{"gene":"LGR6","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2000,"finding":"LGR6 was identified as a leucine-rich repeat-containing G protein-coupled receptor with a subgroup-specific hinge region after leucine-rich repeats. Unlike LGR7, LGR6 lacks the LDL receptor cysteine-rich motif at the N terminus. Phylogenetic analysis placed LGR6 in the LGR4-6 subgroup, distinct from glycoprotein hormone receptors and LGR7.","method":"Molecular cloning, phylogenetic analysis, structural domain analysis","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular cloning with domain characterization, single lab but orthogonal structural and phylogenetic analyses","pmids":["10935549"],"is_preprint":false},{"year":2012,"finding":"LGR6 binds R-spondins 1–3 with high affinity and potentiates Wnt/β-catenin signaling through increased LRP6 phosphorylation. LGR6 is not coupled to heterotrimeric G proteins or β-arrestin following R-spondin stimulation. A colon cancer somatic mutation in LGR6 abolishes R-spondin binding and response (loss-of-function), while two other cancer mutations had no significant effect on receptor function. Overexpression of wild-type LGR6 in HeLa cells increases cell migration following co-treatment with R-spondin1 and Wnt3a compared to loss-of-function mutant.","method":"Binding assays, luciferase reporter (Wnt/β-catenin), LRP6 phosphorylation western blot, β-arrestin recruitment assay, G protein coupling assay, cell migration assay, site-directed mutagenesis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including binding assays, signaling readouts, mutagenesis, and functional migration assays in a single study","pmids":["22615920"],"is_preprint":false},{"year":2017,"finding":"In the adult lung, Lgr6+ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia. These Lgr6+ mesenchymal cells promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair in vivo.","method":"Genetic lineage tracing, single-cell RNA sequencing, organoid culture, genetic cell ablation, in vivo injury model","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (lineage tracing, scRNA-seq, organoids, genetic ablation) in a single rigorous study","pmids":["28886383"],"is_preprint":false},{"year":2019,"finding":"Maresin 1 (MaR1) is a stereoselective activator of human LGR6 identified by unbiased screening of >200 GPCRs. MaR1 specifically binds LGR6 (confirmed by [3H]-labeled MaR1 binding). MaR1 activation of LGR6 in phagocytes enhanced phagocytosis, efferocytosis, and phosphorylation of ERK and CREB. These actions were amplified by LGR6 overexpression and diminished by LGR6 gene silencing.","method":"Unbiased GPCR screen (>200 receptors), reporter cell assay, functional impedance sensing, radioligand binding ([3H]-MaR1), LGR6 overexpression and siRNA knockdown, phagocytosis/efferocytosis assays, phosphoprotein analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — radioligand binding, functional reporter assays, and gain/loss-of-function experiments with defined cellular phenotypes, multiple orthogonal methods in one study","pmids":["31657786"],"is_preprint":false},{"year":2010,"finding":"Lgr6 marks the most primitive epidermal stem cell population located in a region directly above the follicle bulge in adult hair follicles, expressing none of the known bulge stem cell markers. Prenatal Lgr6+ cells established the hair follicle, sebaceous gland, and interfollicular epidermis. Postnatally, Lgr6+ cells generated sebaceous gland and interfollicular epidermis, with contribution to hair lineages diminishing with age. Adult Lgr6+ cells executed long-term wound repair including formation of new hair follicles.","method":"Knock-in allele generation, genetic lineage tracing, histology, immunofluorescence","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in reporter alleles with comprehensive lineage tracing across developmental stages, replicated across multiple tissue compartments","pmids":["20223988"],"is_preprint":false},{"year":2015,"finding":"Lgr6 is expressed within cells of the nail matrix epithelium and in a subset of bone and eccrine sweat gland cells. Genetic lineage tracing demonstrated that Lgr6-expressing cells give rise to the nail during homeostatic growth, establishing Lgr6 as a nail stem cell marker. Lgr6-expressing cells contribute to the blastema during digit tip regeneration. Lgr6-deficient mice exhibit nail and bone regeneration defects.","method":"Genetic lineage tracing, Lgr6-deficient mouse analysis, histology, digit tip amputation/regeneration model","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — lineage tracing combined with loss-of-function (Lgr6-deficient mice) showing defined regeneration phenotype","pmids":["26460010"],"is_preprint":false},{"year":2021,"finding":"Lgr6 marks a regionally restricted population of epidermal stem cells that interact with nerves and specialize in wound re-epithelialization. Diphtheria toxin-mediated ablation of Lgr6+ stem cells delays wound healing. Skin denervation phenocopies this effect, diminishing wound re-epithelialization by Lgr6+ stem cells. Loss of nerve niche shifts fate of Lgr6+ stem cells toward differentiation.","method":"Diphtheria toxin-mediated cell ablation, skin denervation, intravital imaging, single-cell lineage tracing, gene expression analysis","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic ablation, intravital imaging, and nerve denervation experiments with specific wound healing phenotype, multiple orthogonal methods","pmids":["34102139"],"is_preprint":false},{"year":2019,"finding":"Silencing LGR6 in ovarian cancer cells inhibited cancer stem cell-like phenotype and chemoresistance in vitro and improved cisplatin sensitivity in vivo. Mechanistic investigation showed that silencing LGR6 repressed Wnt/β-catenin signaling, as determined by luciferase assays and GSEA.","method":"siRNA knockdown, luciferase reporter assay (Wnt/β-catenin), GSEA, in vitro functional assays, in vivo xenograft","journal":"Molecular therapy oncolytics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and Wnt signaling readout, single lab","pmids":["31193124"],"is_preprint":false},{"year":2021,"finding":"LGR6 promotes osteogenesis in vitro and in vivo. In murine osteoblastic cells, LGR6 overexpression increased β-catenin stability to potentiate Wnt/β-catenin signaling, promoting osteogenic differentiation and mineralization. LGR6 knockdown decreased β-catenin stability and inhibited osteogenesis. CRISPR-Cas9 Lgr6 knockout mice have reduced trabecular bone mass. Mechanistically, RSPO2 stimulates LGR6-mediated Wnt/β-catenin signaling, whereas MaR1 stimulates LGR6-mediated cAMP activity, indicating two ligand-dependent signaling functions.","method":"Lentiviral overexpression/knockdown, CRISPR-Cas9 knockout mice, microCT, ex vivo osteodifferentiation, in vitro signaling assays (Wnt reporter, cAMP assay), western blot","journal":"Bone","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro and in vivo experiments with defined molecular mechanism, CRISPR knockout model, and distinct ligand-dependent signaling dissected by orthogonal assays","pmids":["34856421"],"is_preprint":false},{"year":2021,"finding":"LGR6 activation by MaR1 attenuated abdominal aortic aneurysm (AAA) growth in mice. In vivo inhibition of LGR6 receptors abolished MaR1-dependent protection. MaR1-LGR6 interaction upregulated TGF-β2 expression and decreased MMP2 activity in macrophage-apoptotic SMC crosstalk in vitro. MaR1 via LGR6 also upregulated macrophage-dependent efferocytosis of apoptotic SMCs.","method":"In vivo LGR6 inhibition, elastase AAA mouse model, smooth muscle cell-specific TGFβr2 knockout mice, in vitro macrophage-SMC co-culture, MMP2 activity assay, efferocytosis assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo receptor inhibition with defined phenotype, in vitro mechanistic follow-up, single lab","pmids":["34320253"],"is_preprint":false},{"year":2021,"finding":"LGR6 activates the Wnt/β-catenin signaling pathway in cervical cancer stem cells and forms a positive feedback loop: LGR6 activates Wnt/β-catenin signaling, which upregulates TCF7L2 expression; TCF7L2 then complexes with β-catenin in the nucleus to enhance LGR6 transcription by binding the LGR6 promoter.","method":"RNA sequencing, TOP/FOP luciferase reporter assay, RT-PCR, western blotting, FACS isolation of LGR6high cells, transcription factor binding assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays and chromatin binding demonstrating feedback loop, multiple methods, single lab","pmids":["34489551"],"is_preprint":false},{"year":2024,"finding":"LGR6 regulates mitochondrial biogenesis and suppresses ferroptosis in diabetic cardiomyopathy via the STAT3/PGC1α signaling pathway. LGR6 knockout aggravated, and cardiomyocyte-specific LGR6 overexpression ameliorated, cardiac dysfunction, ferroptosis, and mitochondrial biogenesis disruption. STAT3 inhibition and PGC1α activation abrogated LGR6 knockout-induced mitochondrial dysfunction. LGR6 activation by recombinant RSPO3 ameliorated cardiac dysfunction, ferroptosis, and mitochondrial dysfunction in diabetic mice.","method":"LGR6 knockout mice, cardiomyocyte-specific AAV9-LGR6 overexpression, RNA sequencing, chromatin immunoprecipitation (ChIP), in vitro high glucose model, RSPO3 treatment","journal":"Metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO and OE with defined molecular mechanism via RNA-seq and ChIP, RSPO3 rescue experiment, multiple orthogonal approaches","pmids":["39038735"],"is_preprint":false},{"year":2024,"finding":"LGR6 protects against myocardial ischemia-reperfusion injury by suppressing necroptosis via the Wnt signaling pathway. LGR6 regulates expression of STAT2 and ZBP1 by activating Wnt signaling, thereby inhibiting cardiomyocyte necroptosis. LGR6 deficiency promoted and overexpression inhibited necroptosis and acute myocardial injury after I/R. RSPO3 activation of LGR6 protected mice from acute myocardial I/R injury. Inhibiting STAT2 and ZBP1 alleviated LGR6 deficiency-induced necroptosis.","method":"LGR6 knockout mice, in vivo I/R model (left anterior descending coronary artery ligation), RNA sequencing, ChIP assay, RSPO3 treatment, in vitro hypoxia-reoxygenation model","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO and rescue with defined STAT2/ZBP1/Wnt mechanism, RNA-seq and ChIP validation, multiple orthogonal methods","pmids":["39471639"],"is_preprint":false},{"year":2022,"finding":"MaR1-LGR6 signaling mitigated CXCL1 secretion by epithelial cells in the context of lung ischemia-reperfusion injury. LGR6 siRNA treatment in mice abolished MaR1-dependent protection against lung I/R injury.","method":"LGR6 siRNA in vivo treatment, hilar-ligation lung I/R model, orthotopic lung transplantation model, in vitro alveolar macrophage and type II epithelial cell assays","journal":"The Journal of heart and lung transplantation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown in vivo with defined signaling readout, single lab","pmids":["36628837"],"is_preprint":false},{"year":2023,"finding":"LGR6 is required for proper fracture healing and bone regeneration. Lgr6-null mice showed deficiency in periosteal progenitor proliferation, reduced ALP activity, impaired endochondral ossification, and decreased mineralization during fracture repair. Skeletal progenitors from Lgr6-null mice had reduced colony-forming potential and attenuated canonical Wnt signaling. Lgr6-null mice also comprised a lower proportion of self-renewing stem cells.","method":"Lgr6-null mouse model, fracture healing model, ALP activity assay, colony-forming assay, Wnt signaling analysis, histological analysis","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive null mouse analysis with defined molecular and cellular phenotype in fracture repair, multiple orthogonal methods","pmids":["36708855"],"is_preprint":false},{"year":2022,"finding":"Mechanical tension preferentially activates and drives differentiation of Lgr6+ epidermal stem cells to achieve skin growth, driven in part by the Hippo pathway. This was established through a controlled tissue expansion system in mice combined with machine learning-guided 3D tissue reconstruction and single-cell RNA sequencing.","method":"Controlled tissue expansion in mice, machine learning-guided 3D tissue reconstruction, single-cell RNA sequencing, lineage tracing","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo lineage tracing with scRNA-seq mechanosensitive pathway analysis, single lab, multiple methods","pmids":["35476447"],"is_preprint":false},{"year":2023,"finding":"The lncRNA LITTIP binds to mRNA of LGR6 and to the RNA-binding protein HnRNPK, forming a LITTIP/Lgr6/HnRNPK complex. LITTIP promotes LGR6 expression via HnRNPK, and this elevated LGR6 activates Wnt/β-catenin signaling to negatively regulate cementogenesis.","method":"ChIRP (chromatin isolation by RNA purification), RNA immunoprecipitation (RIP), co-transfection, RNA microarray, western blot","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIRP and RIP demonstrate direct binding, co-transfection confirms complex formation, single lab","pmids":["37558690"],"is_preprint":false},{"year":2017,"finding":"Two anti-LGR6 monoclonal antibodies (43A6 and 43D10) that recognize the large N-terminal extracellular domain of LGR6 competitively blocked the binding of R-spondin 1, confirming that R-spondin 1 binds to the extracellular domain of LGR6.","method":"Monoclonal antibody generation, competitive binding assay, flow cytometry with LGR4/5/6-transfected cells (specificity), immunoblot","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive binding assay with specific antibodies confirming ligand-binding domain, single lab","pmids":["28013222"],"is_preprint":false},{"year":2023,"finding":"LGR6 expression is transiently induced during myogenic differentiation in a retinoic acid receptor (RARα/RARγ)-dependent manner, requiring ATRA. LGR6 loss decreased myoblast differentiation and fusion indices. LGR6 promotes Wnt/β-catenin signaling induced by Wnt3a and R-spondin 2 in myoblasts. LGR6 expression is downregulated by the ubiquitin-proteasome system involving ZNRF3.","method":"siRNA knockdown, lentiviral overexpression, differentiation/fusion index assays, RAR agonist treatment, proteasome inhibitor treatment, Znrf3 knockdown, Wnt reporter assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype and pathway, multiple orthogonal approaches, single lab","pmids":["37240382"],"is_preprint":false},{"year":2024,"finding":"An LGR6 frameshift variant leads to significant downregulation of LGR6 expression specifically in neutrophils, monocytes, and NK cells but not in monocyte-derived macrophages or CD8+ T cells. Loss of LGR6 in neutrophils and monocytes was linked to decreased phagocytosis of bacteria, increased neutrophil chemotaxis, elevated leukotriene B4 production, and increased activation markers. Neutrophils, NK cells, and CD8+ T cells from variant carriers displayed altered responses to TLR3, TLR7/8, and TLR9 agonists.","method":"Human genetic variant analysis, flow cytometry, phagocytosis assay, chemotaxis assay, leukotriene B4 measurement, TLR agonist stimulation, UK Biobank epidemiological data","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic variant with multiple functional readouts in primary cells, single lab, multiple orthogonal methods","pmids":["38718314"],"is_preprint":false},{"year":2022,"finding":"Maresin 1 alleviates diabetic kidney disease via LGR6-mediated cAMP-SOD2 antioxidant pathway. LGR6 expression was downregulated in DKD and high-glucose-treated HK-2 cells but upregulated by MaR1. LGR6 siRNA knockdown abrogated MaR1's protective effects against glucotoxicity-induced inflammation.","method":"LGR6 siRNA knockdown, in vivo diabetic mouse model (STZ/high fat diet), HK-2 cell high glucose model, cAMP measurement, SOD2 activity assay, inflammatory marker analysis","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro siRNA knockdown and in vivo model with defined cAMP-SOD2 pathway, single lab","pmids":["35498124"],"is_preprint":false},{"year":2024,"finding":"Maresin 1 activates LGR6 in microglia to attenuate neuroinflammation after subarachnoid hemorrhage via CREB/JMJD3/IRF4 signaling. Knockdown of LGR6, inhibition of CREB phosphorylation, or inhibition of JMJD3 activity abolished MaR1's anti-neuroinflammatory effects. LGR6 and JMJD3 are co-localized with microglia.","method":"LGR6 siRNA knockdown in rats, SAH model (endovascular perforation), immunohistochemistry, neurobehavioral testing, CREB inhibitor (KG-501), JMJD3 inhibitor (GSK-J4), cytokine analysis","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo siRNA with pharmacological inhibitors, defined CREB/JMJD3/IRF4 pathway, single lab","pmids":["38340785"],"is_preprint":false},{"year":2023,"finding":"In