts as a non-canonical Wnt (ncWnt) ligand in concert with Wnt5a to regulate cochlear duct elongation and planar cell polarity; Wnt5a/Wnt7b are redundantly required for cochlear morphogenesis; mechanistically, Wnt5a/Wnt7b-mediated ncWnt signaling promotes membrane recruitment of Daple (a Gαi guanine nucleotide exchange factor) and activates PI3K/AKT and ERK signaling to regulate asymmetric Fzd6 localization.","method":"Conditional/conventional loss-of-function mouse genetics (Wnt5a/Wnt7b double KO), PI3K/AKT and ERK pathway analysis, PCP protein localization (Fzd6, Dvl2), Daple membrane recruitment assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double KO, molecular pathway dissection (Daple/Gαi/PI3K/AKT/ERK), PCP protein localization, multiple orthogonal methods","pmids":["39172791"],"is_preprint":false},{"year":2022,"finding":"The WNT7A/WNT7B-FRIZZLED-LRP5/LRP6-GPR124-RECK signaling system functions as an integral unit in limb development; loss-of-function alleles for Wnt7a, Wnt7b, Gpr124, and Reck synergize to cause reduced and dysmorphic limb bone growth, and a Reck allele specifically defective in WNT7A/WNT7B signaling recapitulates limb phenotypes.","method":"Combinations of conventional and conditional loss-of-function alleles for Wnt7a, Wnt7b, Gpr124, Reck in mice; Reck structure-function allele specifically defective in WNT7A/WNT7B signaling; limb bone growth and patterning analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional/conventional alleles in combination, structure-function allele with pathway specificity, strong genetic epistasis","pmids":["35552394"],"is_preprint":false},{"year":2021,"finding":"WNT7B/FZD5 signaling activates a pathway involving ELF3 transcription factor, which in turn transcriptionally modulates NOTCH1, functioning as a tumor-suppressing axis in bladder urothelial carcinoma that represses EMT, stem-like properties, and chemoresistance.","method":"Loss-of-function and gain-of-function studies in bladder cancer cell lines, receptor identification (FZD5 as WNT7B receptor), downstream ELF3/NOTCH1 pathway analysis, EMT and stemness marker assays","journal":"Biochimica et Biophysica Acta – Molecular Basis of Disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — receptor-pathway axis identified by loss/gain of function, downstream transcriptional target (ELF3-NOTCH1) proposed but mechanistic depth limited to expression assays","pmids":["34562599"],"is_preprint":false},{"year":2015,"finding":"In human pancreatic progenitor cells (PPCs), WNT7B (and Wnt7a) specifically promotes progenitor cell proliferation through the non-canonical Wnt/PKC pathway, not the canonical Wnt pathway; YY1 functions as a transcriptional regulator of WNT7B expression in PPCs.","method":"siRNA screening, feeder cell lines stably expressing individual Wnt ligands, canonical vs. non-canonical Wnt pathway reporters, phosphoproteome analysis, YY1 transcriptional regulator identification","journal":"Cell Chemical Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway specificity established by reporter assays, stable Wnt7b expression system, phosphoproteomics for YY1, single lab","pmids":["33125912"],"is_preprint":false},{"year":2019,"finding":"Wnt7b promotes dentinogenesis by increasing proliferation and differentiation of dental mesenchymal cells partly through the ERK1/2 pathway; transgenic mice overexpressing Wnt7b in odontoblasts show increased p-ERK1/2, thinner predentin, and thicker intertubular dentin with higher mineral content; ERK1/2 inhibition partly rescues Wnt7b-induced differentiation.","method":"Dmp1-cre;ROSA26-Wnt7b transgenic mice, adenoviral Wnt7b overexpression in dental papillae cells, ERK1/2 inhibitor, Western blot, micro-CT, ALP/alizarin red staining","journal":"Archives of Oral Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic plus in vitro adenoviral overexpression with pharmacological pathway inhibition, single lab","pmids":["31181411"],"is_preprint":false},{"year":2022,"finding":"Bi-allelic loss-of-function variants in WNT7B cause PDAC syndrome (pulmonary hypoplasia, diaphragmatic anomalies, anophthalmia/microphthalmia, cardiac defects); functional validation using a canonical WNT signaling luciferase assay demonstrated that identified WNT7B variants (p.Arg98*, p.Tyr75*, p.Gly188Ser) are deleterious to WNT7B signaling activity.","method":"Whole-exome sequencing, canonical WNT signaling luciferase reporter assay for variant functional validation, wnt7bb mutant zebrafish (swimbladder phenotype)","journal":"Journal of Medical Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional luciferase assay validates loss-of-function, zebrafish ortholog confirms evolutionary conservation of lung development function, human genetics + functional validation","pmids":["35790350"],"is_preprint":false},{"year":2023,"finding":"Wnt7b expressed by hypertrophic chondrocytes promotes endochondral ossification; Wnt7b expression in growth plate cartilage is suppressed by BMP4/Smad4 signaling; ablation of Wnt7b in Smad4 cKO mice blunts the increased bone volume phenotype, establishing Wnt7b-β-catenin as a downstream effector of Smad4-BMP signaling during endochondral ossification.","method":"Conditional Smad4 knockout, conditional Wnt7b knockout in Smad4 cKO background (genetic epistasis), BMP4 stimulation in chondrocytes, bone volume analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Wnt7b KO in Smad4 KO background), BMP4 suppression of Wnt7b in vitro, single lab","pmids":["37539462"],"is_preprint":false},{"year":2024,"finding":"WNT7B binds to FZD4 (frizzled-4) receptor in periodontal ligament stem cells; Wnt7b overexpression promotes osteogenic differentiation and suppresses M1 macrophage polarization; FZD4 silencing reverses these effects, placing FZD4 as the receptor mediating WNT7B function in this context.","method":"Co-immunoprecipitation (WNT7B-FZD4 binding), FZD4 siRNA rescue experiments, osteogenic differentiation assays, macrophage polarization assays, Western blot","journal":"Molecular Medicine Reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP establishes binding, rescue experiment with FZD4 KD confirms receptor specificity, single lab","pmids":["39301638"],"is_preprint":false},{"year":2021,"finding":"WNT7B in cholangiocytes induces a proproliferative, proinflammatory program: in vitro, Wnt7b induces cholangiocyte proliferation and secretion of proinflammatory cytokines in an autocrine manner; loss of cholangiocyte/hepatocyte Wnt7b in vivo improves biliary injury and decreases cellular senescence in cholestasis, and Wnt7b suppression promotes hepatocyte reprogramming toward a biliary phenotype.","method":"Conditional Wnt7b knockout (Krt19-Cre and Albumin-Cre), DDC cholestasis model, proliferation assays, cytokine secretion assays, senescence markers, hepatocyte reprogramming markers","journal":"Hepatology Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two conditional knockout models (cell-type specificity), autocrine signaling established in vitro, single lab with multiple readouts","pmids":["34558852"],"is_preprint":false},{"year":2018,"finding":"In the context of partially impaired Norrin signaling, the Wnt7a/Wnt7b system makes a contribution to blood-retina barrier (BRB) development; combined loss of Wnt7a and Norrin or Wnt7a and Frizzled4 causes far more severe BBB defects than loss of any single component, demonstrating partial redundancy between the Wnt7a/Wnt7b and Norrin signaling systems in BBB/BRB