{"gene":"LGR6","run_date":"2026-04-28T18:30:27","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, belonging to a subfamily (LGR4-6) distinct from glycoprotein hormone receptors and LGR7. LGR6 is not coupled to heterotrimeric G proteins following ligand stimulation (established by analogy with LGR7 mutagenesis studies).","method":"Phylogenetic analysis, sequence analysis, single amino acid mutagenesis of conserved residues to produce constitutively active receptors, signaling pathway analysis (PKA vs PLC)","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 1-2 — original identification with mutagenesis; direct signaling data was for LGR7, LGR6 inferred by homology","pmids":["10935549"],"is_preprint":false},{"year":2010,"finding":"Lgr6 marks the most primitive epidermal stem cells residing in a region directly above the follicle bulge. Prenatal Lgr6+ cells established the hair follicle, sebaceous gland, and interfollicular epidermis; postnatal Lgr6+ cells generate sebaceous gland and interfollicular epidermis; adult Lgr6+ cells execute long-term wound repair including formation of new hair follicles.","method":"Knock-in reporter alleles (Lgr6-EGFP-IRES-CreERT2), genetic lineage tracing in mice, cell ablation, wound healing assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — foundational study, knock-in genetics with lineage tracing and multiple functional readouts, highly cited","pmids":["20223988"],"is_preprint":false},{"year":2012,"finding":"LGR6 binds R-spondins 1-3 with high affinity and responds to R-spondin stimulation to enhance Wnt/β-catenin signaling through increased LRP6 phosphorylation. LGR6 is not coupled to heterotrimeric G proteins or β-arrestin following R-spondin stimulation. A somatic colon cancer mutant of LGR6 fails to bind and respond to R-spondin (loss-of-function). Overexpression of wild-type LGR6 in HeLa cells leads to increased cell migration following co-treatment with R-spondin1 and Wnt3a.","method":"Binding affinity assays, LRP6 phosphorylation assays, G protein coupling assays, β-arrestin recruitment assays, functional analysis of cancer-associated mutants, cell migration assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods, direct binding and signaling assays, mutagenesis","pmids":["22615920"],"is_preprint":false},{"year":2014,"finding":"Lgr6 expression in 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, demonstrating niche-dependent regulation of Lgr6 expression.","method":"Immunofluorescence localization, nerve ablation experiments, analysis of Lgr6 expression changes post-denervation in mouse skin","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct nerve ablation experiment with defined molecular readout, single lab","pmids":["24499442"],"is_preprint":false},{"year":2014,"finding":"Single isolated Lgr6+ taste cells can generate continuously expanding 3D organoids containing mature taste receptor cells; genetic lineage tracing showed Lgr6+ cells give rise to taste bud cells in taste papillae in both anterior and posterior tongue, demonstrating Lgr6 marks taste stem/progenitor cells.","method":"Single-cell organoid culture, calcium imaging assays, genetic lineage tracing (Lgr6-EGFP-CreERT2), RT-PCR","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 — single-cell reconstitution assay combined with in vivo lineage tracing and functional calcium imaging","pmids":["25368147"],"is_preprint":false},{"year":2015,"finding":"Lgr6 is expressed in nail matrix epithelium and marks nail stem cells; genetic lineage analysis shows Lgr6+ cells give rise to the nail during homeostatic growth and contribute to the blastema during digit tip regeneration. Lgr6-deficient mice exhibit nail and bone regeneration defects, establishing a direct functional role in digit tip regeneration.","method":"Genetic lineage tracing (Lgr6-EGFP-CreERT2/Rosa26 reporter), Lgr6 knockout mouse analysis, histology, microCT","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — lineage tracing combined with knockout phenotype, multiple tissue readouts","pmids":["26460010"],"is_preprint":false},{"year":2015,"finding":"Lgr6+ cells in skin (IFE, isthmus, SG) constitute long-term self-renewing populations; quantitative clonal dynamics analysis revealed Lgr6+ progenitor cells compete neutrally in the IFE, isthmus, and SG, indicating population asymmetry as the underlying mode of tissue renewal.","method":"Multicolor lineage tracing (Confetti reporter), quantitative clonal analysis, transcriptional profiling of sorted Lgr6+ cells","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 — multicolor clonal tracing with quantitative mathematical modeling, multiple skin compartments","pmids":["26607954"],"is_preprint":false},{"year":2016,"finding":"Lgr6 marks rare mammary gland progenitor cells that are unipotent, expand clonally during puberty, regain proliferative potency during pregnancy, and can initiate luminal mammary tumors upon oncogenic mutation. Depletion of Lgr6+ cells in the MMTV-PyMT model significantly impaired tumor growth.","method":"Genetic lineage tracing, conditional oncogenic mutation in Lgr6+ cells, diphtheria toxin-mediated cell depletion, tumor growth analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — lineage tracing combined with cell ablation and tumor initiation experiments, multiple orthogonal approaches","pmids":["27798604"],"is_preprint":false},{"year":2017,"finding":"Lgr6+ cells in the adult lung comprise a subpopulation of smooth muscle cells surrounding airway epithelia. 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 co-culture, genetic ablation (diphtheria toxin), airway injury model","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including scRNAseq, organoid culture, and in vivo ablation with defined phenotypes","pmids":["28886383"],"is_preprint":false},{"year":2017,"finding":"Lgr6 downregulation in vivo causes increased epidermal proliferation with expanded lineage tracing from epidermal stem cells. Germline knockout of Lgr6 predisposes mice to squamous cell carcinoma development through a mechanism including compensatory upregulation of Lgr5.","method":"Lgr6-EGFP-CreERT2/Rosa26-Tomato reporter lineage tracing, germline Lgr6 knockout, single-molecule in situ hybridization, FACS sorting, skin carcinogenesis model","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — knockout phenotype with epistasis (Lgr5 compensation), lineage tracing, multiple orthogonal methods","pmids":["28945253"],"is_preprint":false},{"year":2019,"finding":"Maresin 1 (MaR1) is a stereoselective activator of human LGR6. MaR1 specifically binds LGR6 (confirmed with 3H-labeled MaR1) and activates it in phagocytes to enhance phagocytosis, efferocytosis, and phosphorylation of ERK and CREB. MaR1 actions were amplified by LGR6 overexpression and diminished by LGR6 gene silencing.","method":"Unbiased GPCR screening (>200 GPCRs), reporter cells expressing LGR6, functional impedance sensing, radiolabeled ligand binding (3H-MaR1), LGR6 overexpression and siRNA knockdown in phagocytes, phagocytosis/efferocytosis assays, phosphoprotein analysis","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1 — unbiased receptor screen, direct radioligand binding, gain- and loss-of-function with multiple functional readouts","pmids":["31657786"],"is_preprint":false},{"year":2019,"finding":"LGR6 promotes Wnt/β-catenin signaling in osteoblastic progenitors by stabilizing β-catenin; LGR6 overexpression promotes osteogenic differentiation and mineralization while LGR6 knockdown inhibits these processes via β-catenin