mice lacking Lgr6, RSV infection caused exacerbated type 2 immune responses with increased viral burden and blunted responses to exogenous MaR1. LGR6 was constitutively expressed on regulatory T cells (Tregs). MaR1-LGR6 signaling improved Tregs' suppressive function and upregulated host antiviral genes.","method":"Lgr6 knockout mice, RSV infection model, flow cytometry, cytokine measurement, viral transcript quantification, MaR1 treatment","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Lgr6 KO mice with defined viral infection phenotype and MaR1 rescue, single lab","pmids":["36595677"],"is_preprint":false},{"year":2024,"finding":"MaR1 reduces blood pressure elevation and alleviates vascular remodeling in angiotensin II-infused mice through LGR6. LGR6 knockout aggravated pathological vascular remodeling and could not be reversed by additional MaR1 treatment. Mechanistically, MaR1 regulates vascular smooth muscle cell activity through LGR6 via Ca2+/calmodulin-dependent protein kinase II/NRF2/HO-1 signaling.","method":"LGR6 knockout mice, angiotensin II infusion model, VSMC culture, western blot, functional VSMC assays (proliferation, migration, phenotype switching, pyroptosis)","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LGR6 knockout rescue experiment with defined CaMKII/NRF2/HO-1 signaling pathway, single lab","pmids":["38463394"],"is_preprint":false},{"year":2024,"finding":"LGR6 overexpression in macrophages enhanced efferocytosis of apoptotic nucleus pulposus cells, increased ECM components (COL2A1), decreased matrix-degrading enzymes (MMP13), and inhibited IL-1β-induced apoptosis by upregulating BCL2 and downregulating cleaved caspase 3 and BAX. LGR6 knockdown impaired these effects.","method":"LGR6 shRNA knockdown and overexpression, macrophage-NPC co-culture, efferocytosis assay, western blot, in vivo mouse IVDD model (disc puncture)","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss-of-function in vitro with in vivo corroboration, defined efferocytosis and apoptosis mechanism, single lab","pmids":["40281518"],"is_preprint":false},{"year":2014,"finding":"Lgr6 expression in the skin epidermis is controlled by nerve endings and Schwann cells. Ablation of cutaneous nerves leads to degeneration of Schwann cells and diminished expression of Lgr6 in skin.","method":"Nerve ablation experiments, immunofluorescence co-localization, histological analysis across hair cycle stages","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nerve ablation with defined Lgr6 expression phenotype, single lab, two orthogonal approaches","pmids":["24499442"],"is_preprint":false},{"year":2018,"finding":"LGR6 knockdown in gastric cancer cells downregulated phosphorylated AKT and mTOR and upregulated proapoptotic proteins Bax and Caspase-3, while decreasing antiapoptotic Bcl2. LGR6 controls gastric cancer cell proliferation, apoptosis, migration, and invasion through the PI3K/AKT/mTOR pathway.","method":"Lentiviral shRNA knockdown, lentiviral overexpression, western blot (pAKT, pmTOR), functional assays (proliferation, apoptosis, migration, invasion)","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single approach per pathway component, no pathway rescue experiments","pmids":["29872314"],"is_preprint":false},{"year":2019,"finding":"LGR6 promotes osteogenic differentiation and mineralization in osteoblastic progenitor MC3T3-E1 cells by stabilizing β-catenin to potentiate the Wnt/β-catenin signaling pathway. LGR6 knockdown inhibited osteogenesis by enhancing β-catenin degradation.","method":"Lentiviral overexpression and knockdown, β-catenin stability assay, osteogenic differentiation and mineralization assays, western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss-of-function with defined β-catenin stability mechanism, single lab, multiple functional readouts","pmids":["31500806"],"is_preprint":false},{"year":2016,"finding":"Lgr6 marks rare mammary gland progenitor cells. Lgr6+ cells in mammary gland are unipotent progenitors that expand clonally during puberty and regain proliferative potency during pregnancy or following ovarian hormone stimulation. Oncogenic mutations in Lgr6+ cells result in expansion of luminal cells and mammary tumors. Depletion of Lgr6+ cells in the MMTV-PyMT model significantly impaired tumor growth.","method":"Lineage tracing, cell depletion experiments, hormonal stimulation, oncogenic mutation induction, MMTV-PyMT tumor model","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive lineage tracing, genetic cell depletion in tumor model, and hormone stimulation experiments with defined cellular phenotype","pmids":["27798604"],"is_preprint":false},{"year":2017,"finding":"Lgr6, but not Lgr5, acts as an epithelial stem cell marker in squamous cell carcinomas (SCC). Lgr6 downregulation in vivo causes increased epidermal proliferation with expanded lineage tracing from Lgr6+ epidermal stem cells. Lgr6 germline knockout mice are predisposed to SCC development, through a mechanism that includes compensatory upregulation of Lgr5.","method":"Lineage tracing in reporter mice, Lgr6 germline knockout mice, single-molecule in situ hybridization, cell sorting, SCC mouse model","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — lineage tracing, germline knockout with defined carcinogenesis phenotype and compensatory Lgr5 upregulation mechanism, multiple orthogonal methods","pmids":["28945253"],"is_preprint":false},{"year":2016,"finding":"High levels of miR-19 family members (from the miR-17-92 cluster) target and downregulate p38α kinase in Lgr6+ NSCLC cells, providing a survival signal mediated by increased Wnt/β-catenin activity. Defective repression of the miR-17-92 cluster is responsible for selection of Lgr6+ NSCLC cells with self-renewal and higher tumorigenic potential.","method":"miR target validation, p38α kinase measurement, Wnt/β-catenin reporter assays, cell sorting, tumor formation assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — miR target validation with defined p38α-Wnt signaling mechanism, single lab","pmids":["27197183"],"is_preprint":false},{"year":2024,"finding":"Lgr6 is expressed in osteoprogenitor cells and is dynamically regulated during BMP-mediated osteogenesis. BMP signaling elements including pSMAD and BMP-related gene ontology pathways are downregulated in the absence of Lgr6, indicating a molecular interdependency between Lgr6 and the BMP pathway.","method":"RNA sequencing, bioinformatic analysis of published single-cell data, biochemical assays, BMP stimulation experiments with Lgr6 KO and WT cells","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq and biochemical approaches identifying BMP-Lgr6 interdependency, single lab","pmids":["39033993"],"is_preprint":false}],"current_model":"LGR6 is a leucine-rich repeat-containing G protein-coupled receptor that functions as a high-affinity receptor for R-spondins (particularly RSPO1–3) and maresin 1 (MaR1), transducing two distinct ligand-dependent signals: R-spondin binding potentiates Wnt/β-catenin signaling through LRP6 phosphorylation and β-catenin stabilization (without G protein or β-arrestin coupling), while MaR1 binding stimulates cAMP activity; these signaling functions support stem cell maintenance in skin, bone, lung, mammary gland, and other epithelia, and mediate pro-resolving immune functions including enhanced phagocytosis, efferocytosis, and anti-inflammatory signaling in macrophages, neutrophils, and T cells."