maintenance.","method":"Compound conditional knockouts (Wnt7a, Wnt7b, Norrin, Frizzled4, Tspan12) in mice, BBB/BRB phenotype analysis, glial-specific Wnt7a deletion","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — extensive combinatorial genetic analysis in multiple tissue-specific conditional knockouts, threshold and redundancy effects rigorously established","pmids":["30478038"],"is_preprint":false},{"year":2024,"finding":"A founder WNT7B variant (Arg247Trp) significantly impairs WNT7B canonical signaling activity as demonstrated by luciferase reporter assay, causing variable PDAC syndrome phenotypes including isolated genitourinary anomalies, expanding the known phenotypic spectrum.","method":"Canonical WNT signaling luciferase reporter assay for variant functional validation","journal":"Clinical Genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (luciferase reporter), single lab, confirms prior findings but adds limited new mechanistic insight","pmids":["38417950"],"is_preprint":false}],"current_model":"WNT7B is a secreted Wnt ligand that signals predominantly through canonical (β-catenin/LRP5-6/Frizzled-1, -4, -7, -10) and non-canonical (JNK, CaMKII, PKC, PI3K-AKT-mTORC1) pathways in a context-dependent manner; in CNS and retinal vasculature, WNT7B-specific signaling requires the co-activator complex of RECK and GPR124 in addition to Frizzled/LRP receptors; macrophage-derived WNT7B acts as a paracrine signal to drive canonical Wnt responses in adjacent epithelial or endothelial cells during organ development, repair, and tumor angiogenesis; in bone, WNT7B activates mTORC1 via PI3K-AKT and stimulates glycolysis via GLUT1 to promote osteoblast activity; in neurons, Wnt7b signals through Frizzled-7 to activate CaMKII and JNK for dendritic arborization; and epigenetic regulators including LSD1 and the lncRNA Lnc-Rewind control WNT7B transcription by modulating histone methylation at its locus."},"narrative":{"mechanistic_narrative":"WNT7B is a secreted Wnt ligand that coordinates proliferation, differentiation, and morphogenesis across developing and regenerating tissues by activating both canonical (β-catenin) and non-canonical Wnt responses in adjacent or autocrine target cells [PMID:15923619, PMID:18367557]. It binds Frizzled receptors at the cell surface—Frizzled-1 and -10 in cooperation with the LRP5 co-receptor to drive canonical signaling [PMID:15923619], and Frizzled-7, -4, or -5 in other contexts [PMID:29898920, PMID:39301638, PMID:34562599]—and in CNS, retinal, and limb vasculature WNT7-specific signaling additionally requires the membrane co-activator complex of RECK and the orphan GPCR GPR124, which assemble with Frizzled into a multiprotein receptor unit [PMID:28803732, PMID:35552394, PMID:30478038]. A recurring theme is paracrine action: macrophage- or myeloid-derived WNT7B activates canonical Wnt responses in neighboring endothelial and epithelial cells to drive hyaloid vessel regression, kidney repair, and tumor angiogenesis through induction of VEGFA [PMID:16163358, PMID:20160075, PMID:24638982], while epithelium-derived WNT7B instructs mesenchymal and mural-cell behavior during lung, kidney, and placental development [PMID:12361974, PMID:19060336, PMID:11543617, PMID:27432740]. In bone, WNT7B promotes osteoblast activity through PI3K-AKT-driven mTORC1 activation and GLUT1-dependent glycolysis [PMID:24497849, PMID:30913395], and through β-catenin-independent Ca2+/NFATc1-SOX11 signaling [PMID:32346881]. Non-canonical outputs—JNK, CaMKII, PKC, and ERK1/2—mediate neuronal dendritic arborization, neurite outgrowth, and odontoblast differentiation [PMID:29898920, PMID:18177422, PMID:33125912, PMID:31181411]. WNT7B transcription is set by tissue-restricted factors (TTF-1/GATA6/Foxa2 in lung) and by BMP and androgen-receptor signaling, and is repressed epigenetically by LSD1 and by the G9a-recruiting lncRNA Lnc-Rewind [PMID:11914369, PMID:24222445, PMID:23386686, PMID:29707403, PMID:33432928]. Bi-allelic loss-of-function variants in WNT7B cause PDAC syndrome (pulmonary hypoplasia, diaphragmatic anomalies, anophthalmia/microphthalmia, cardiac and genitourinary defects), with variant deleteriousness validated by canonical WNT signaling reporter assays [PMID:35790350].","teleology":[{"year":2002,"claim":"Establishing how WNT7B transcription is restricted to specific epithelia answered which upstream regulators license its expression, and identified epithelial WNT7B as an essential paracrine signal for mesenchymal development.","evidence":"EMSA, reporter, Co-IP, and promoter mutagenesis defining TTF-1/GATA6/Foxa2 regulation; germline lacZ knockout showing lung hypoplasia and pulmonary vascular smooth-muscle defects","pmids":["11914369","12361974"],"confidence":"High","gaps":["Did not resolve the receptor on responding mesenchymal cells","Transcriptional control characterized only in lung context"]},{"year":2005,"claim":"Identifying the receptor partners answered whether WNT7B is intrinsically canonical, showing it binds Frizzled-1/-10 with LRP5 to activate β-catenin and, in macrophages, acts as a short-range paracrine signal driving endothelial apoptosis.","evidence":"Cell-surface binding and canonical-vs-noncanonical reporter assays; macrophage-specific conditional Wnt7b deletion in mouse eye","pmids":["15923619","16163358"],"confidence":"High","gaps":["Pathway choice shown to be cell-type dependent, not explained at the molecular level","Receptor identity in macrophage-endothelial paracrine signaling not directly mapped"]},{"year":2009,"claim":"Genetic epistasis with β-catenin established that epithelial WNT7B controls mesenchymal/interstitial cell-division plane orientation, defining its role in organ axis formation beyond simple proliferation.","evidence":"Conditional Wnt7b and interstitial β-catenin knockouts with division-plane and urine-concentration analysis in kidney","pmids":["19060336","18367557"],"confidence":"High","gaps":["Effector genes downstream of β-catenin in oriented division not identified","Autocrine vs paracrine contributions only partially separated"]},{"year":2013,"claim":"Cancer and vascular studies answered whether WNT7B acts autocrine or paracrine in disease, showing autocrine β-catenin signaling sustains PDAC growth while AR-driven WNT7B uses non-canonical PKC, and EC-intrinsic WNT7B suppresses endothelial-mesenchymal transition.","evidence":"siRNA/WLS/IWP-2 reporter assays in PDAC; AR ChIP and PKC inhibitors in CRPC; endothelial-specific Cdh5-Cre knockout with osteogenic-gene and Smad1/5 analysis","pmids":["23416978","23386686","23685555"],"confidence":"Medium","gaps":["Receptors mediating autocrine signaling in these contexts not defined","PKC isozyme specificity not fully resolved"]},{"year":2014,"claim":"Bone and tumor-angiogenesis work answered how WNT7B couples to metabolism and the angiogenic switch, placing PI3K-AKT-mTORC1 downstream in osteoblasts and VEGFA induction downstream in tumor endothelium.","evidence":"Raptor-deletion epistasis rescuing WNT7B high-bone-mass phenotype; myeloid-specific Wnt7b knockout in MMTV-PyMT with VEC reporter and VEGFA analysis","pmids":["24497849","24638982"],"confidence":"High","gaps":["How a Wnt ligand engages PI3K-AKT mechanistically not resolved","Link between canonical signaling and VEGFA transcription not directly mapped"]},{"year":2017,"claim":"Discovery of the RECK-GPR124 co-activator complex answered how WNT7B achieves ligand-specific signaling in CNS