degradation.","method":"Lentiviral LGR6 overexpression and knockdown in MC3T3-E1 preosteoblastic cells, β-catenin stability assays, osteogenic differentiation assays, mineralization assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — gain and loss of function with defined molecular mechanism (β-catenin stabilization), single lab","pmids":["31500806"],"is_preprint":false},{"year":2021,"finding":"LGR6 marks epidermal stem cells that specialize in wound re-epithelialization; diphtheria toxin-mediated ablation of Lgr6 stem cells delays wound healing. Nerve denervation phenocopies Lgr6 stem cell ablation. Intravital imaging showed wound re-epithelialization by Lgr6 stem cells is diminished following loss of nerves, inducing recruitment of hair follicle stem cells as compensatory response. Loss of niche (nerve) shifts Lgr6 stem cell fate toward differentiation.","method":"Diphtheria toxin ablation, skin denervation, intravital two-photon microscopy, single-cell lineage tracing, single-cell RNA sequencing","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 — cell ablation with defined phenotype, live intravital imaging, scRNAseq, multiple orthogonal approaches","pmids":["34102139"],"is_preprint":false},{"year":2021,"finding":"RSPO2 stimulates LGR6-mediated WNT/β-catenin signaling whereas MaR1 stimulates LGR6-mediated cAMP activity, demonstrating two distinct ligand-dependent signaling functions for LGR6. Lgr6 knockout mice have less trabecular bone mass and reduced ex vivo osteodifferentiation of primary MSCs, establishing that Lgr6 is necessary for normal osteogenesis.","method":"In vitro LGR6 knockdown and overexpression in murine osteoblastic cells, CRISPR-Cas9 Lgr6 knockout mice, microCT bone analysis, ex vivo MSC osteodifferentiation, cAMP signaling assays, WNT/β-catenin signaling assays with RSPO2 and MaR1","journal":"Bone","confidence":"High","confidence_rationale":"Tier 1-2 — CRISPR knockout with in vivo phenotype, dual ligand signaling dissection with orthogonal pathway readouts","pmids":["34856421"],"is_preprint":false},{"year":2021,"finding":"MaR1 activates LGR6 receptors to upregulate macrophage-dependent efferocytosis, increase TGF-β2 expression, decrease MMP2 activity, and attenuate abdominal aortic aneurysm formation. In vivo inhibition of LGR6 receptors obliterated MaR1-dependent protection. SMC-specific TGFβ receptor knockout abolished MaR1/LGR6 protection, placing TGF-β2 downstream of MaR1-LGR6 signaling.","method":"In vivo LGR6 receptor inhibition, AAA mouse model, SMC-TGFβr2 knockout mice, macrophage efferocytosis assays, in vitro MaR1-LGR6 crosstalk studies, MMP2 activity assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — in vivo receptor inhibition, genetic epistasis with SMC-TGFβr2-KO, multiple functional readouts","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 → upregulates TCF7L2 → TCF7L2/β-catenin complex binds LGR6 promoter → enhances LGR6 transcription.","method":"RNA sequencing, TOP/FOP luciferase reporter assays, RT-PCR, western blotting, ChIP or promoter binding assays for TCF7L2/β-catenin at LGR6 promoter, FACS sorting of LGR6high cells, functional stemness assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter combined with promoter binding evidence and functional stemness assays, single lab","pmids":["34489551"],"is_preprint":false},{"year":2022,"finding":"Mechanical tension preferentially activates and drives differentiation of Lgr6+ epidermal stem cells to promote skin growth, driven in part by the Hippo pathway.","method":"Controlled tissue expansion in mice, machine learning-guided 3D tissue reconstruction, single-cell RNA sequencing, Lgr6 lineage tracing","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mechanical model with lineage tracing and scRNAseq, single lab","pmids":["35476447"],"is_preprint":false},{"year":2022,"finding":"MaR1/LGR6 signaling mitigates CXCL1 secretion by epithelial cells in the context of lung ischemia-reperfusion injury, placing LGR6 in a specific cell-type and molecular pathway for resolution of inflammation.","method":"LGR6 siRNA knockdown in mice, murine orthotopic lung transplant model, in vitro type II epithelial cell activation studies, cytokine measurement","journal":"Journal of heart and lung transplantation","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo siRNA knockdown with defined cytokine readout, single lab","pmids":["36628837"],"is_preprint":false},{"year":2023,"finding":"The lncRNA LITTIP binds to LGR6 mRNA and the RNA-binding protein HnRNPK to form a LITTIP/Lgr6/HnRNPK complex; LITTIP promotes LGR6 expression via HnRNPK, and this complex regulates cementogenesis via Wnt/β-catenin signaling.","method":"ChIRP (chromatin isolation by RNA purification), RIP (RNA immunoprecipitation), co-transfection experiments, RNA microarray, in vivo PTH administration, Wnt pathway assays","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 — ChIRP and RIP directly demonstrate LITTIP/LGR6/HnRNPK complex formation, single lab","pmids":["37558690"],"is_preprint":false},{"year":2023,"finding":"Lgr6 is expressed in osteoprogenitors in response to fracture injury; Lgr6-null mice have reduced colony-forming potential, reduced osteogenic differentiation due to attenuated canonical Wnt signaling, lower proportion of self-renewing stem cells, and impaired endochondral ossification and mineralization during fracture healing.","method":"Lgr6-null mouse model, colony-forming assays, osteogenic differentiation, Wnt signaling assays, fracture healing model with ALP activity, microCT, histology","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with multiple orthogonal functional readouts across in vitro and in vivo contexts","pmids":["36708855"],"is_preprint":false},{"year":2023,"finding":"LGR6 expression is enhanced during BMP-mediated osteogenesis; Lgr6 loss results in downregulation of BMP signaling elements including pSMAD and BMP-associated gene ontology pathways, revealing a molecular interdependency between BMP signaling and Lgr6 in osteogenesis.","method":"Lgr6 knockout cells and mice, RNA sequencing, bioinformatic analysis of published single-cell data, biochemical pSMAD assays, gene ontology pathway analysis","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA-seq with biochemical validation, single lab","pmids":["39033993"],"is_preprint":false},{"year":2024,"finding":"LGR6 deficiency in cardiomyocytes aggravates ferroptosis and disrupted mitochondrial biogenesis in diabetic cardiomyopathy by regulating STAT3/PGC1α signaling; cardiomyocyte-specific LGR6 overexpression ameliorates cardiac dysfunction. LGR6 activation by recombinant RSPO3 treatment also ameliorated cardiac dysfunction and mitochondrial dysfunction.","method":"LGR6 knockout mice, AAV9-mediated cardiomyocyte-specific LGR6 overexpression, streptozotocin/high-fat diet diabetes model, RNA sequencing, ChIP assay, STAT3 inhibition, PGC1α activation experiments","journal":"Metabolism: clinical and experimental","confidence":"High","confidence_rationale":"Tier 2 — cardiac-specific gain and loss of function, RNA-seq with ChIP, RSPO3 ligand activation, multiple in vivo readouts","pmids":["39038735"],"is_preprint":false},{"year":2024,"finding":"RSPO3-LGR6 axis activates Wnt signaling to downregulate STAT2 and ZBP1 expression, thereby inhibiting cardiomyocyte necroptosis after ischemia-reperfusion injury. LGR6 deficiency promoted necroptosis while LGR6 overexpression inhibited it; RSPO3 treatment protected from acute myocardial I/R injury.","method":"LGR6 knockout mice, coronary artery ligation I/R