},"narrative":{"mechanistic_narrative":"LGR6 is a leucine-rich repeat-containing G protein-coupled receptor of the LGR4-6 subgroup that marks and sustains tissue-resident stem and progenitor populations across multiple epithelia while transducing two distinct ligand-dependent signals [PMID:10935549, PMID:20223988, PMID:34856421]. As a high-affinity receptor for R-spondins 1-3, binding through its large N-terminal extracellular domain, LGR6 potentiates canonical Wnt/β-catenin signaling by promoting LRP6 phosphorylation and β-catenin stabilization without coupling to heterotrimeric G proteins or β-arrestin [PMID:22615920, PMID:28013222, PMID:31500806]. A second ligand, the pro-resolving lipid mediator maresin 1 (MaR1), is a stereoselective LGR6 agonist that drives cAMP-dependent and ERK/CREB signaling in phagocytes to enhance phagocytosis and efferocytosis, establishing LGR6 as a receptor with both Wnt-potentiating and cAMP-coupled outputs [PMID:31657786, PMID:34856421]. Through Wnt/β-catenin activation, LGR6 maintains the most primitive epidermal stem cells and drives wound re-epithelialization, nail and digit-tip regeneration, mammary progenitor expansion, lung airway repair, and osteogenic differentiation and fracture healing [PMID:20223988, PMID:26460010, PMID:34102139, PMID:34856421, PMID:36708855, PMID:27798604]. The Wnt-potentiating axis also underlies oncogenic roles, where LGR6 supports cancer stem-cell phenotypes and chemoresistance and can engage a TCF7L2-β-catenin positive feedback loop that amplifies its own transcription [PMID:31193124, PMID:34489551, PMID:28945253]. Via the MaR1 axis, LGR6 mediates pro-resolving and cytoprotective functions in macrophages, neutrophils, regulatory T cells, and parenchymal cells, attenuating injury in vascular, cardiac, renal, pulmonary, and neuroinflammatory disease models through pathways including cAMP-SOD2, STAT3/PGC1α, and Wnt-dependent suppression of necroptosis [PMID:34320253, PMID:39038735, PMID:39471639, PMID:35498124, PMID:36595677]. A human LGR6 frameshift variant downregulates the receptor in neutrophils, monocytes, and NK cells and alters their phagocytic, chemotactic, and TLR-responsive functions, linking LGR6 to innate immune competence [PMID:38718314].","teleology":[{"year":2000,"claim":"Established LGR6 as a distinct leucine-rich repeat GPCR, defining its receptor architecture before any ligand was known.","evidence":"molecular cloning, phylogenetic and structural domain analysis","pmids":["10935549"],"confidence":"Medium","gaps":["no ligand identified","no signaling output defined","no tissue function established"]},{"year":2010,"claim":"Resolved whether LGR6 marks a functional stem cell pool by showing Lgr6+ cells are the most primitive epidermal stem cells generating all skin lineages and executing wound repair.","evidence":"knock-in reporter alleles with genetic lineage tracing in mouse skin","pmids":["20223988"],"confidence":"High","gaps":["ligand and receptor signaling driving the stem state not addressed","molecular mechanism of fate choice unresolved"]},{"year":2012,"claim":"Identified the first LGR6 ligand and its signaling logic, showing R-spondins bind LGR6 and potentiate Wnt/β-catenin via LRP6 without G protein or β-arrestin coupling.","evidence":"binding assays, Wnt luciferase reporter, LRP6 phosphorylation blots, G protein/β-arrestin assays, cancer mutagenesis in cell lines","pmids":["22615920"],"confidence":"High","gaps":["downstream effector beyond LRP6 not detailed","no structural model of R-spondin–LGR6 binding","mechanism of Wnt potentiation without canonical GPCR coupling unexplained"]},{"year":2016,"claim":"Extended LGR6 stem/progenitor function beyond skin to mammary gland and linked it to tumorigenesis.","evidence":"lineage tracing, cell depletion, oncogenic induction, MMTV-PyMT tumor model; parallel NSCLC miR-17-92/p38α-Wnt study","pmids":["27798604","27197183"],"confidence":"High","gaps":["receptor signaling requirement in mammary progenitors not directly tested","ligand source in tumors undefined"]},{"year":2017,"claim":"Localized R-spondin binding to the LGR6 N-terminal ectodomain and defined Lgr6 as a niche-supplying mesenchymal marker in lung repair.","evidence":"competitive antibody binding to ectodomain; lung lineage tracing, scRNA-seq, organoids and genetic ablation","pmids":["28013222","28886383","28945253"],"confidence":"High","gaps":["structural binding interface not mapped","how Lgr6+ mesenchyme signals to epithelium beyond Wnt-Fgf10 unclear"]},{"year":2019,"claim":"Discovered a second, structurally unrelated ligand by identifying MaR1 as a stereoselective LGR6 agonist that drives phagocyte pro-resolving functions, revealing dual ligand recognition.","evidence":"unbiased >200 GPCR screen, [3H]-MaR1 radioligand binding, reporter assays, gain/loss-of-function phagocytosis/efferocytosis with ERK/CREB phosphorylation","pmids":["31657786","31193124","31500806"],"confidence":"High","gaps":["MaR1 binding site relative to R-spondin site unmapped","G protein coupling for cAMP output not directly demonstrated in this study"]},{"year":2021,"claim":"Formally separated LGR6's two signaling arms, showing RSPO2 drives Wnt/β-catenin while MaR1 drives cAMP from the same receptor, with bone as the in vivo readout.","evidence":"CRISPR-Cas9 Lgr6 knockout mice, microCT, osteodifferentiation, Wnt reporter and cAMP assays","pmids":["34856421","34489551"],"confidence":"High","gaps":["determinants of ligand-biased output not defined","whether the two ligands compete or act on distinct receptor states unknown"]},{"year":2022,"claim":"Demonstrated MaR1-LGR6 pro-resolving signaling protects multiple tissues, defining cAMP-SOD2 and Treg-mediated antiviral mechanisms.","evidence":"in vivo LGR6 siRNA/knockout in diabetic kidney, lung I/R, and RSV models; 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spondylitis: A case-control study.","date":"2023","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37802707","citation_count":4,"is_preprint":false},{"pmid":"32244172","id":"PMC_32244172","title":"Epithelial stem cell marker LGR6 expression identifies a low-risk subgroup in human papillomavirus positive oropharyngeal squamous cell carcinoma.","date":"2020","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32244172","citation_count":4,"is_preprint":false},{"pmid":"39040684","id":"PMC_39040684","title":"Reassessing the genetic lineage tracing of lingual Lgr5 and Lgr6 cells in vivo.","date":"2024","source":"Animal cells and systems","url":"https://pubmed.ncbi.nlm.nih.gov/39040684","citation_count":3,"is_preprint":false},{"pmid":"28013222","id":"PMC_28013222","title":"Generation and characterization of monoclonal antibodies against human LGR6.","date":"2017","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28013222","citation_count":2,"is_preprint":false},{"pmid":"37770230","id":"PMC_37770230","title":"WNT enhancing signals in pancreatic cancer are transmitted by LGR6.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/37770230","citation_count":2,"is_preprint":false},{"pmid":"36371908","id":"PMC_36371908","title":"LGR6-dependent conditional inactivation of E-cadherin and p53 leads to invasive skin and mammary carcinomas in mice.","date":"2022","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/36371908","citation_count":2,"is_preprint":false},{"pmid":"22576653","id":"PMC_22576653","title":"Identification and developmental expression of leucine-rich repeat-containing G protein-coupled receptor 6 (lgr6) in the medaka fish, Oryzias latipes.","date":"2012","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/22576653","citation_count":2,"is_preprint":false},{"pmid":"28987003","id":"PMC_28987003","title":"RNA-seq analysis of Lgr6+ stem cells and identification of an Lgr6 isoform.","date":"2017","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/28987003","citation_count":1,"is_preprint":false},{"pmid":"38743670","id":"PMC_38743670","title":"Lgr6-expressing functional nail stem-like cells differentiated from human-induced pluripotent stem cells.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38743670","citation_count":1,"is_preprint":false},{"pmid":"41380874","id":"PMC_41380874","title":"Recombinant human collagen XVII promotes skin repair and regeneration by upregulating Lgr6 signaling pathway.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41380874","citation_count":0,"is_preprint":false},{"pmid":"41938713","id":"PMC_41938713","title":"Lgr6+ cells in the biological system during homeostasis and injury.","date":"2025","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41938713","citation_count":0,"is_preprint":false},{"pmid":"41956197","id":"PMC_41956197","title":"Maresin1 mitigates morphine analgesic tolerance via the Lgr6 pathway.","date":"2026","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/41956197","citation_count":0,"is_preprint":false},{"pmid":"42159296","id":"PMC_42159296","title":"Omega-3 DHA as a blank canvas: A molecular approximation to how lipid mediators modulate LGR6 in inflammation resolution.","date":"2026","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/42159296","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.31.635899","title":"R-Spondin1 regulates fate of enteric neural progenitors via differential LGR4/5/6-expression in mice and humans","date":"2025-02-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.31.635899","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.01.612096","title":"A spatially-resolved blueprint of the developing human lung reveals a WNT-driven niche for basal stem cells","date":"2024-10-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.01.612096","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38027,"output_tokens":8622,"usd":0.121705,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18504,"output_tokens":3618,"usd":0.091485,"stage2_stop_reason":"end_turn"},"total_usd":0.21319,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"LGR6 was identified as a leucine-rich repeat-containing G protein-coupled receptor with a subgroup-specific hinge region after leucine-rich repeats. Unlike LGR7, LGR6 lacks the LDL receptor cysteine-rich motif at the N terminus. Phylogenetic analysis placed LGR6 in the LGR4-6 subgroup, distinct from glycoprotein hormone receptors and LGR7.