endothelium, defining a multiprotein receptor unit assembled with Frizzled.","evidence":"EC-specific Reck knockouts, interface mutagenesis, and soluble-domain probe binding assays demonstrating Frizzled-WNT7-RECK-GPR124 assembly","pmids":["28803732"],"confidence":"High","gaps":["Stoichiometry and structure of the assembled complex not solved","How RECK/GPR124 bias signaling output not defined"]},{"year":2018,"claim":"Neuronal and barrier studies answered which non-canonical effectors WNT7B uses and how it cooperates with related ligands, identifying Frizzled-7/Dvl1-CaMKII/JNK signaling for dendrites and partial redundancy with Norrin for the blood-brain/retina barrier.","evidence":"Fz7 loss-of-function with CaMKII/JNK phospho-readouts in hippocampus; combinatorial Wnt7a/Wnt7b/Norrin/Frizzled4 conditional knockouts with BBB/BRB phenotyping","pmids":["29898920","30478038","18177422"],"confidence":"High","gaps":["Functional separation of WNT7A vs WNT7B contributions limited","Connection between CaMKII/JNK activation and cytoskeletal remodeling not detailed"]},{"year":2021,"claim":"Epigenetic and stem-cell studies answered how WNT7B levels are tuned and how it signals β-catenin-independently, defining LSD1 and Lnc-Rewind/G9a-H3K9 repression and a Ca2+/NFATc1-SOX11 osteogenic axis.","evidence":"LSD1 conditional knockout with WNT7B epistasis; RIP/ChIP for G9a-H3K9me2 at the Wnt7b locus; transgenic overexpression with ChIP-qPCR for NFATc1-SOX11 targets","pmids":["29707403","33432928","32346881"],"confidence":"Medium","gaps":["Epigenetic regulators tested in single lineages only","Receptor coupling to the Ca2+/NFATc1 branch not identified"]},{"year":2022,"claim":"Human genetics and limb genetics answered whether WNT7B loss is disease-causing and whether the RECK-GPR124 unit operates outside CNS, defining PDAC syndrome and a WNT7-FZD-LRP5/6-GPR124-RECK module in limb skeletal growth.","evidence":"Exome sequencing with canonical WNT luciferase validation and zebrafish ortholog; combinatorial Wnt7a/Wnt7b/Gpr124/Reck alleles with a signaling-specific Reck allele in limb","pmids":["35790350","35552394"],"confidence":"Medium","gaps":["Genotype-phenotype correlation across PDAC variants incompletely defined","Tissue-specific deployment of the RECK-GPR124 module not comprehensively mapped"]},{"year":2024,"claim":"Cochlear and additional disease studies answered how WNT7B drives planar cell polarity and clarified receptor usage, defining a Wnt5a/Wnt7b-Daple-Gαi-PI3K/AKT/ERK PCP pathway and FZD4/FZD5 receptor contexts.","evidence":"Wnt5a/Wnt7b double knockout with Daple recruitment, PI3K/AKT/ERK and Fzd6 localization analysis; FZD4 Co-IP/rescue and FZD5-ELF3-NOTCH1 axis studies; founder-variant reporter assay","pmids":["39172791","39301638","34562599","38417950"],"confidence":"Medium","gaps":["Multiple Frizzled receptors implicated without a unifying selectivity rule","Whether the same Daple/PCP machinery operates in other WNT7B-dependent tissues unknown"]},{"year":null,"claim":"It remains unresolved what determines WNT7B's choice between canonical and non-canonical outputs across tissues, and how its diverse Frizzled receptors and the RECK-GPR124 co-activator are selected in each context.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of WNT7B-receptor-coreceptor complexes","Rules governing canonical vs non-canonical pathway selection unknown","Receptor-effector matching across tissues not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,9,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,18,25]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,18,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4,6,27]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,12,31]}],"complexes":["WNT7-Frizzled-LRP5/6-GPR124-RECK signaling complex"],"partners":["FZD1","FZD10","FZD7","FZD4","FZD5","LRP5","RECK","GPR124"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P56706","full_name":"Protein Wnt-7b","aliases":[],"length_aa":349,"mass_kda":39.3,"function":"Ligand for members of the frizzled family of seven transmembrane receptors that functions in the canonical Wnt/beta-catenin signaling pathway (PubMed:30026314). Required for normal fusion of the chorion and the allantois during placenta development (By similarity). Required for central nervous system (CNS) angiogenesis and blood-brain barrier regulation (PubMed:30026314)","subcellular_location":"Secreted, extracellular space, extracellular matrix; Secreted","url":"https://www.uniprot.org/uniprotkb/P56706/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WNT7B","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/WNT7B","total_profiled":1310},"omim":[{"mim_id":"604616","title":"T-BOX, BRAIN, 1; TBR1","url":"https://www.omim.org/entry/604616"},{"mim_id":"603490","title":"WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 4; WNT4","url":"https://www.omim.org/entry/603490"},{"mim_id":"601967","title":"WINGLESS-TYPE MMTV INTEGRATION SITE 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fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26429533","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52265,"output_tokens":10060,"usd":0.153847,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20523,"output_tokens":4384,"usd":0.106107,"stage2_stop_reason":"end_turn"},"total_usd":0.259954,"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\": 2005,\n      \"finding\": \"WNT7B activates canonical (β-catenin) Wnt signaling by binding to Frizzled-1 (Fzd1) and Frizzled-10 (Fzd10) on the cell surface, and cooperatively activates canonical Wnt signaling with these receptors in the presence of LRP5 co-receptor; it does not activate the noncanonical Wnt pathway in these cell types.\",\n      \"method\": \"Cell transfection assays, biochemical cell-surface binding studies, canonical vs. non-canonical Wnt pathway reporter assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical binding assays combined with pathway reporter assays, multiple receptor-ligand interactions tested, single lab but orthogonal methods\",\n      \"pmids\": [\"15923619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Macrophage-derived WNT7B acts as a short-range paracrine signal that activates the canonical WNT pathway in vascular endothelial cells of hyaloid vessels, triggering programmed cell death (apoptosis) and vessel regression during eye development.\",\n      \"method\": \"Conditional genetic deletion of Wnt7b in macrophages in mice, analysis of canonical WNT pathway responses and apoptosis in hyaloid vessel endothelial cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockout with defined molecular and cellular phenotype, published in high-impact journal, replicated across multiple analyses\",\n      \"pmids\": [\"16163358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Macrophage-derived WNT7B stimulates canonical Wnt pathway responses in kidney epithelial cells to promote tissue repair and regeneration after injury; inducible ablation of macrophages reduces canonical Wnt pathway activity in kidney epithelium, and somatic deletion of Wnt7b in macrophages greatly diminishes kidney repair.\",\n      \"method\": \"Inducible macrophage ablation, conditional somatic deletion of Wnt7b in macrophages, canonical Wnt pathway reporter analysis in kidney epithelial cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two complementary conditional genetic loss-of-function approaches with defined pathway and cellular phenotype readouts\",\n      \"pmids\": [\"20160075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Wnt7b expressed in airway epithelium is required for mesenchymal proliferation and vascular smooth muscle development in the lung; germline deletion causes lung hypoplasia and defects in smooth muscle of major pulmonary vessels leading to hemorrhage.