model, RNA sequencing, ChIP assays, STAT2 and ZBP1 inhibition experiments, RSPO3 treatment","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with ligand (RSPO3) rescue, RNA-seq, ChIP, epistasis through STAT2/ZBP1 inhibition","pmids":["39471639"],"is_preprint":false},{"year":2024,"finding":"MaR1 regulates hypertensive vascular remodeling through LGR6 via a Ca2+/calmodulin-dependent protein kinase II/Nrf2/HO-1 signaling pathway; LGR6 knockout aggravated pathological vascular remodeling that could not be reversed by MaR1 treatment.","method":"LGR6 knockout mice, angiotensin II-infused hypertension model, VSMC functional assays (proliferation, migration, phenotype switching, pyroptosis), CaMKII/Nrf2/HO-1 pathway analysis","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2-3 — LGR6 knockout with defined signaling pathway, single lab","pmids":["38463394"],"is_preprint":false},{"year":2024,"finding":"A frameshift variant in LGR6 leads to downregulation of LGR6 expression selectively in neutrophils, monocytes, and NK cells (but not macrophages or CD8+ T cells), linking LGR6 expression to decreased bacterial phagocytosis, increased neutrophil chemotaxis, increased leukotriene B4 production, and altered antiviral responses via TLR3/7/8/9 pathways.","method":"Human genetic variant analysis, flow cytometry for LGR6 expression on leukocyte subsets, phagocytosis assays, chemotaxis assays, leukotriene B4 measurement, TLR agonist stimulation, UK Biobank population analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — human loss-of-function variant with cell-type specific expression data and multiple orthogonal functional immune readouts","pmids":["38718314"],"is_preprint":false},{"year":2017,"finding":"Monoclonal antibodies against the N-terminal extracellular domain of human LGR6 competitively block R-spondin 1 binding to LGR6, confirming that R-spondin 1 binds to the large ectodomain of LGR6.","method":"DNA immunization, whole-cell immunization, flow cytometry screening of hybridomas, competitive binding assays with mAbs and R-spondin 1","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — competitive binding assay with specificity confirmed against LGR4, LGR5, and LGR6 transfectants","pmids":["28013222"],"is_preprint":false},{"year":2023,"finding":"LGR6 activates MaR1-LGR6-CREB/JMJD3/IRF4 signaling pathway to attenuate neuroinflammation after subarachnoid hemorrhage; LGR6 knockdown, CREB inhibition, or JMJD3 inhibition abolished MaR1's anti-neuroinflammatory effects on microglial activation and cytokine expression.","method":"SAH rat model, intranasal MaR1 administration, LGR6 siRNA knockdown, KG-501 (CREB inhibitor), GSK-J4 (JMJD3 inhibitor), neurobehavioral testing, histology, biochemical cytokine analysis, microglial activation assessment","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo pathway dissection with multiple inhibitors and siRNA, single lab","pmids":["38340785"],"is_preprint":false},{"year":2023,"finding":"MaR1 alleviates RSV-induced lung inflammation via LGR6 expressed constitutively on Tregs; Lgr6-deficient mice had exacerbated type 2 immune responses, increased viral burden, and blunted responses to MaR1, establishing a MaR1-LGR6 axis that improves Treg suppressive function and upregulates host antiviral genes.","method":"Lgr6 knockout mice, RSV infection model, flow cytometry, IL-13 measurement, amphiregulin measurement, interferon-β measurement, RSV viral transcript quantification","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — LGR6 knockout with multiple immune and viral readouts, defined receptor-ligand axis on specific immune cell type","pmids":["36595677"],"is_preprint":false},{"year":2023,"finding":"LGR6 promotes myoblast differentiation and fusion; Lgr6 mRNA is transiently expressed during myogenic differentiation in response to ATRA (requiring RARα and RARγ agonism). LGR6 loss decreased differentiation and fusion indices; LGR6 expression is downregulated by the ubiquitin-proteasome system involving ZNRF3. LGR6 augments Wnt/β-catenin signaling activity induced by Wnt3a and R-spondin 2 in myoblasts.","method":"C2C12 myoblast differentiation assay, siRNA knockdown of LGR6, exogenous LGR6 expression, ATRA/RAR agonist treatment, proteasome inhibitor treatment, Znrf3 knockdown, Wnt/β-catenin luciferase reporter assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — gain and loss of function with multiple mechanistic interventions, single lab, cell line model","pmids":["37240382"],"is_preprint":false}],"current_model":"LGR6 is a leucine-rich repeat-containing G protein-coupled receptor that functions primarily as a high-affinity receptor for R-spondins (RSPO1-3) and the pro-resolving lipid mediator maresin 1 (MaR1); R-spondin binding potentiates Wnt/β-catenin signaling (via LRP6 phosphorylation and β-catenin stabilization, without G protein or β-arrestin coupling), while MaR1 binding activates cAMP signaling, with both ligands promoting stem/progenitor cell function in tissues including skin, bone, lung, heart, and immune cells, and with downstream pathway outputs including Wnt/TCF7L2 feedback loops, STAT3/PGC1α-mediated mitochondrial biogenesis, STAT2/ZBP1-regulated necroptosis, and CaMKII/Nrf2/HO-1-mediated vascular remodeling depending on cellular context."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of LGR6 as a distinct subfamily member of leucine-rich repeat GPCRs established its structural class but left its ligand and signaling mode unknown.","evidence":"Phylogenetic and sequence analysis with mutagenesis of related LGR7; LGR6 signaling inferred by homology","pmids":["10935549"],"confidence":"Medium","gaps":["LGR6 signaling inferred from LGR7 rather than directly tested","no endogenous ligand identified","no functional role assigned"]},{"year":2010,"claim":"The demonstration that Lgr6 marks the most primitive epidermal stem cells capable of generating all skin lineages established LGR6 as a bona fide stem cell marker, shifting the field from receptor characterization to stem cell biology.","evidence":"Knock-in reporter alleles with genetic lineage tracing, cell ablation, and wound healing in mice","pmids":["20223988"],"confidence":"High","gaps":["ligand for LGR6 still unknown","mechanism by which LGR6 maintains stemness undefined","unclear whether LGR6 is functionally required or merely a marker"]},{"year":2012,"claim":"Identification of R-spondins 1–3 as high-affinity LGR6 ligands that potentiate Wnt/β-catenin signaling via LRP6 phosphorylation—without G protein or β-arrestin coupling—defined LGR6's molecular signaling mechanism and distinguished it from classical GPCR activation.","evidence":"Direct binding affinity assays, LRP6 phosphorylation, G protein/β-arrestin coupling assays, cancer mutant loss-of-function analysis","pmids":["22615920"],"confidence":"High","gaps":["whether additional non-R-spondin ligands exist was unknown","structural basis of R-spondin binding unresolved","in vivo consequence of R-spondin–LGR6 interaction not demonstrated"]},{"year":2014,"claim":"Extending LGR6's stem cell role beyond skin, the finding that Lgr6+ cells generate taste bud organoids and contribute to taste papillae in vivo established LGR6 as a pan-tissue stem/progenitor marker, while nerve-dependence of Lgr6 expression revealed niche-dependent regulation.","evidence":"Single-cell organoid culture from Lgr6+ taste cells with lineage tracing; nerve ablation with Lgr6 expression analysis in skin","pmids":["25368147","24499442"],"confidence":"High","gaps":["whether LGR6 is functionally required