\",\n      \"method\": \"Molecular cloning, phylogenetic analysis, structural domain analysis\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular cloning with domain characterization, single lab but orthogonal structural and phylogenetic analyses\",\n      \"pmids\": [\"10935549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LGR6 binds R-spondins 1–3 with high affinity and potentiates Wnt/β-catenin signaling through increased LRP6 phosphorylation. LGR6 is not coupled to heterotrimeric G proteins or β-arrestin following R-spondin stimulation. A colon cancer somatic mutation in LGR6 abolishes R-spondin binding and response (loss-of-function), while two other cancer mutations had no significant effect on receptor function. Overexpression of wild-type LGR6 in HeLa cells increases cell migration following co-treatment with R-spondin1 and Wnt3a compared to loss-of-function mutant.\",\n      \"method\": \"Binding assays, luciferase reporter (Wnt/β-catenin), LRP6 phosphorylation western blot, β-arrestin recruitment assay, G protein coupling assay, cell migration assay, site-directed mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including binding assays, signaling readouts, mutagenesis, and functional migration assays in a single study\",\n      \"pmids\": [\"22615920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In the adult lung, Lgr6+ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia. These Lgr6+ mesenchymal cells promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair in vivo.\",\n      \"method\": \"Genetic lineage tracing, single-cell RNA sequencing, organoid culture, genetic cell ablation, in vivo injury model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (lineage tracing, scRNA-seq, organoids, genetic ablation) in a single rigorous study\",\n      \"pmids\": [\"28886383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Maresin 1 (MaR1) is a stereoselective activator of human LGR6 identified by unbiased screening of >200 GPCRs. MaR1 specifically binds LGR6 (confirmed by [3H]-labeled MaR1 binding). MaR1 activation of LGR6 in phagocytes enhanced phagocytosis, efferocytosis, and phosphorylation of ERK and CREB. These actions were amplified by LGR6 overexpression and diminished by LGR6 gene silencing.\",\n      \"method\": \"Unbiased GPCR screen (>200 receptors), reporter cell assay, functional impedance sensing, radioligand binding ([3H]-MaR1), LGR6 overexpression and siRNA knockdown, phagocytosis/efferocytosis assays, phosphoprotein analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — radioligand binding, functional reporter assays, and gain/loss-of-function experiments with defined cellular phenotypes, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31657786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Lgr6 marks the most primitive epidermal stem cell population located in a region directly above the follicle bulge in adult hair follicles, expressing none of the known bulge stem cell markers. Prenatal Lgr6+ cells established the hair follicle, sebaceous gland, and interfollicular epidermis. Postnatally, Lgr6+ cells generated sebaceous gland and interfollicular epidermis, with contribution to hair lineages diminishing with age. Adult Lgr6+ cells executed long-term wound repair including formation of new hair follicles.\",\n      \"method\": \"Knock-in allele generation, genetic lineage tracing, histology, immunofluorescence\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in reporter alleles with comprehensive lineage tracing across developmental stages, replicated across multiple tissue compartments\",\n      \"pmids\": [\"20223988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Lgr6 is expressed within cells of the nail matrix epithelium and in a subset of bone and eccrine sweat gland cells. Genetic lineage tracing demonstrated that Lgr6-expressing cells give rise to the nail during homeostatic growth, establishing Lgr6 as a nail stem cell marker. Lgr6-expressing cells contribute to the blastema during digit tip regeneration. Lgr6-deficient mice exhibit nail and bone regeneration defects.\",\n      \"method\": \"Genetic lineage tracing, Lgr6-deficient mouse analysis, histology, digit tip amputation/regeneration model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — lineage tracing combined with loss-of-function (Lgr6-deficient mice) showing defined regeneration phenotype\",\n      \"pmids\": [\"26460010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Lgr6 marks a regionally restricted population of epidermal stem cells that interact with nerves and specialize in wound re-epithelialization. Diphtheria toxin-mediated ablation of Lgr6+ stem cells delays wound healing. Skin denervation phenocopies this effect, diminishing wound re-epithelialization by Lgr6+ stem cells. Loss of nerve niche shifts fate of Lgr6+ stem cells toward differentiation.\",\n      \"method\": \"Diphtheria toxin-mediated cell ablation, skin denervation, intravital imaging, single-cell lineage tracing, gene expression analysis\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic ablation, intravital imaging, and nerve denervation experiments with specific wound healing phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"34102139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Silencing LGR6 in ovarian cancer cells inhibited cancer stem cell-like phenotype and chemoresistance in vitro and improved cisplatin sensitivity in vivo. Mechanistic investigation showed that silencing LGR6 repressed Wnt/β-catenin signaling, as determined by luciferase assays and GSEA.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay (Wnt/β-catenin), GSEA, in vitro functional assays, in vivo xenograft\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and Wnt signaling readout, single lab\",\n      \"pmids\": [\"31193124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LGR6 promotes osteogenesis in vitro and in vivo. In murine osteoblastic cells, LGR6 overexpression increased β-catenin stability to potentiate Wnt/β-catenin signaling, promoting osteogenic differentiation and mineralization. LGR6 knockdown decreased β-catenin stability and inhibited osteogenesis. CRISPR-Cas9 Lgr6 knockout mice have reduced trabecular bone mass. Mechanistically, RSPO2 stimulates LGR6-mediated Wnt/β-catenin signaling, whereas MaR1 stimulates LGR6-mediated cAMP activity, indicating two ligand-dependent signaling functions.\",\n      \"method\": \"Lentiviral overexpression/knockdown, CRISPR-Cas9 knockout mice, microCT, ex vivo osteodifferentiation, in vitro signaling assays (Wnt reporter, cAMP assay), western blot\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro and in vivo experiments with defined molecular mechanism, CRISPR knockout model, and distinct ligand-dependent signaling dissected by orthogonal assays\",\n      \"pmids\": [\"34856421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LGR6 activation by MaR1 attenuated abdominal aortic aneurysm (AAA) growth in mice. In vivo inhibition of LGR6 receptors abolished MaR1-dependent protection. MaR1-LGR6 interaction upregulated TGF-β2 expression and decreased MMP2 activity in macrophage-apoptotic SMC crosstalk in vitro. MaR1 via LGR6 also upregulated macrophage-dependent efferocytosis of apoptotic SMCs.