\",\n      \"method\": \"Germline knockout mouse (replacement of first exon with lacZ), histological and phenotypic analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — germline loss-of-function with clear paracrine signaling phenotype (epithelium to mesenchyme), replicated in conditional model\",\n      \"pmids\": [\"12361974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Wnt7b expressed in collecting duct epithelium regulates the orientation of epithelial cell division planes (longitudinal vs. radial axis) via paracrine canonical Wnt signaling through β-catenin in the underlying interstitium, thereby establishing the cortico-medullary axis and enabling urine concentration; removal of β-catenin from Wnt-responsive interstitium phenocopies the Wnt7b mutant medullary defect.\",\n      \"method\": \"Conditional Wnt7b knockout, β-catenin conditional knockout in interstitium, analysis of cell division plane orientation, urine concentration assays, genetic epistasis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with β-catenin plus cell division plane analysis, two complementary loss-of-function models, multiple readouts\",\n      \"pmids\": [\"19060336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Conditional Wnt7b-null lungs are hypoplastic due to decreased replication of both epithelium and mesenchyme; Wnt7b activates both autocrine and paracrine canonical Wnt signaling cascades and modulates multiple downstream signaling pathways to coordinate proliferation of adjacent cell types.\",\n      \"method\": \"Conditional Wnt7b knockout mouse, BrdU/proliferation assays, canonical Wnt pathway analysis in epithelium and mesenchyme\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional loss-of-function with autocrine/paracrine signaling dissection and multiple pathway readouts\",\n      \"pmids\": [\"18367557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Wnt7b expression in the chorion is required for chorion-allantois fusion during placental development; in Wnt7b mutant mice, α4 integrin protein (required for chorioallantoic fusion) is not expressed by cells in the mutant chorion.\",\n      \"method\": \"Targeted germline mutation of mouse Wnt7b, immunohistochemistry for α4 integrin, histological analysis\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — germline loss-of-function with identification of downstream molecular target (α4 integrin), clear mechanistic link\",\n      \"pmids\": [\"11543617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"WNT7B promoter is directly regulated by the lung-restricted transcription factors TTF-1, GATA6, and Foxa2; TTF-1 and GATA6 physically interact in vivo and synergistically activate the WNT7B promoter, and GATA6/Foxa2 binding site truncations reduce trans-activation.\",\n      \"method\": \"Electrophoretic mobility shift assays (EMSA), cotransfection reporter assays, promoter truncation analysis, co-immunoprecipitation (TTF-1/GATA6 interaction)\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — EMSA, reporter assay, Co-IP, and mutagenesis in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"11914369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"WNT7B promotes bone formation by activating mTORC1 through the PI3K-AKT signaling pathway; genetic disruption of mTORC1 (by deleting Raptor in the osteoblast lineage) alleviates the WNT7B-induced high-bone-mass phenotype, establishing mTORC1 as a required downstream effector.\",\n      \"method\": \"Conditional transgenic overexpression of WNT7B in osteoblasts, conditional knockout of Raptor in osteoblasts, bone mass analysis, pathway activity assays\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (Raptor KO rescues WNT7B gain-of-function phenotype), conditional mouse models, rigorous pathway analysis\",\n      \"pmids\": [\"24497849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Reck (GPI-anchored membrane protein) and Gpr124 (orphan GPCR) function as essential receptor cofactors for WNT7A/WNT7B-specific signaling in CNS vascular endothelial cells; the most N-terminal domain of Reck binds to the LRR and Ig domains of Gpr124; soluble Gpr124(LRR-Ig) probe binds to cells expressing Frizzled, WNT7A or WNT7B, and Reck; soluble Reck(CC1-5) probe binds to cells expressing Frizzled, WNT7A or WNT7B, and Gpr124, indicating a multiprotein complex.\",\n      \"method\": \"EC-specific conditional knockouts of Reck, targeted mutagenesis of Reck-Gpr124 interface, soluble probe binding assays, CNS angiogenesis and BBB phenotype analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of protein-protein interface validated in cell culture and in vivo, soluble domain binding experiments, multiple orthogonal methods\",\n      \"pmids\": [\"28803732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Myeloid cell-derived WNT7B mediates the angiogenic switch in breast cancer by activating Wnt/β-catenin signaling specifically in vascular endothelial cells (VECs), increasing VEGFA mRNA and protein expression in VECs; myeloid-specific Wnt7b deletion reduces VEC Wnt/β-catenin target gene expression, reduces tumor-associated VEGFA, impairs angiogenesis, and diminishes macrophage-mediated tumor cell invasion and lung metastasis.\",\n      \"method\": \"Myeloid-specific conditional Wnt7b knockout in MMTV-PymT breast cancer model, Wnt/β-catenin pathway reporter analysis in VECs, VEGFA expression analysis, tumor angiogenesis and metastasis assays\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with VEC-specific pathway readout, multiple phenotypic endpoints, mechanistic attribution to VEGFA\",\n      \"pmids\": [\"24638982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wnt7b signals through the Frizzled-7 (Fz7) receptor in hippocampal neurons to promote dendritic arborization via a non-canonical Wnt pathway; Fz7 loss-of-function impairs dendritic growth both in vitro and in vivo in the mouse hippocampus; Wnt7b-Fz7 signaling induces phosphorylation of CaMKII and JNK, both required for dendritic development.\",\n      \"method\": \"Fz7 loss-of-function (shRNA and dominant-negative), in vivo dendritic analysis in mouse hippocampus, Western blot for CaMKII and JNK phosphorylation, pharmacological inhibition\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identified by loss-of-function in vitro and in vivo, downstream kinase signaling validated by phosphorylation assays and pharmacological inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"29898920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WNT7B drives autocrine Wnt/β-catenin signaling in pancreatic adenocarcinoma (PDAC) cells; WNT7B knockdown reduces Wnt/β-catenin transcriptional activity and anchorage-independent growth, and WLS silencing or IWP-2 (which blocks Wnt ligand processing/secretion) also inhibits Wnt/β-catenin activity, placing WNT7B upstream as the primary ligand.