in taste or merely marks progenitors","molecular mediator of nerve-to-Lgr6 signaling unknown"]},{"year":2015,"claim":"Demonstration that Lgr6 knockout mice have impaired nail and digit tip regeneration, and that Lgr6+ skin progenitors undergo neutral competition, established LGR6 as functionally required for regeneration rather than merely a passive marker.","evidence":"Lgr6 knockout mouse phenotyping with microCT; multicolor Confetti lineage tracing with quantitative clonal analysis","pmids":["26460010","26607954"],"confidence":"High","gaps":["downstream signaling pathway mediating regeneration unresolved","whether Wnt potentiation is the operative mechanism in regeneration untested"]},{"year":2016,"claim":"Lgr6+ mammary progenitors were shown to be unipotent yet capable of tumor initiation upon oncogenic mutation, linking LGR6-marked cells to cancer biology and demonstrating that depletion of Lgr6+ cells impairs tumor growth.","evidence":"Genetic lineage tracing with conditional oncogene activation and diphtheria toxin-mediated cell depletion in MMTV-PyMT model","pmids":["27798604"],"confidence":"High","gaps":["whether LGR6 signaling itself drives tumor initiation or merely marks the cell of origin","applicability to human breast cancer undetermined"]},{"year":2017,"claim":"Three advances refined LGR6 biology: Lgr6+ lung mesenchymal cells were shown to promote airway repair via Wnt-Fgf10 cooperation; Lgr6 knockout predisposed to squamous cell carcinoma with compensatory Lgr5 upregulation; and monoclonal antibodies confirmed R-spondin 1 binding to the LGR6 ectodomain.","evidence":"scRNA-seq and organoid co-culture with genetic ablation in lung; germline Lgr6 knockout with skin carcinogenesis; competitive mAb binding assays","pmids":["28886383","28945253","28013222"],"confidence":"High","gaps":["LGR5/LGR6 functional redundancy mechanisms unclear","structural detail of R-spondin–ectodomain interaction lacking","whether Lgr6+ lung cells are stem cells or niche support cells debated"]},{"year":2019,"claim":"Discovery of maresin 1 (MaR1) as a second, structurally distinct LGR6 ligand that activates phagocyte functions via ERK/CREB phosphorylation revealed LGR6 as a dual-ligand receptor bridging Wnt potentiation and pro-resolving lipid mediator biology.","evidence":"Unbiased GPCR screen of >200 receptors, radiolabeled 3H-MaR1 binding, LGR6 overexpression/siRNA with phagocytosis and efferocytosis assays","pmids":["31657786"],"confidence":"High","gaps":["structural basis for dual ligand recognition unknown","whether MaR1 and R-spondin compete for the same binding site unresolved","downstream G protein coupling for MaR1 signaling not fully characterized"]},{"year":2021,"claim":"The dual signaling modes of LGR6 were formally dissected: RSPO2 activates Wnt/β-catenin while MaR1 activates cAMP, and Lgr6 knockout mice show reduced trabecular bone mass, establishing pathway-specific ligand outputs and an in vivo osteogenic requirement.","evidence":"CRISPR Lgr6 knockout mice with microCT and MSC osteodifferentiation; parallel Wnt and cAMP pathway assays with RSPO2 vs MaR1","pmids":["34856421"],"confidence":"High","gaps":["signaling intermediates coupling LGR6 to cAMP production unidentified","whether both pathways operate simultaneously in vivo unclear"]},{"year":2021,"claim":"MaR1–LGR6 signaling was placed upstream of macrophage efferocytosis and TGF-β2 in vascular protection, while in epidermis intravital imaging confirmed nerve-dependent Lgr6 stem cell wound repair with compensatory hair follicle stem cell recruitment, and a Wnt/β-catenin–TCF7L2 positive feedback loop was identified in cervical cancer stem cells.","evidence":"AAA model with SMC-TGFβr2 knockout epistasis; intravital two-photon imaging with cell ablation and scRNA-seq; TOP/FOP reporter with ChIP at LGR6 promoter","pmids":["34320253","34102139","34489551"],"confidence":"High","gaps":["TGF-β2 induction mechanism downstream of LGR6 undefined","whether TCF7L2 feedback loop operates in normal tissue or only cancer stem cells unknown"]},{"year":2023,"claim":"Multiple studies expanded LGR6's immune and skeletal roles: MaR1–LGR6 on Tregs resolves RSV-induced lung inflammation; MaR1–LGR6–CREB/JMJD3/IRF4 attenuates neuroinflammation; Lgr6-null osteoprogenitors show impaired fracture healing via attenuated Wnt signaling; and LGR6 is regulated by ZNRF3-mediated proteasomal degradation in myoblasts.","evidence":"Lgr6 knockout mice with RSV infection and immune profiling; SAH rat model with pathway inhibitors; Lgr6-null fracture model with microCT; C2C12 siRNA/overexpression with ZNRF3 knockdown","pmids":["36595677","38340785","36708855","37240382"],"confidence":"High","gaps":["ZNRF3-LGR6 ubiquitination sites and regulation not mapped","whether JMJD3/IRF4 pathway is specific to microglia or generalizable unknown","BMP–Wnt crosstalk through LGR6 only partially characterized"]},{"year":2024,"claim":"Cardiac and vascular studies revealed LGR6 as a cardioprotective receptor: RSPO3–LGR6 activates STAT3/PGC1α to prevent ferroptosis in diabetic cardiomyopathy, suppresses STAT2/ZBP1-mediated necroptosis after I/R injury, and MaR1–LGR6 signals via CaMKII/Nrf2/HO-1 to attenuate hypertensive vascular remodeling; a human LGR6 frameshift variant linked receptor loss to impaired neutrophil phagocytosis and altered innate immunity.","evidence":"Cardiac-specific LGR6 KO/overexpression with RSPO3 rescue in diabetes and I/R models; LGR6 KO hypertension model; human variant analysis with functional immune assays in UK Biobank","pmids":["39038735","39471639","38463394","38718314"],"confidence":"High","gaps":["structural basis for RSPO3 vs MaR1 pathway divergence at LGR6 unresolved","human genetic confirmation of cardiac phenotypes lacking","whether LGR6 frameshift variant affects Wnt signaling in human immune cells untested"]},{"year":null,"claim":"Key unresolved questions include the structural basis for dual ligand recognition (R-spondins vs MaR1), whether both ligand systems operate in the same cell simultaneously, the complete signaling intermediates linking LGR6 to cAMP production, and the extent of functional redundancy with LGR4 and LGR5 across tissues.","evidence":"","pmids":[],"confidence":"Low","gaps":["no crystal/cryo-EM structure of LGR6 with either ligand","G protein coupling mechanism for MaR1 signaling undefined","systematic comparison of LGR4/5/6 functional redundancy across tissues lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,10,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,11,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,10,25]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,10,11,13,15,21,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,4,5,7,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,14,24,27]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[21,22]}],"complexes":[],"partners":["RSPO1","RSPO2","RSPO3","CTNNB1","LRP6","ZNRF3","TCF7L2","HNRNPK"],"other_free_text":[]},"mechanistic_narrative":"LGR6 is a leucine-rich repeat-containing G protein-coupled receptor that functions as a stem/progenitor cell marker and signaling hub across multiple tissues, integrating R-spondin–dependent Wnt/β-catenin potentiation with maresin 1 (MaR1)–dependent pro-resolving signaling. LGR6 binds R-spondins 1–3 with high affinity to enhance Wnt/β-catenin signaling via LRP6 phosphorylation and β-catenin stabilization—without coupling to heterotrimeric G proteins or β-arrestin—while MaR1 binding activates cAMP/CREB signaling, establishing two distinct ligand-dependent signaling modes through a single receptor [PMID:22615920, PMID:34856421, PMID:31657786]. Lgr6 marks self-renewing stem/progenitor populations in skin epidermis, hair follicle, taste buds, nail, mammary gland, lung mesenchyme, and bone, where it is functionally required for tissue homeostasis, wound repair, and regeneration; Lgr6 loss impairs wound healing, fracture repair, osteogenesis, and digit tip regeneration, and predisposes to squamous cell carcinoma [PMID:20223988, PMID:26460010, PMID:28945253, PMID:36708855]. MaR1–LGR6 signaling drives pro-resolving immune functions including macrophage efferocytosis, Treg-mediated suppression of type 2 inflammation, attenuation of vascular remodeling, and anti-neuroinflammatory microglial polarization, while a human frameshift variant in LGR6 reduces neutrophil phagocytosis and alters innate immune responses [PMID:31657786, PMID:36595677, PMID:34320253, PMID:38718314]."