\",\n      \"method\": \"In vivo LGR6 inhibition, elastase AAA mouse model, smooth muscle cell-specific TGFβr2 knockout mice, in vitro macrophage-SMC co-culture, MMP2 activity assay, efferocytosis assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo receptor inhibition with defined phenotype, in vitro mechanistic follow-up, single lab\",\n      \"pmids\": [\"34320253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LGR6 activates the Wnt/β-catenin signaling pathway in cervical cancer stem cells and forms a positive feedback loop: LGR6 activates Wnt/β-catenin signaling, which upregulates TCF7L2 expression; TCF7L2 then complexes with β-catenin in the nucleus to enhance LGR6 transcription by binding the LGR6 promoter.\",\n      \"method\": \"RNA sequencing, TOP/FOP luciferase reporter assay, RT-PCR, western blotting, FACS isolation of LGR6high cells, transcription factor binding assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays and chromatin binding demonstrating feedback loop, multiple methods, single lab\",\n      \"pmids\": [\"34489551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGR6 regulates mitochondrial biogenesis and suppresses ferroptosis in diabetic cardiomyopathy via the STAT3/PGC1α signaling pathway. LGR6 knockout aggravated, and cardiomyocyte-specific LGR6 overexpression ameliorated, cardiac dysfunction, ferroptosis, and mitochondrial biogenesis disruption. STAT3 inhibition and PGC1α activation abrogated LGR6 knockout-induced mitochondrial dysfunction. LGR6 activation by recombinant RSPO3 ameliorated cardiac dysfunction, ferroptosis, and mitochondrial dysfunction in diabetic mice.\",\n      \"method\": \"LGR6 knockout mice, cardiomyocyte-specific AAV9-LGR6 overexpression, RNA sequencing, chromatin immunoprecipitation (ChIP), in vitro high glucose model, RSPO3 treatment\",\n      \"journal\": \"Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO and OE with defined molecular mechanism via RNA-seq and ChIP, RSPO3 rescue experiment, multiple orthogonal approaches\",\n      \"pmids\": [\"39038735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGR6 protects against myocardial ischemia-reperfusion injury by suppressing necroptosis via the Wnt signaling pathway. LGR6 regulates expression of STAT2 and ZBP1 by activating Wnt signaling, thereby inhibiting cardiomyocyte necroptosis. LGR6 deficiency promoted and overexpression inhibited necroptosis and acute myocardial injury after I/R. RSPO3 activation of LGR6 protected mice from acute myocardial I/R injury. Inhibiting STAT2 and ZBP1 alleviated LGR6 deficiency-induced necroptosis.\",\n      \"method\": \"LGR6 knockout mice, in vivo I/R model (left anterior descending coronary artery ligation), RNA sequencing, ChIP assay, RSPO3 treatment, in vitro hypoxia-reoxygenation model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO and rescue with defined STAT2/ZBP1/Wnt mechanism, RNA-seq and ChIP validation, multiple orthogonal methods\",\n      \"pmids\": [\"39471639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MaR1-LGR6 signaling mitigated CXCL1 secretion by epithelial cells in the context of lung ischemia-reperfusion injury. LGR6 siRNA treatment in mice abolished MaR1-dependent protection against lung I/R injury.\",\n      \"method\": \"LGR6 siRNA in vivo treatment, hilar-ligation lung I/R model, orthotopic lung transplantation model, in vitro alveolar macrophage and type II epithelial cell assays\",\n      \"journal\": \"The Journal of heart and lung transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown in vivo with defined signaling readout, single lab\",\n      \"pmids\": [\"36628837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGR6 is required for proper fracture healing and bone regeneration. Lgr6-null mice showed deficiency in periosteal progenitor proliferation, reduced ALP activity, impaired endochondral ossification, and decreased mineralization during fracture repair. Skeletal progenitors from Lgr6-null mice had reduced colony-forming potential and attenuated canonical Wnt signaling. Lgr6-null mice also comprised a lower proportion of self-renewing stem cells.\",\n      \"method\": \"Lgr6-null mouse model, fracture healing model, ALP activity assay, colony-forming assay, Wnt signaling analysis, histological analysis\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive null mouse analysis with defined molecular and cellular phenotype in fracture repair, multiple orthogonal methods\",\n      \"pmids\": [\"36708855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mechanical tension preferentially activates and drives differentiation of Lgr6+ epidermal stem cells to achieve skin growth, driven in part by the Hippo pathway. This was established through a controlled tissue expansion system in mice combined with machine learning-guided 3D tissue reconstruction and single-cell RNA sequencing.\",\n      \"method\": \"Controlled tissue expansion in mice, machine learning-guided 3D tissue reconstruction, single-cell RNA sequencing, lineage tracing\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo lineage tracing with scRNA-seq mechanosensitive pathway analysis, single lab, multiple methods\",\n      \"pmids\": [\"35476447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The lncRNA LITTIP binds to mRNA of LGR6 and to the RNA-binding protein HnRNPK, forming a LITTIP/Lgr6/HnRNPK complex. LITTIP promotes LGR6 expression via HnRNPK, and this elevated LGR6 activates Wnt/β-catenin signaling to negatively regulate cementogenesis.\",\n      \"method\": \"ChIRP (chromatin isolation by RNA purification), RNA immunoprecipitation (RIP), co-transfection, RNA microarray, western blot\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIRP and RIP demonstrate direct binding, co-transfection confirms complex formation, single lab\",\n      \"pmids\": [\"37558690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Two anti-LGR6 monoclonal antibodies (43A6 and 43D10) that recognize the large N-terminal extracellular domain of LGR6 competitively blocked the binding of R-spondin 1, confirming that R-spondin 1 binds to the extracellular domain of LGR6.\",\n      \"method\": \"Monoclonal antibody generation, competitive binding assay, flow cytometry with LGR4/5/6-transfected cells (specificity), immunoblot\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive binding assay with specific antibodies confirming ligand-binding domain, single lab\",\n      \"pmids\": [\"28013222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGR6 expression is transiently induced during myogenic differentiation in a retinoic acid receptor (RARα/RARγ)-dependent manner, requiring ATRA. LGR6 loss decreased myoblast differentiation and fusion indices. LGR6 promotes Wnt/β-catenin signaling induced by Wnt3a and R-spondin 2 in myoblasts. LGR6 expression is downregulated by the ubiquitin-proteasome system involving ZNRF3.\",\n      \"method\": \"siRNA knockdown, lentiviral overexpression, differentiation/fusion index assays, RAR agonist treatment, proteasome inhibitor treatment, Znrf3 knockdown, Wnt reporter assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype and pathway, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"37240382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"An LGR6 frameshift variant leads to significant downregulation of LGR6 expression specifically in neutrophils, monocytes, and NK cells but not in monocyte-derived macrophages or CD8+ T cells. Loss of LGR6 in neutrophils and monocytes was linked to decreased phagocytosis of bacteria, increased neutrophil chemotaxis, elevated leukotriene B4 production, and increased activation markers. Neutrophils, NK cells, and CD8+ T cells from variant carriers displayed altered responses to TLR3, TLR7/8, and TLR9 agonists.\",\n      \"method\": \"Human genetic variant analysis, flow cytometry, phagocytosis assay, chemotaxis assay, leukotriene B4 measurement, TLR agonist stimulation, UK Biobank epidemiological data\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic variant with multiple functional readouts in primary cells, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38718314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Maresin 1 alleviates diabetic kidney disease via LGR6-mediated cAMP-SOD2 antioxidant pathway. LGR6 expression was downregulated in DKD and high-glucose-treated HK-2 cells but upregulated by MaR1. LGR6 siRNA knockdown abrogated MaR1's protective effects against glucotoxicity-induced inflammation.