\",\n      \"method\": \"siRNA knockdown of WNT7B in PDAC cell lines, WLS silencing, IWP-2 treatment, Wnt/β-catenin luciferase reporter assay, anchorage-independent growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (genetic knockdown, secretion inhibitor, reporter assay) in multiple cell lines demonstrating autocrine mechanism\",\n      \"pmids\": [\"23416978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WNT7B is a direct androgen receptor (AR) target gene in castration-resistant prostate cancer (CRPC); WNT7B promotes androgen-independent growth of CRPC cells through activation of protein kinase C (PKC) isozymes (non-canonical Wnt pathway); WNT7B produced by prostate cancer cells induces osteoblast differentiation through direct cell-cell interaction.\",\n      \"method\": \"AR chromatin immunoprecipitation, WNT7B knockdown in CRPC cells, PKC pathway inhibitors, osteoblast co-culture differentiation assays\",\n      \"journal\": \"Molecular Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AR ChIP establishes direct transcriptional target, knockdown with PKC pathway analysis, but osteoblast induction relies on co-culture without full mechanistic dissection\",\n      \"pmids\": [\"23386686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dkk1 (a Wnt antagonist) inhibits Wnt7b-induced canonical Wnt signaling in kidney collecting duct cells; Dkk1 deficiency in the developing kidney leads to increased expression of canonical Wnt target Lef-1 in stromal cells, and Dkk1 regulates the degree of Wnt7b signaling during kidney papilla development.\",\n      \"method\": \"Recombinant Dkk1 protein treatment of cultured cells with Wnt7b stimulation, conditional Dkk1 knockout mouse, Lef-1 expression analysis\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro antagonism of Wnt7b by Dkk1 plus in vivo genetic analysis, but mechanistic dissection limited to reporter gene readouts\",\n      \"pmids\": [\"21354128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In aortic endothelial cells, Wnt7b and Msx2 preserve endothelial cell phenotype and maintain expression of EC differentiation markers; endothelial cell-specific deletion of Wnt7b (using Cdh5-Cre) in Wnt7b(fl/fl);LDLR(-/-) mice upregulates aortic osteogenic genes (Osx, Sox9, Runx2, Msx2) and activates Smad1/5 phosphorylation, indicating that EC Wnt7b suppresses endothelial-mesenchymal transition.\",\n      \"method\": \"Endothelial-specific conditional Wnt7b knockout (Cdh5-Cre), adenoviral Dkk1/Wnt7b/Msx2 overexpression in primary aortic ECs, Western blot, gene expression analysis\",\n      \"journal\": \"Arteriosclerosis, Thrombosis, and Vascular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional knockout in mice plus gain-of-function in primary cells, multiple markers measured, two orthogonal experimental systems\",\n      \"pmids\": [\"23685555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wnt7b promotes bone formation through stimulation of glucose metabolism (glycolysis) in osteoblast lineage cells; Wnt7b increases GLUT1 expression and glucose consumption, and genetic deletion of GLUT1 (Glut1) essentially abolishes Wnt7b-induced bone formation in vivo, demonstrating GLUT1-dependent glycolysis as a required downstream mechanism.\",\n      \"method\": \"Compound transgenic mice overexpressing Wnt7b with conditional Glut1 deletion, in vivo bone formation assays (μCT), primary osteoblast culture differentiation, glucose consumption assays\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (Glut1 deletion abolishes Wnt7b effect), in vivo and in vitro orthogonal methods, rigorous compound transgenic model\",\n      \"pmids\": [\"30913395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wnt7b acts through Frizzled-7 (Fz7) and the scaffold protein Dvl1 to modulate dendrite arborisation via non-canonical Wnt signaling in hippocampal neurons (β-catenin-independent pathway).\",\n      \"method\": \"Loss-of-function (Fz7 knockdown), in vitro and in vivo dendritic arborization analysis, reference to Dvl1 scaffold role\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function plus prior mechanistic work cited, single lab, non-canonical pathway dissection\",\n      \"pmids\": [\"29898920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Wnt7b is a p53 transcriptional target gene in PC12 neuronal cells; NGF signaling stabilizes p53, which induces wnt7b expression in a p53-dependent manner; secreted Wnt7b promotes neurite outgrowth through non-canonical JNK signaling (not β-catenin nuclear translocation); sFRP1 inhibits wnt7b-dependent JNK phosphorylation, confirming that Wnt7b is secreted and acts extracellularly.\",\n      \"method\": \"Stable shRNA-mediated p53 silencing, wnt7b overexpression rescue of neurite outgrowth in p53-silenced cells, JNK inhibitor (SP600125), sFRP1 treatment, β-catenin nuclear localization assay\",\n      \"journal\": \"Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic tools, rescue experiment, secretion confirmed by sFRP1 inhibition, single lab\",\n      \"pmids\": [\"18177422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In hair follicle stem cells (hfSCs), Wnt7b is a direct transcriptional target of canonical BMP signaling; conditional Wnt7b gene targeting disrupts hair follicle cycling (shorter anagen, premature catagen), diminishes HF differentiation markers, and delays HF activation, demonstrating a non-redundant role for Wnt7b in anagen length and catagen entry.\",\n      \"method\": \"Conditional Wnt7b knockout (morphogenesis and postnatal), BMP signaling manipulation, flow cytometry, BrdU labeling, marker expression analysis\",\n      \"journal\": \"Stem Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with molecular mechanism (BMP target) and multiple defined phenotypic readouts, single lab but orthogonal methods\",\n      \"pmids\": [\"24222445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The lncRNA Lnc-Rewind acts as an epigenetic regulator that represses Wnt7b expression in muscle stem cells (MuSCs) in cis; Lnc-Rewind interacts with the G9a histone lysine methyltransferase and mediates repression of Wnt7b by H3K9me2 deposition at the Wnt7b locus.\",\n      \"method\": \"RNA immunoprecipitation (RIP) for G9a interaction, ChIP for H3K9me2 at Wnt7b locus, lncRNA loss-of-function, RNA-seq in MuSCs\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and ChIP establish the epigenetic mechanism, loss-of-function confirms functional relevance, single lab\",\n      \"pmids\": [\"33432928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The histone demethylase LSD1 (KDM1A) epigenetically represses WNT7B expression in osteoblasts; LSD1 deficiency results in increased WNT7B expression, enhanced osteoblast differentiation, and increased bone mass; genetic downregulation of WNT7B-related signaling attenuates the bone phenotype in LSD1-deficient mice.\",\n      \"method\": \"LSD1 knockdown in human MSCs, conditional LSD1 knockout mice, WNT7B expression analysis, genetic inhibition of WNT7B signaling, small-molecule inhibitor studies\",\n      \"journal\": \"Bone Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus genetic epistasis with WNT7B, single lab, multiple readouts\",\n      \"pmids\": [\"29707403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wnt7b expressed in ureteric bud epithelium activates canonical Wnt signaling in mural cells of periureteric bud capillaries in the renal medulla; Wnt7b loss enhances proliferation of target mural cells (associated with decreased PDGFRβ and p57kip2 expression) and impairs capillary lumen formation by reducing VE-cadherin at the cell surface of medullary capillary endothelium.