},"prefetch_data":{"uniprot":{"accession":"Q9HBX8","full_name":"Leucine-rich repeat-containing G-protein coupled receptor 6","aliases":[],"length_aa":967,"mass_kda":104.3,"function":"Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and acts as a marker of multipotent stem cells in the epidermis. Upon binding to R-spondins (RSPO1, RSPO2, RSPO3 or RSPO4), associates with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. In contrast to classical G-protein coupled receptors, does not activate heterotrimeric G-proteins to transduce the signal. 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LGR6 is not coupled to heterotrimeric G proteins following ligand stimulation (established by analogy with LGR7 mutagenesis studies).\",\n      \"method\": \"Phylogenetic analysis, sequence analysis, single amino acid mutagenesis of conserved residues to produce constitutively active receptors, signaling pathway analysis (PKA vs PLC)\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — original identification with mutagenesis; direct signaling data was for LGR7, LGR6 inferred by homology\",\n      \"pmids\": [\"10935549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Lgr6 marks the most primitive epidermal stem cells residing in a region directly above the follicle bulge. Prenatal Lgr6+ cells established the hair follicle, sebaceous gland, and interfollicular epidermis; postnatal Lgr6+ cells generate sebaceous gland and interfollicular epidermis; adult Lgr6+ cells execute long-term wound repair including formation of new hair follicles.\",\n      \"method\": \"Knock-in reporter alleles (Lgr6-EGFP-IRES-CreERT2), genetic lineage tracing in mice, cell ablation, wound healing assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational study, knock-in genetics with lineage tracing and multiple functional readouts, highly cited\",\n      \"pmids\": [\"20223988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LGR6 binds R-spondins 1-3 with high affinity and responds to R-spondin stimulation to enhance Wnt/β-catenin signaling through increased LRP6 phosphorylation. LGR6 is not coupled to heterotrimeric G proteins or β-arrestin following R-spondin stimulation. A somatic colon cancer mutant of LGR6 fails to bind and respond to R-spondin (loss-of-function). Overexpression of wild-type LGR6 in HeLa cells leads to increased cell migration following co-treatment with R-spondin1 and Wnt3a.\",\n      \"method\": \"Binding affinity assays, LRP6 phosphorylation assays, G protein coupling assays, β-arrestin recruitment assays, functional analysis of cancer-associated mutants, cell migration assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods, direct binding and signaling assays, mutagenesis\",\n      \"pmids\": [\"22615920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Lgr6 expression in 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, demonstrating niche-dependent regulation of Lgr6 expression.\",\n      \"method\": \"Immunofluorescence localization, nerve ablation experiments, analysis of Lgr6 expression changes post-denervation in mouse skin\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct nerve ablation experiment with defined molecular readout, single lab\",\n      \"pmids\": [\"24499442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Single isolated Lgr6+ taste cells can generate continuously expanding 3D organoids containing mature taste receptor cells; genetic lineage tracing showed Lgr6+ cells give rise to taste bud cells in taste papillae in both anterior and posterior tongue, demonstrating Lgr6 marks taste stem/progenitor cells.\",\n      \"method\": \"Single-cell organoid culture, calcium imaging assays, genetic lineage tracing (Lgr6-EGFP-CreERT2), RT-PCR\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — single-cell reconstitution assay combined with in vivo lineage tracing and functional calcium imaging\",\n      \"pmids\": [\"25368147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Lgr6 is expressed in nail matrix epithelium and marks nail stem cells; genetic lineage analysis shows Lgr6+ cells give rise to the nail during homeostatic growth and contribute to the blastema during digit tip regeneration. Lgr6-deficient mice exhibit nail and bone regeneration defects, establishing a direct functional role in digit tip regeneration.\",\n      \"method\": \"Genetic lineage tracing (Lgr6-EGFP-CreERT2/Rosa26 reporter), Lgr6 knockout mouse analysis, histology, microCT\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — lineage tracing combined with knockout phenotype, multiple tissue readouts\",\n      \"pmids\": [\"26460010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Lgr6+ cells in skin (IFE, isthmus, SG) constitute long-term self-renewing populations; quantitative clonal dynamics analysis revealed Lgr6+ progenitor cells compete neutrally in the IFE, isthmus, and SG, indicating population asymmetry as the underlying mode of tissue renewal.\",\n      \"method\": \"Multicolor lineage tracing (Confetti reporter), quantitative clonal analysis, transcriptional profiling of sorted Lgr6+ cells\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multicolor clonal tracing with quantitative mathematical modeling, multiple skin compartments\",\n      \"pmids\": [\"26607954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Lgr6 marks rare mammary gland progenitor cells that are unipotent, expand clonally during puberty, regain proliferative potency during pregnancy, and can initiate luminal mammary tumors upon oncogenic mutation. Depletion of Lgr6+ cells in the MMTV-PyMT model significantly impaired tumor growth.\",\n      \"method\": \"Genetic lineage tracing, conditional oncogenic mutation in Lgr6+ cells, diphtheria toxin-mediated cell depletion, tumor growth analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — lineage tracing combined with cell ablation and tumor initiation experiments, multiple orthogonal approaches\",\n      \"pmids\": [\"27798604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lgr6+ cells in the adult lung comprise a subpopulation of smooth muscle cells surrounding airway epithelia. 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 co-culture, genetic ablation (diphtheria toxin), airway injury model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including scRNAseq, organoid culture, and in vivo ablation with defined phenotypes\",\n      \"pmids\": [\"28886383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lgr6 downregulation in vivo causes increased epidermal proliferation with expanded lineage tracing from epidermal stem cells. Germline knockout of Lgr6 predisposes mice to squamous cell carcinoma development through a mechanism including compensatory upregulation of Lgr5.