\",\n      \"method\": \"LGR6 siRNA knockdown, in vivo diabetic mouse model (STZ/high fat diet), HK-2 cell high glucose model, cAMP measurement, SOD2 activity assay, inflammatory marker analysis\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro siRNA knockdown and in vivo model with defined cAMP-SOD2 pathway, single lab\",\n      \"pmids\": [\"35498124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Maresin 1 activates LGR6 in microglia to attenuate neuroinflammation after subarachnoid hemorrhage via CREB/JMJD3/IRF4 signaling. Knockdown of LGR6, inhibition of CREB phosphorylation, or inhibition of JMJD3 activity abolished MaR1's anti-neuroinflammatory effects. LGR6 and JMJD3 are co-localized with microglia.\",\n      \"method\": \"LGR6 siRNA knockdown in rats, SAH model (endovascular perforation), immunohistochemistry, neurobehavioral testing, CREB inhibitor (KG-501), JMJD3 inhibitor (GSK-J4), cytokine analysis\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo siRNA with pharmacological inhibitors, defined CREB/JMJD3/IRF4 pathway, single lab\",\n      \"pmids\": [\"38340785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In mice lacking Lgr6, RSV infection caused exacerbated type 2 immune responses with increased viral burden and blunted responses to exogenous MaR1. LGR6 was constitutively expressed on regulatory T cells (Tregs). MaR1-LGR6 signaling improved Tregs' suppressive function and upregulated host antiviral genes.\",\n      \"method\": \"Lgr6 knockout mice, RSV infection model, flow cytometry, cytokine measurement, viral transcript quantification, MaR1 treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Lgr6 KO mice with defined viral infection phenotype and MaR1 rescue, single lab\",\n      \"pmids\": [\"36595677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MaR1 reduces blood pressure elevation and alleviates vascular remodeling in angiotensin II-infused mice through LGR6. LGR6 knockout aggravated pathological vascular remodeling and could not be reversed by additional MaR1 treatment. Mechanistically, MaR1 regulates vascular smooth muscle cell activity through LGR6 via Ca2+/calmodulin-dependent protein kinase II/NRF2/HO-1 signaling.\",\n      \"method\": \"LGR6 knockout mice, angiotensin II infusion model, VSMC culture, western blot, functional VSMC assays (proliferation, migration, phenotype switching, pyroptosis)\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LGR6 knockout rescue experiment with defined CaMKII/NRF2/HO-1 signaling pathway, single lab\",\n      \"pmids\": [\"38463394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGR6 overexpression in macrophages enhanced efferocytosis of apoptotic nucleus pulposus cells, increased ECM components (COL2A1), decreased matrix-degrading enzymes (MMP13), and inhibited IL-1β-induced apoptosis by upregulating BCL2 and downregulating cleaved caspase 3 and BAX. LGR6 knockdown impaired these effects.\",\n      \"method\": \"LGR6 shRNA knockdown and overexpression, macrophage-NPC co-culture, efferocytosis assay, western blot, in vivo mouse IVDD model (disc puncture)\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss-of-function in vitro with in vivo corroboration, defined efferocytosis and apoptosis mechanism, single lab\",\n      \"pmids\": [\"40281518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Lgr6 expression in the skin epidermis is controlled by nerve endings and Schwann cells. Ablation of cutaneous nerves leads to degeneration of Schwann cells and diminished expression of Lgr6 in skin.\",\n      \"method\": \"Nerve ablation experiments, immunofluorescence co-localization, histological analysis across hair cycle stages\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nerve ablation with defined Lgr6 expression phenotype, single lab, two orthogonal approaches\",\n      \"pmids\": [\"24499442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LGR6 knockdown in gastric cancer cells downregulated phosphorylated AKT and mTOR and upregulated proapoptotic proteins Bax and Caspase-3, while decreasing antiapoptotic Bcl2. LGR6 controls gastric cancer cell proliferation, apoptosis, migration, and invasion through the PI3K/AKT/mTOR pathway.\",\n      \"method\": \"Lentiviral shRNA knockdown, lentiviral overexpression, western blot (pAKT, pmTOR), functional assays (proliferation, apoptosis, migration, invasion)\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single approach per pathway component, no pathway rescue experiments\",\n      \"pmids\": [\"29872314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LGR6 promotes osteogenic differentiation and mineralization in osteoblastic progenitor MC3T3-E1 cells by stabilizing β-catenin to potentiate the Wnt/β-catenin signaling pathway. LGR6 knockdown inhibited osteogenesis by enhancing β-catenin degradation.\",\n      \"method\": \"Lentiviral overexpression and knockdown, β-catenin stability assay, osteogenic differentiation and mineralization assays, western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss-of-function with defined β-catenin stability mechanism, single lab, multiple functional readouts\",\n      \"pmids\": [\"31500806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Lgr6 marks rare mammary gland progenitor cells. Lgr6+ cells in mammary gland are unipotent progenitors that expand clonally during puberty and regain proliferative potency during pregnancy or following ovarian hormone stimulation. Oncogenic mutations in Lgr6+ cells result in expansion of luminal cells and mammary tumors. Depletion of Lgr6+ cells in the MMTV-PyMT model significantly impaired tumor growth.\",\n      \"method\": \"Lineage tracing, cell depletion experiments, hormonal stimulation, oncogenic mutation induction, MMTV-PyMT tumor model\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive lineage tracing, genetic cell depletion in tumor model, and hormone stimulation experiments with defined cellular phenotype\",\n      \"pmids\": [\"27798604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lgr6, but not Lgr5, acts as an epithelial stem cell marker in squamous cell carcinomas (SCC). Lgr6 downregulation in vivo causes increased epidermal proliferation with expanded lineage tracing from Lgr6+ epidermal stem cells. Lgr6 germline knockout mice are predisposed to SCC development, through a mechanism that includes compensatory upregulation of Lgr5.\",\n      \"method\": \"Lineage tracing in reporter mice, Lgr6 germline knockout mice, single-molecule in situ hybridization, cell sorting, SCC mouse model\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — lineage tracing, germline knockout with defined carcinogenesis phenotype and compensatory Lgr5 upregulation mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"28945253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"High levels of miR-19 family members (from the miR-17-92 cluster) target and downregulate p38α kinase in Lgr6+ NSCLC cells, providing a survival signal mediated by increased Wnt/β-catenin activity. Defective repression of the miR-17-92 cluster is responsible for selection of Lgr6+ NSCLC cells with self-renewal and higher tumorigenic potential.\",\n      \"method\": \"miR target validation, p38α kinase measurement, Wnt/β-catenin reporter assays, cell sorting, tumor formation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — miR target validation with defined p38α-Wnt signaling mechanism, single lab\",\n      \"pmids\": [\"27197183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lgr6 is expressed in osteoprogenitor cells and is dynamically regulated during BMP-mediated osteogenesis. BMP signaling elements including pSMAD and BMP-related gene ontology pathways are downregulated in the absence of Lgr6, indicating a molecular interdependency between Lgr6 and the BMP pathway.