\",\n      \"method\": \"Conditional Wnt7b knockout, immunofluorescence for mural cell markers, VE-cadherin localization analysis, proliferation assays\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with cell-type-specific molecular pathway readouts and VE-cadherin mechanistic attribution, single lab\",\n      \"pmids\": [\"27432740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EZH2 interacts with HP1BP3 in glioma stem cells, impairing H3K9 methylation, and this EZH2-HP1BP3 complex co-activates WNT7B expression; autocrine WNT7B/β-catenin signaling promotes TMZ resistance and stemness in GBM, and WNT7B inhibition (LGK974) reverses TMZ resistance.\",\n      \"method\": \"Co-immunoprecipitation plus mass spectrometry, ChIP, WNT7B overexpression/knockdown, LGK974 WNT secretion inhibitor, TMZ resistance assays, glioma stem cell self-renewal assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identifies complex, ChIP links complex to WNT7B locus, pharmacological inhibition confirms pathway dependence, single lab\",\n      \"pmids\": [\"36517590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wnt7b-induced Sox11 expression in bone marrow mesenchymal stem cells (BMSCs) enhances self-renewal and osteogenic differentiation; this signaling is β-catenin-independent and instead activates Ca2+-dependent Nfatc1 signaling to directly induce Sox11 transcription; Sox11 in turn activates transcription of proliferation-related (Ccnb1, Sox2) and osteogenesis-related (Runx2, Sp7) factors.\",\n      \"method\": \"Transgenic mouse overexpression, RNA-seq, ChIP-qPCR (Sox11 binding to target promoters), shRNA knockdown, colony formation and osteogenic differentiation assays, Nfatc1 pathway analysis\",\n      \"journal\": \"Stem Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes direct transcriptional target, Ca2+/Nfatc1 pathway dissected, β-catenin independence shown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32346881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WNT7B promotes migration and differentiation (odontogenic/osteogenic) of human dental pulp cells partly through activation of both the canonical WNT/β-catenin pathway and the non-canonical JNK pathway; pharmacological inhibition of either pathway (XAV939 or SP600125) partly offsets WNT7B-induced differentiation.\",\n      \"method\": \"Recombinant WNT7B protein treatment, WNT/β-catenin luciferase reporter, Western blot for pathway activation, pathway inhibitors (XAV939, SP600125), ALP activity, alizarin red staining, scratch assay\",\n      \"journal\": \"Archives of Oral Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple pathway readouts and orthogonal pharmacological inhibitors, recombinant protein approach, single lab\",\n      \"pmids\": [\"29268145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Wnt7b acts as a non-canonical Wnt (ncWnt) ligand in concert with Wnt5a to regulate cochlear duct elongation and planar cell polarity; Wnt5a/Wnt7b are redundantly required for cochlear morphogenesis; mechanistically, Wnt5a/Wnt7b-mediated ncWnt signaling promotes membrane recruitment of Daple (a Gαi guanine nucleotide exchange factor) and activates PI3K/AKT and ERK signaling to regulate asymmetric Fzd6 localization.\",\n      \"method\": \"Conditional/conventional loss-of-function mouse genetics (Wnt5a/Wnt7b double KO), PI3K/AKT and ERK pathway analysis, PCP protein localization (Fzd6, Dvl2), Daple membrane recruitment assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double KO, molecular pathway dissection (Daple/Gαi/PI3K/AKT/ERK), PCP protein localization, multiple orthogonal methods\",\n      \"pmids\": [\"39172791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The WNT7A/WNT7B-FRIZZLED-LRP5/LRP6-GPR124-RECK signaling system functions as an integral unit in limb development; loss-of-function alleles for Wnt7a, Wnt7b, Gpr124, and Reck synergize to cause reduced and dysmorphic limb bone growth, and a Reck allele specifically defective in WNT7A/WNT7B signaling recapitulates limb phenotypes.\",\n      \"method\": \"Combinations of conventional and conditional loss-of-function alleles for Wnt7a, Wnt7b, Gpr124, Reck in mice; Reck structure-function allele specifically defective in WNT7A/WNT7B signaling; limb bone growth and patterning analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional/conventional alleles in combination, structure-function allele with pathway specificity, strong genetic epistasis\",\n      \"pmids\": [\"35552394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WNT7B/FZD5 signaling activates a pathway involving ELF3 transcription factor, which in turn transcriptionally modulates NOTCH1, functioning as a tumor-suppressing axis in bladder urothelial carcinoma that represses EMT, stem-like properties, and chemoresistance.\",\n      \"method\": \"Loss-of-function and gain-of-function studies in bladder cancer cell lines, receptor identification (FZD5 as WNT7B receptor), downstream ELF3/NOTCH1 pathway analysis, EMT and stemness marker assays\",\n      \"journal\": \"Biochimica et Biophysica Acta – Molecular Basis of Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — receptor-pathway axis identified by loss/gain of function, downstream transcriptional target (ELF3-NOTCH1) proposed but mechanistic depth limited to expression assays\",\n      \"pmids\": [\"34562599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In human pancreatic progenitor cells (PPCs), WNT7B (and Wnt7a) specifically promotes progenitor cell proliferation through the non-canonical Wnt/PKC pathway, not the canonical Wnt pathway; YY1 functions as a transcriptional regulator of WNT7B expression in PPCs.\",\n      \"method\": \"siRNA screening, feeder cell lines stably expressing individual Wnt ligands, canonical vs. non-canonical Wnt pathway reporters, phosphoproteome analysis, YY1 transcriptional regulator identification\",\n      \"journal\": \"Cell Chemical Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway specificity established by reporter assays, stable Wnt7b expression system, phosphoproteomics for YY1, single lab\",\n      \"pmids\": [\"33125912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wnt7b promotes dentinogenesis by increasing proliferation and differentiation of dental mesenchymal cells partly through the ERK1/2 pathway; transgenic mice overexpressing Wnt7b in odontoblasts show increased p-ERK1/2, thinner predentin, and thicker intertubular dentin with higher mineral content; ERK1/2 inhibition partly rescues Wnt7b-induced differentiation.\",\n      \"method\": \"Dmp1-cre;ROSA26-Wnt7b transgenic mice, adenoviral Wnt7b overexpression in dental papillae cells, ERK1/2 inhibitor, Western blot, micro-CT, ALP/alizarin red staining\",\n      \"journal\": \"Archives of Oral Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic plus in vitro adenoviral overexpression with pharmacological pathway inhibition, single lab\",\n      \"pmids\": [\"31181411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Bi-allelic loss-of-function variants in WNT7B cause PDAC syndrome (pulmonary hypoplasia, diaphragmatic anomalies, anophthalmia/microphthalmia, cardiac defects); functional validation using a canonical WNT signaling luciferase assay demonstrated that identified WNT7B variants (p.Arg98*, p.Tyr75*, p.Gly188Ser) are deleterious to WNT7B signaling activity.