\",\n      \"method\": \"Lgr6-EGFP-CreERT2/Rosa26-Tomato reporter lineage tracing, germline Lgr6 knockout, single-molecule in situ hybridization, FACS sorting, skin carcinogenesis model\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout phenotype with epistasis (Lgr5 compensation), lineage tracing, multiple orthogonal methods\",\n      \"pmids\": [\"28945253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Maresin 1 (MaR1) is a stereoselective activator of human LGR6. MaR1 specifically binds LGR6 (confirmed with 3H-labeled MaR1) and activates it in phagocytes to enhance phagocytosis, efferocytosis, and phosphorylation of ERK and CREB. MaR1 actions were amplified by LGR6 overexpression and diminished by LGR6 gene silencing.\",\n      \"method\": \"Unbiased GPCR screening (>200 GPCRs), reporter cells expressing LGR6, functional impedance sensing, radiolabeled ligand binding (3H-MaR1), LGR6 overexpression and siRNA knockdown in phagocytes, phagocytosis/efferocytosis assays, phosphoprotein analysis\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — unbiased receptor screen, direct radioligand binding, gain- and loss-of-function with multiple functional readouts\",\n      \"pmids\": [\"31657786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LGR6 promotes Wnt/β-catenin signaling in osteoblastic progenitors by stabilizing β-catenin; LGR6 overexpression promotes osteogenic differentiation and mineralization while LGR6 knockdown inhibits these processes via β-catenin degradation.\",\n      \"method\": \"Lentiviral LGR6 overexpression and knockdown in MC3T3-E1 preosteoblastic cells, β-catenin stability assays, osteogenic differentiation assays, mineralization assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gain and loss of function with defined molecular mechanism (β-catenin stabilization), single lab\",\n      \"pmids\": [\"31500806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LGR6 marks epidermal stem cells that specialize in wound re-epithelialization; diphtheria toxin-mediated ablation of Lgr6 stem cells delays wound healing. Nerve denervation phenocopies Lgr6 stem cell ablation. Intravital imaging showed wound re-epithelialization by Lgr6 stem cells is diminished following loss of nerves, inducing recruitment of hair follicle stem cells as compensatory response. Loss of niche (nerve) shifts Lgr6 stem cell fate toward differentiation.\",\n      \"method\": \"Diphtheria toxin ablation, skin denervation, intravital two-photon microscopy, single-cell lineage tracing, single-cell RNA sequencing\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell ablation with defined phenotype, live intravital imaging, scRNAseq, multiple orthogonal approaches\",\n      \"pmids\": [\"34102139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RSPO2 stimulates LGR6-mediated WNT/β-catenin signaling whereas MaR1 stimulates LGR6-mediated cAMP activity, demonstrating two distinct ligand-dependent signaling functions for LGR6. Lgr6 knockout mice have less trabecular bone mass and reduced ex vivo osteodifferentiation of primary MSCs, establishing that Lgr6 is necessary for normal osteogenesis.\",\n      \"method\": \"In vitro LGR6 knockdown and overexpression in murine osteoblastic cells, CRISPR-Cas9 Lgr6 knockout mice, microCT bone analysis, ex vivo MSC osteodifferentiation, cAMP signaling assays, WNT/β-catenin signaling assays with RSPO2 and MaR1\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CRISPR knockout with in vivo phenotype, dual ligand signaling dissection with orthogonal pathway readouts\",\n      \"pmids\": [\"34856421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MaR1 activates LGR6 receptors to upregulate macrophage-dependent efferocytosis, increase TGF-β2 expression, decrease MMP2 activity, and attenuate abdominal aortic aneurysm formation. In vivo inhibition of LGR6 receptors obliterated MaR1-dependent protection. SMC-specific TGFβ receptor knockout abolished MaR1/LGR6 protection, placing TGF-β2 downstream of MaR1-LGR6 signaling.\",\n      \"method\": \"In vivo LGR6 receptor inhibition, AAA mouse model, SMC-TGFβr2 knockout mice, macrophage efferocytosis assays, in vitro MaR1-LGR6 crosstalk studies, MMP2 activity assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo receptor inhibition, genetic epistasis with SMC-TGFβr2-KO, multiple functional readouts\",\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 → upregulates TCF7L2 → TCF7L2/β-catenin complex binds LGR6 promoter → enhances LGR6 transcription.\",\n      \"method\": \"RNA sequencing, TOP/FOP luciferase reporter assays, RT-PCR, western blotting, ChIP or promoter binding assays for TCF7L2/β-catenin at LGR6 promoter, FACS sorting of LGR6high cells, functional stemness assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter combined with promoter binding evidence and functional stemness assays, single lab\",\n      \"pmids\": [\"34489551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mechanical tension preferentially activates and drives differentiation of Lgr6+ epidermal stem cells to promote skin growth, driven in part by the Hippo pathway.\",\n      \"method\": \"Controlled tissue expansion in mice, machine learning-guided 3D tissue reconstruction, single-cell RNA sequencing, Lgr6 lineage tracing\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mechanical model with lineage tracing and scRNAseq, single lab\",\n      \"pmids\": [\"35476447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MaR1/LGR6 signaling mitigates CXCL1 secretion by epithelial cells in the context of lung ischemia-reperfusion injury, placing LGR6 in a specific cell-type and molecular pathway for resolution of inflammation.\",\n      \"method\": \"LGR6 siRNA knockdown in mice, murine orthotopic lung transplant model, in vitro type II epithelial cell activation studies, cytokine measurement\",\n      \"journal\": \"Journal of heart and lung transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo siRNA knockdown with defined cytokine readout, single lab\",\n      \"pmids\": [\"36628837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The lncRNA LITTIP binds to LGR6 mRNA and the RNA-binding protein HnRNPK to form a LITTIP/Lgr6/HnRNPK complex; LITTIP promotes LGR6 expression via HnRNPK, and this complex regulates cementogenesis via Wnt/β-catenin signaling.\",\n      \"method\": \"ChIRP (chromatin isolation by RNA purification), RIP (RNA immunoprecipitation), co-transfection experiments, RNA microarray, in vivo PTH administration, Wnt pathway assays\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIRP and RIP directly demonstrate LITTIP/LGR6/HnRNPK complex formation, single lab\",\n      \"pmids\": [\"37558690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Lgr6 is expressed in osteoprogenitors in response to fracture injury; Lgr6-null mice have reduced colony-forming potential, reduced osteogenic differentiation due to attenuated canonical Wnt signaling, lower proportion of self-renewing stem cells, and impaired endochondral ossification and mineralization during fracture healing.\",\n      \"method\": \"Lgr6-null mouse model, colony-forming assays, osteogenic differentiation, Wnt signaling assays, fracture healing model with ALP activity, microCT, histology\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with multiple orthogonal functional readouts across in vitro and in vivo contexts\",\n      \"pmids\": [\"36708855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGR6 expression is enhanced during BMP-mediated osteogenesis; Lgr6 loss results in downregulation of BMP signaling elements including pSMAD and BMP-associated gene ontology pathways, revealing a molecular interdependency between BMP signaling and Lgr6 in osteogenesis.