\",\n      \"method\": \"RNA sequencing, bioinformatic analysis of published single-cell data, biochemical assays, BMP stimulation experiments with Lgr6 KO and WT cells\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq and biochemical approaches identifying BMP-Lgr6 interdependency, single lab\",\n      \"pmids\": [\"39033993\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGR6 is a leucine-rich repeat-containing G protein-coupled receptor that functions as a high-affinity receptor for R-spondins (particularly RSPO1–3) and maresin 1 (MaR1), transducing two distinct ligand-dependent signals: R-spondin binding potentiates Wnt/β-catenin signaling through LRP6 phosphorylation and β-catenin stabilization (without G protein or β-arrestin coupling), while MaR1 binding stimulates cAMP activity; these signaling functions support stem cell maintenance in skin, bone, lung, mammary gland, and other epithelia, and mediate pro-resolving immune functions including enhanced phagocytosis, efferocytosis, and anti-inflammatory signaling in macrophages, neutrophils, and T cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LGR6 is a leucine-rich repeat-containing G protein-coupled receptor of the LGR4-6 subgroup that marks and sustains tissue-resident stem and progenitor populations across multiple epithelia while transducing two distinct ligand-dependent signals [#0, #4, #8]. As a high-affinity receptor for R-spondins 1-3, binding through its large N-terminal extracellular domain, LGR6 potentiates canonical Wnt/\\u03b2-catenin signaling by promoting LRP6 phosphorylation and \\u03b2-catenin stabilization without coupling to heterotrimeric G proteins or \\u03b2-arrestin [#1, #17, #27]. A second ligand, the pro-resolving lipid mediator maresin 1 (MaR1), is a stereoselective LGR6 agonist that drives cAMP-dependent and ERK/CREB signaling in phagocytes to enhance phagocytosis and efferocytosis, establishing LGR6 as a receptor with both Wnt-potentiating and cAMP-coupled outputs [#3, #8]. Through Wnt/\\u03b2-catenin activation, LGR6 maintains the most primitive epidermal stem cells and drives wound re-epithelialization, nail and digit-tip regeneration, mammary progenitor expansion, lung airway repair, and osteogenic differentiation and fracture healing [#4, #5, #6, #8, #14, #28]. The Wnt-potentiating axis also underlies oncogenic roles, where LGR6 supports cancer stem-cell phenotypes and chemoresistance and can engage a TCF7L2-\\u03b2-catenin positive feedback loop that amplifies its own transcription [#7, #10, #29]. Via the MaR1 axis, LGR6 mediates pro-resolving and cytoprotective functions in macrophages, neutrophils, regulatory T cells, and parenchymal cells, attenuating injury in vascular, cardiac, renal, pulmonary, and neuroinflammatory disease models through pathways including cAMP-SOD2, STAT3/PGC1\\u03b1, and Wnt-dependent suppression of necroptosis [#9, #11, #12, #20, #22]. A human LGR6 frameshift variant downregulates the receptor in neutrophils, monocytes, and NK cells and alters their phagocytic, chemotactic, and TLR-responsive functions, linking LGR6 to innate immune competence [#19].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established LGR6 as a distinct leucine-rich repeat GPCR, defining its receptor architecture before any ligand was known.\",\n      \"evidence\": \"molecular cloning, phylogenetic and structural domain analysis\",\n      \"pmids\": [\"10935549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no ligand identified\", \"no signaling output defined\", \"no tissue function established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved whether LGR6 marks a functional stem cell pool by showing Lgr6+ cells are the most primitive epidermal stem cells generating all skin lineages and executing wound repair.\",\n      \"evidence\": \"knock-in reporter alleles with genetic lineage tracing in mouse skin\",\n      \"pmids\": [\"20223988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ligand and receptor signaling driving the stem state not addressed\", \"molecular mechanism of fate choice unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the first LGR6 ligand and its signaling logic, showing R-spondins bind LGR6 and potentiate Wnt/\\u03b2-catenin via LRP6 without G protein or \\u03b2-arrestin coupling.\",\n      \"evidence\": \"binding assays, Wnt luciferase reporter, LRP6 phosphorylation blots, G protein/\\u03b2-arrestin assays, cancer mutagenesis in cell lines\",\n      \"pmids\": [\"22615920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"downstream effector beyond LRP6 not detailed\", \"no structural model of R-spondin\\u2013LGR6 binding\", \"mechanism of Wnt potentiation without canonical GPCR coupling unexplained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended LGR6 stem/progenitor function beyond skin to mammary gland and linked it to tumorigenesis.\",\n      \"evidence\": \"lineage tracing, cell depletion, oncogenic induction, MMTV-PyMT tumor model; parallel NSCLC miR-17-92/p38\\u03b1-Wnt study\",\n      \"pmids\": [\"27798604\", \"27197183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"receptor signaling requirement in mammary progenitors not directly tested\", \"ligand source in tumors undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localized R-spondin binding to the LGR6 N-terminal ectodomain and defined Lgr6 as a niche-supplying mesenchymal marker in lung repair.\",\n      \"evidence\": \"competitive antibody binding to ectodomain; lung lineage tracing, scRNA-seq, organoids and genetic ablation\",\n      \"pmids\": [\"28013222\", \"28886383\", \"28945253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural binding interface not mapped\", \"how Lgr6+ mesenchyme signals to epithelium beyond Wnt-Fgf10 unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovered a second, structurally unrelated ligand by identifying MaR1 as a stereoselective LGR6 agonist that drives phagocyte pro-resolving functions, revealing dual ligand recognition.\",\n      \"evidence\": \"unbiased >200 GPCR screen, [3H]-MaR1 radioligand binding, reporter assays, gain/loss-of-function phagocytosis/efferocytosis with ERK/CREB phosphorylation\",\n      \"pmids\": [\"31657786\", \"31193124\", \"31500806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MaR1 binding site relative to R-spondin site unmapped\", \"G protein coupling for cAMP output not directly demonstrated in this study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Formally separated LGR6's two signaling arms, showing RSPO2 drives Wnt/\\u03b2-catenin while MaR1 drives cAMP from the same receptor, with bone as the in vivo readout.\",\n      \"evidence\": \"CRISPR-Cas9 Lgr6 knockout mice, microCT, osteodifferentiation, Wnt reporter and cAMP assays\",\n      \"pmids\": [\"34856421\", \"34489551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"determinants of ligand-biased output not defined\", \"whether the two ligands compete or act on distinct receptor states unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated MaR1-LGR6 pro-resolving signaling protects multiple tissues, defining cAMP-SOD2 and Treg-mediated antiviral mechanisms.\",\n      \"evidence\": \"in vivo LGR6 siRNA/knockout in diabetic kidney, lung I/R, and RSV models; cAMP/SOD2 and Treg suppressive function assays\",\n      \"pmids\": [\"35498124\", \"36628837\", \"36595677\", \"34320253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"receptor-proximal coupling to each downstream pathway not reconstituted\", \"single-lab models per disease\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected LGR6 to mitochondrial, cell-death, and vascular protective programs and to human innate immune function via a loss-of-function variant.\",\n      \"evidence\": \"LGR6 KO/OE mice with RNA-seq and ChIP defining STAT3/PGC1\\u03b1, STAT2/ZBP1/Wnt, and CaMKII/NRF2/HO-1 axes; human frameshift variant with primary-cell phenotyping and UK Biobank data\",\n      \"pmids\": [\"39038735\", \"39471639\", \"38463394\", \"38718314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether these transcriptional axes are direct receptor outputs or secondary is unresolved\", \"human variant phenotype not mechanistically tied to a specific ligand axis\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single receptor selects between R-spondin/Wnt-potentiating and MaR1/cAMP outputs, and the structural basis for binding two unrelated ligands, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no structure of LGR6 with either ligand\", \"molecular basis of ligand-biased signaling unknown\", \"in vivo relevance of dual signaling in the same cell type untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 3, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 8, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5, 14, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 19, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 11, 12, 29]}\n    ],\n    \"complexes\": [\"LITTIP/LGR6/HnRNPK RNA-protein complex\"],\n    \"partners\": [\"RSPO1\", \"RSPO2\", \"RSPO3\", \"LRP6\", \"ZNRF3\", \"HNRNPK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}