\",\n      \"method\": \"Whole-exome sequencing, canonical WNT signaling luciferase reporter assay for variant functional validation, wnt7bb mutant zebrafish (swimbladder phenotype)\",\n      \"journal\": \"Journal of Medical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional luciferase assay validates loss-of-function, zebrafish ortholog confirms evolutionary conservation of lung development function, human genetics + functional validation\",\n      \"pmids\": [\"35790350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Wnt7b expressed by hypertrophic chondrocytes promotes endochondral ossification; Wnt7b expression in growth plate cartilage is suppressed by BMP4/Smad4 signaling; ablation of Wnt7b in Smad4 cKO mice blunts the increased bone volume phenotype, establishing Wnt7b-β-catenin as a downstream effector of Smad4-BMP signaling during endochondral ossification.\",\n      \"method\": \"Conditional Smad4 knockout, conditional Wnt7b knockout in Smad4 cKO background (genetic epistasis), BMP4 stimulation in chondrocytes, bone volume analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Wnt7b KO in Smad4 KO background), BMP4 suppression of Wnt7b in vitro, single lab\",\n      \"pmids\": [\"37539462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WNT7B binds to FZD4 (frizzled-4) receptor in periodontal ligament stem cells; Wnt7b overexpression promotes osteogenic differentiation and suppresses M1 macrophage polarization; FZD4 silencing reverses these effects, placing FZD4 as the receptor mediating WNT7B function in this context.\",\n      \"method\": \"Co-immunoprecipitation (WNT7B-FZD4 binding), FZD4 siRNA rescue experiments, osteogenic differentiation assays, macrophage polarization assays, Western blot\",\n      \"journal\": \"Molecular Medicine Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP establishes binding, rescue experiment with FZD4 KD confirms receptor specificity, single lab\",\n      \"pmids\": [\"39301638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WNT7B in cholangiocytes induces a proproliferative, proinflammatory program: in vitro, Wnt7b induces cholangiocyte proliferation and secretion of proinflammatory cytokines in an autocrine manner; loss of cholangiocyte/hepatocyte Wnt7b in vivo improves biliary injury and decreases cellular senescence in cholestasis, and Wnt7b suppression promotes hepatocyte reprogramming toward a biliary phenotype.\",\n      \"method\": \"Conditional Wnt7b knockout (Krt19-Cre and Albumin-Cre), DDC cholestasis model, proliferation assays, cytokine secretion assays, senescence markers, hepatocyte reprogramming markers\",\n      \"journal\": \"Hepatology Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two conditional knockout models (cell-type specificity), autocrine signaling established in vitro, single lab with multiple readouts\",\n      \"pmids\": [\"34558852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In the context of partially impaired Norrin signaling, the Wnt7a/Wnt7b system makes a contribution to blood-retina barrier (BRB) development; combined loss of Wnt7a and Norrin or Wnt7a and Frizzled4 causes far more severe BBB defects than loss of any single component, demonstrating partial redundancy between the Wnt7a/Wnt7b and Norrin signaling systems in BBB/BRB maintenance.\",\n      \"method\": \"Compound conditional knockouts (Wnt7a, Wnt7b, Norrin, Frizzled4, Tspan12) in mice, BBB/BRB phenotype analysis, glial-specific Wnt7a deletion\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — extensive combinatorial genetic analysis in multiple tissue-specific conditional knockouts, threshold and redundancy effects rigorously established\",\n      \"pmids\": [\"30478038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A founder WNT7B variant (Arg247Trp) significantly impairs WNT7B canonical signaling activity as demonstrated by luciferase reporter assay, causing variable PDAC syndrome phenotypes including isolated genitourinary anomalies, expanding the known phenotypic spectrum.\",\n      \"method\": \"Canonical WNT signaling luciferase reporter assay for variant functional validation\",\n      \"journal\": \"Clinical Genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (luciferase reporter), single lab, confirms prior findings but adds limited new mechanistic insight\",\n      \"pmids\": [\"38417950\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WNT7B is a secreted Wnt ligand that signals predominantly through canonical (β-catenin/LRP5-6/Frizzled-1, -4, -7, -10) and non-canonical (JNK, CaMKII, PKC, PI3K-AKT-mTORC1) pathways in a context-dependent manner; in CNS and retinal vasculature, WNT7B-specific signaling requires the co-activator complex of RECK and GPR124 in addition to Frizzled/LRP receptors; macrophage-derived WNT7B acts as a paracrine signal to drive canonical Wnt responses in adjacent epithelial or endothelial cells during organ development, repair, and tumor angiogenesis; in bone, WNT7B activates mTORC1 via PI3K-AKT and stimulates glycolysis via GLUT1 to promote osteoblast activity; in neurons, Wnt7b signals through Frizzled-7 to activate CaMKII and JNK for dendritic arborization; and epigenetic regulators including LSD1 and the lncRNA Lnc-Rewind control WNT7B transcription by modulating histone methylation at its locus.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WNT7B is a secreted Wnt ligand that coordinates proliferation, differentiation, and morphogenesis across developing and regenerating tissues by activating both canonical (β-catenin) and non-canonical Wnt responses in adjacent or autocrine target cells [#0, #5]. It binds Frizzled receptors at the cell surface—Frizzled-1 and -10 in cooperation with the LRP5 co-receptor to drive canonical signaling [#0], and Frizzled-7, -4, or -5 in other contexts [#11, #33, #28]—and in CNS, retinal, and limb vasculature WNT7-specific signaling additionally requires the membrane co-activator complex of RECK and the orphan GPCR GPR124, which assemble with Frizzled into a multiprotein receptor unit [#9, #27, #35]. A recurring theme is paracrine action: macrophage- or myeloid-derived WNT7B activates canonical Wnt responses in neighboring endothelial and epithelial cells to drive hyaloid vessel regression, kidney repair, and tumor angiogenesis through induction of VEGFA [#1, #2, #10], while epithelium-derived WNT7B instructs mesenchymal and mural-cell behavior during lung, kidney, and placental development [#3, #4, #6, #22]. In bone, WNT7B promotes osteoblast activity through PI3K-AKT-driven mTORC1 activation and GLUT1-dependent glycolysis [#8, #16], and through β-catenin-independent Ca2+/NFATc1-SOX11 signaling [#24]. Non-canonical outputs—JNK, CaMKII, PKC, and ERK1/2—mediate neuronal dendritic arborization, neurite outgrowth, and odontoblast differentiation [#11, #18, #29, #30]. WNT7B transcription is set by tissue-restricted factors (TTF-1/GATA6/Foxa2 in lung) and by BMP and androgen-receptor signaling, and is repressed epigenetically by LSD1 and by the G9a-recruiting lncRNA Lnc-Rewind [#7, #19, #13, #21, #20]. Bi-allelic loss-of-function variants in WNT7B cause PDAC syndrome (pulmonary hypoplasia, diaphragmatic anomalies, anophthalmia/microphthalmia, cardiac and genitourinary defects), with variant deleteriousness validated by canonical WNT signaling reporter assays [#31].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing how WNT7B transcription is restricted to specific epithelia answered which upstream regulators license its expression, and identified epithelial WNT7B as an essential paracrine signal for mesenchymal development.