\",\n      \"method\": \"Lgr6 knockout cells and mice, RNA sequencing, bioinformatic analysis of published single-cell data, biochemical pSMAD assays, gene ontology pathway analysis\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA-seq with biochemical validation, single lab\",\n      \"pmids\": [\"39033993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGR6 deficiency in cardiomyocytes aggravates ferroptosis and disrupted mitochondrial biogenesis in diabetic cardiomyopathy by regulating STAT3/PGC1α signaling; cardiomyocyte-specific LGR6 overexpression ameliorates cardiac dysfunction. LGR6 activation by recombinant RSPO3 treatment also ameliorated cardiac dysfunction and mitochondrial dysfunction.\",\n      \"method\": \"LGR6 knockout mice, AAV9-mediated cardiomyocyte-specific LGR6 overexpression, streptozotocin/high-fat diet diabetes model, RNA sequencing, ChIP assay, STAT3 inhibition, PGC1α activation experiments\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cardiac-specific gain and loss of function, RNA-seq with ChIP, RSPO3 ligand activation, multiple in vivo readouts\",\n      \"pmids\": [\"39038735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RSPO3-LGR6 axis activates Wnt signaling to downregulate STAT2 and ZBP1 expression, thereby inhibiting cardiomyocyte necroptosis after ischemia-reperfusion injury. LGR6 deficiency promoted necroptosis while LGR6 overexpression inhibited it; RSPO3 treatment protected from acute myocardial I/R injury.\",\n      \"method\": \"LGR6 knockout mice, coronary artery ligation I/R model, RNA sequencing, ChIP assays, STAT2 and ZBP1 inhibition experiments, RSPO3 treatment\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with ligand (RSPO3) rescue, RNA-seq, ChIP, epistasis through STAT2/ZBP1 inhibition\",\n      \"pmids\": [\"39471639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MaR1 regulates hypertensive vascular remodeling through LGR6 via a Ca2+/calmodulin-dependent protein kinase II/Nrf2/HO-1 signaling pathway; LGR6 knockout aggravated pathological vascular remodeling that could not be reversed by MaR1 treatment.\",\n      \"method\": \"LGR6 knockout mice, angiotensin II-infused hypertension model, VSMC functional assays (proliferation, migration, phenotype switching, pyroptosis), CaMKII/Nrf2/HO-1 pathway analysis\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — LGR6 knockout with defined signaling pathway, single lab\",\n      \"pmids\": [\"38463394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A frameshift variant in LGR6 leads to downregulation of LGR6 expression selectively in neutrophils, monocytes, and NK cells (but not macrophages or CD8+ T cells), linking LGR6 expression to decreased bacterial phagocytosis, increased neutrophil chemotaxis, increased leukotriene B4 production, and altered antiviral responses via TLR3/7/8/9 pathways.\",\n      \"method\": \"Human genetic variant analysis, flow cytometry for LGR6 expression on leukocyte subsets, phagocytosis assays, chemotaxis assays, leukotriene B4 measurement, TLR agonist stimulation, UK Biobank population analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function variant with cell-type specific expression data and multiple orthogonal functional immune readouts\",\n      \"pmids\": [\"38718314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Monoclonal antibodies against the N-terminal extracellular domain of human LGR6 competitively block R-spondin 1 binding to LGR6, confirming that R-spondin 1 binds to the large ectodomain of LGR6.\",\n      \"method\": \"DNA immunization, whole-cell immunization, flow cytometry screening of hybridomas, competitive binding assays with mAbs and R-spondin 1\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — competitive binding assay with specificity confirmed against LGR4, LGR5, and LGR6 transfectants\",\n      \"pmids\": [\"28013222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGR6 activates MaR1-LGR6-CREB/JMJD3/IRF4 signaling pathway to attenuate neuroinflammation after subarachnoid hemorrhage; LGR6 knockdown, CREB inhibition, or JMJD3 inhibition abolished MaR1's anti-neuroinflammatory effects on microglial activation and cytokine expression.\",\n      \"method\": \"SAH rat model, intranasal MaR1 administration, LGR6 siRNA knockdown, KG-501 (CREB inhibitor), GSK-J4 (JMJD3 inhibitor), neurobehavioral testing, histology, biochemical cytokine analysis, microglial activation assessment\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo pathway dissection with multiple inhibitors and siRNA, single lab\",\n      \"pmids\": [\"38340785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MaR1 alleviates RSV-induced lung inflammation via LGR6 expressed constitutively on Tregs; Lgr6-deficient mice had exacerbated type 2 immune responses, increased viral burden, and blunted responses to MaR1, establishing a MaR1-LGR6 axis that improves Treg suppressive function and upregulates host antiviral genes.\",\n      \"method\": \"Lgr6 knockout mice, RSV infection model, flow cytometry, IL-13 measurement, amphiregulin measurement, interferon-β measurement, RSV viral transcript quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — LGR6 knockout with multiple immune and viral readouts, defined receptor-ligand axis on specific immune cell type\",\n      \"pmids\": [\"36595677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGR6 promotes myoblast differentiation and fusion; Lgr6 mRNA is transiently expressed during myogenic differentiation in response to ATRA (requiring RARα and RARγ agonism). LGR6 loss decreased differentiation and fusion indices; LGR6 expression is downregulated by the ubiquitin-proteasome system involving ZNRF3. LGR6 augments Wnt/β-catenin signaling activity induced by Wnt3a and R-spondin 2 in myoblasts.\",\n      \"method\": \"C2C12 myoblast differentiation assay, siRNA knockdown of LGR6, exogenous LGR6 expression, ATRA/RAR agonist treatment, proteasome inhibitor treatment, Znrf3 knockdown, Wnt/β-catenin luciferase reporter assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gain and loss of function with multiple mechanistic interventions, single lab, cell line model\",\n      \"pmids\": [\"37240382\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGR6 is a leucine-rich repeat-containing G protein-coupled receptor that functions primarily as a high-affinity receptor for R-spondins (RSPO1-3) and the pro-resolving lipid mediator maresin 1 (MaR1); R-spondin binding potentiates Wnt/β-catenin signaling (via LRP6 phosphorylation and β-catenin stabilization, without G protein or β-arrestin coupling), while MaR1 binding activates cAMP signaling, with both ligands promoting stem/progenitor cell function in tissues including skin, bone, lung, heart, and immune cells, and with downstream pathway outputs including Wnt/TCF7L2 feedback loops, STAT3/PGC1α-mediated mitochondrial biogenesis, STAT2/ZBP1-regulated necroptosis, and CaMKII/Nrf2/HO-1-mediated vascular remodeling depending on cellular context.