\",\n      \"evidence\": \"EMSA, reporter, Co-IP, and promoter mutagenesis defining TTF-1/GATA6/Foxa2 regulation; germline lacZ knockout showing lung hypoplasia and pulmonary vascular smooth-muscle defects\",\n      \"pmids\": [\"11914369\", \"12361974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the receptor on responding mesenchymal cells\", \"Transcriptional control characterized only in lung context\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying the receptor partners answered whether WNT7B is intrinsically canonical, showing it binds Frizzled-1/-10 with LRP5 to activate β-catenin and, in macrophages, acts as a short-range paracrine signal driving endothelial apoptosis.\",\n      \"evidence\": \"Cell-surface binding and canonical-vs-noncanonical reporter assays; macrophage-specific conditional Wnt7b deletion in mouse eye\",\n      \"pmids\": [\"15923619\", \"16163358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pathway choice shown to be cell-type dependent, not explained at the molecular level\", \"Receptor identity in macrophage-endothelial paracrine signaling not directly mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic epistasis with β-catenin established that epithelial WNT7B controls mesenchymal/interstitial cell-division plane orientation, defining its role in organ axis formation beyond simple proliferation.\",\n      \"evidence\": \"Conditional Wnt7b and interstitial β-catenin knockouts with division-plane and urine-concentration analysis in kidney\",\n      \"pmids\": [\"19060336\", \"18367557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effector genes downstream of β-catenin in oriented division not identified\", \"Autocrine vs paracrine contributions only partially separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Cancer and vascular studies answered whether WNT7B acts autocrine or paracrine in disease, showing autocrine β-catenin signaling sustains PDAC growth while AR-driven WNT7B uses non-canonical PKC, and EC-intrinsic WNT7B suppresses endothelial-mesenchymal transition.\",\n      \"evidence\": \"siRNA/WLS/IWP-2 reporter assays in PDAC; AR ChIP and PKC inhibitors in CRPC; endothelial-specific Cdh5-Cre knockout with osteogenic-gene and Smad1/5 analysis\",\n      \"pmids\": [\"23416978\", \"23386686\", \"23685555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptors mediating autocrine signaling in these contexts not defined\", \"PKC isozyme specificity not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Bone and tumor-angiogenesis work answered how WNT7B couples to metabolism and the angiogenic switch, placing PI3K-AKT-mTORC1 downstream in osteoblasts and VEGFA induction downstream in tumor endothelium.\",\n      \"evidence\": \"Raptor-deletion epistasis rescuing WNT7B high-bone-mass phenotype; myeloid-specific Wnt7b knockout in MMTV-PyMT with VEC reporter and VEGFA analysis\",\n      \"pmids\": [\"24497849\", \"24638982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a Wnt ligand engages PI3K-AKT mechanistically not resolved\", \"Link between canonical signaling and VEGFA transcription not directly mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery of the RECK-GPR124 co-activator complex answered how WNT7B achieves ligand-specific signaling in CNS endothelium, defining a multiprotein receptor unit assembled with Frizzled.\",\n      \"evidence\": \"EC-specific Reck knockouts, interface mutagenesis, and soluble-domain probe binding assays demonstrating Frizzled-WNT7-RECK-GPR124 assembly\",\n      \"pmids\": [\"28803732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the assembled complex not solved\", \"How RECK/GPR124 bias signaling output not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Neuronal and barrier studies answered which non-canonical effectors WNT7B uses and how it cooperates with related ligands, identifying Frizzled-7/Dvl1-CaMKII/JNK signaling for dendrites and partial redundancy with Norrin for the blood-brain/retina barrier.\",\n      \"evidence\": \"Fz7 loss-of-function with CaMKII/JNK phospho-readouts in hippocampus; combinatorial Wnt7a/Wnt7b/Norrin/Frizzled4 conditional knockouts with BBB/BRB phenotyping\",\n      \"pmids\": [\"29898920\", \"30478038\", \"18177422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional separation of WNT7A vs WNT7B contributions limited\", \"Connection between CaMKII/JNK activation and cytoskeletal remodeling not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Epigenetic and stem-cell studies answered how WNT7B levels are tuned and how it signals β-catenin-independently, defining LSD1 and Lnc-Rewind/G9a-H3K9 repression and a Ca2+/NFATc1-SOX11 osteogenic axis.\",\n      \"evidence\": \"LSD1 conditional knockout with WNT7B epistasis; RIP/ChIP for G9a-H3K9me2 at the Wnt7b locus; transgenic overexpression with ChIP-qPCR for NFATc1-SOX11 targets\",\n      \"pmids\": [\"29707403\", \"33432928\", \"32346881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Epigenetic regulators tested in single lineages only\", \"Receptor coupling to the Ca2+/NFATc1 branch not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Human genetics and limb genetics answered whether WNT7B loss is disease-causing and whether the RECK-GPR124 unit operates outside CNS, defining PDAC syndrome and a WNT7-FZD-LRP5/6-GPR124-RECK module in limb skeletal growth.\",\n      \"evidence\": \"Exome sequencing with canonical WNT luciferase validation and zebrafish ortholog; combinatorial Wnt7a/Wnt7b/Gpr124/Reck alleles with a signaling-specific Reck allele in limb\",\n      \"pmids\": [\"35790350\", \"35552394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype-phenotype correlation across PDAC variants incompletely defined\", \"Tissue-specific deployment of the RECK-GPR124 module not comprehensively mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cochlear and additional disease studies answered how WNT7B drives planar cell polarity and clarified receptor usage, defining a Wnt5a/Wnt7b-Daple-Gαi-PI3K/AKT/ERK PCP pathway and FZD4/FZD5 receptor contexts.\",\n      \"evidence\": \"Wnt5a/Wnt7b double knockout with Daple recruitment, PI3K/AKT/ERK and Fzd6 localization analysis; FZD4 Co-IP/rescue and FZD5-ELF3-NOTCH1 axis studies; founder-variant reporter assay\",\n      \"pmids\": [\"39172791\", \"39301638\", \"34562599\", \"38417950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Multiple Frizzled receptors implicated without a unifying selectivity rule\", \"Whether the same Daple/PCP machinery operates in other WNT7B-dependent tissues unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what determines WNT7B's choice between canonical and non-canonical outputs across tissues, and how its diverse Frizzled receptors and the RECK-GPR124 co-activator are selected in each context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of WNT7B-receptor-coreceptor complexes\", \"Rules governing canonical vs non-canonical pathway selection unknown\", \"Receptor-effector matching across tissues not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 9, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 18, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 18, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4, 6, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 12, 31]}\n    ],\n    \"complexes\": [\"WNT7-Frizzled-LRP5/6-GPR124-RECK signaling complex\"],\n    \"partners\": [\"FZD1\", \"FZD10\", \"FZD7\", \"FZD4\", \"FZD5\", \"LRP5\", \"RECK\", \"GPR124\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}