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LGR6 is a leucine-rich repeat-containing G protein-coupled receptor that functions as a stem/progenitor cell marker and signaling hub across multiple tissues, integrating R-spondin–dependent Wnt/β-catenin potentiation with maresin 1 (MaR1)–dependent pro-resolving signaling. LGR6 binds R-spondins 1–3 with high affinity to enhance Wnt/β-catenin signaling via LRP6 phosphorylation and β-catenin stabilization—without coupling to heterotrimeric G proteins or β-arrestin—while MaR1 binding activates cAMP/CREB signaling, establishing two distinct ligand-dependent signaling modes through a single receptor [PMID:22615920, PMID:34856421, PMID:31657786]. Lgr6 marks self-renewing stem/progenitor populations in skin epidermis, hair follicle, taste buds, nail, mammary gland, lung mesenchyme, and bone, where it is functionally required for tissue homeostasis, wound repair, and regeneration; Lgr6 loss impairs wound healing, fracture repair, osteogenesis, and digit tip regeneration, and predisposes to squamous cell carcinoma [PMID:20223988, PMID:26460010, PMID:28945253, PMID:36708855]. MaR1–LGR6 signaling drives pro-resolving immune functions including macrophage efferocytosis, Treg-mediated suppression of type 2 inflammation, attenuation of vascular remodeling, and anti-neuroinflammatory microglial polarization, while a human frameshift variant in LGR6 reduces neutrophil phagocytosis and alters innate immune responses [PMID:31657786, PMID:36595677, PMID:34320253, PMID:38718314].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of LGR6 as a distinct subfamily member of leucine-rich repeat GPCRs established its structural class but left its ligand and signaling mode unknown.\",\n      \"evidence\": \"Phylogenetic and sequence analysis with mutagenesis of related LGR7; LGR6 signaling inferred by homology\",\n      \"pmids\": [\"10935549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LGR6 signaling inferred from LGR7 rather than directly tested\", \"no endogenous ligand identified\", \"no functional role assigned\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The demonstration that Lgr6 marks the most primitive epidermal stem cells capable of generating all skin lineages established LGR6 as a bona fide stem cell marker, shifting the field from receptor characterization to stem cell biology.\",\n      \"evidence\": \"Knock-in reporter alleles with genetic lineage tracing, cell ablation, and wound healing in mice\",\n      \"pmids\": [\"20223988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ligand for LGR6 still unknown\", \"mechanism by which LGR6 maintains stemness undefined\", \"unclear whether LGR6 is functionally required or merely a marker\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of R-spondins 1–3 as high-affinity LGR6 ligands that potentiate Wnt/β-catenin signaling via LRP6 phosphorylation—without G protein or β-arrestin coupling—defined LGR6's molecular signaling mechanism and distinguished it from classical GPCR activation.\",\n      \"evidence\": \"Direct binding affinity assays, LRP6 phosphorylation, G protein/β-arrestin coupling assays, cancer mutant loss-of-function analysis\",\n      \"pmids\": [\"22615920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether additional non-R-spondin ligands exist was unknown\", \"structural basis of R-spondin binding unresolved\", \"in vivo consequence of R-spondin–LGR6 interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extending LGR6's stem cell role beyond skin, the finding that Lgr6+ cells generate taste bud organoids and contribute to taste papillae in vivo established LGR6 as a pan-tissue stem/progenitor marker, while nerve-dependence of Lgr6 expression revealed niche-dependent regulation.\",\n      \"evidence\": \"Single-cell organoid culture from Lgr6+ taste cells with lineage tracing; nerve ablation with Lgr6 expression analysis in skin\",\n      \"pmids\": [\"25368147\", \"24499442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether LGR6 is functionally required in taste or merely marks progenitors\", \"molecular mediator of nerve-to-Lgr6 signaling unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstration that Lgr6 knockout mice have impaired nail and digit tip regeneration, and that Lgr6+ skin progenitors undergo neutral competition, established LGR6 as functionally required for regeneration rather than merely a passive marker.\",\n      \"evidence\": \"Lgr6 knockout mouse phenotyping with microCT; multicolor Confetti lineage tracing with quantitative clonal analysis\",\n      \"pmids\": [\"26460010\", \"26607954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"downstream signaling pathway mediating regeneration unresolved\", \"whether Wnt potentiation is the operative mechanism in regeneration untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Lgr6+ mammary progenitors were shown to be unipotent yet capable of tumor initiation upon oncogenic mutation, linking LGR6-marked cells to cancer biology and demonstrating that depletion of Lgr6+ cells impairs tumor growth.\",\n      \"evidence\": \"Genetic lineage tracing with conditional oncogene activation and diphtheria toxin-mediated cell depletion in MMTV-PyMT model\",\n      \"pmids\": [\"27798604\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether LGR6 signaling itself drives tumor initiation or merely marks the cell of origin\", \"applicability to human breast cancer undetermined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Three advances refined LGR6 biology: Lgr6+ lung mesenchymal cells were shown to promote airway repair via Wnt-Fgf10 cooperation; Lgr6 knockout predisposed to squamous cell carcinoma with compensatory Lgr5 upregulation; and monoclonal antibodies confirmed R-spondin 1 binding to the LGR6 ectodomain.\",\n      \"evidence\": \"scRNA-seq and organoid co-culture with genetic ablation in lung; germline Lgr6 knockout with skin carcinogenesis; competitive mAb binding assays\",\n      \"pmids\": [\"28886383\", \"28945253\", \"28013222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"LGR5/LGR6 functional redundancy mechanisms unclear\", \"structural detail of R-spondin–ectodomain interaction lacking\", \"whether Lgr6+ lung cells are stem cells or niche support cells debated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery of maresin 1 (MaR1) as a second, structurally distinct LGR6 ligand that activates phagocyte functions via ERK/CREB phosphorylation revealed LGR6 as a dual-ligand receptor bridging Wnt potentiation and pro-resolving lipid mediator biology.\",\n      \"evidence\": \"Unbiased GPCR screen of >200 receptors, radiolabeled 3H-MaR1 binding, LGR6 overexpression/siRNA with phagocytosis and efferocytosis assays\",\n      \"pmids\": [\"31657786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis for dual ligand recognition unknown\", \"whether MaR1 and R-spondin compete for the same binding site unresolved\", \"downstream G protein coupling for MaR1 signaling not fully characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The dual signaling modes of LGR6 were formally dissected: RSPO2 activates Wnt/β-catenin while MaR1 activates cAMP, and Lgr6 knockout mice show reduced trabecular bone mass, establishing pathway-specific ligand outputs and an in vivo osteogenic requirement.\",\n      \"evidence\": \"CRISPR Lgr6 knockout mice with microCT and MSC osteodifferentiation; parallel Wnt and cAMP pathway assays with RSPO2 vs MaR1\",\n      \"pmids\": [\"34856421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"signaling intermediates coupling LGR6 to cAMP production unidentified\", \"whether both pathways operate simultaneously in vivo unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"MaR1–LGR6 signaling was placed upstream of macrophage efferocytosis and TGF-β2 in vascular protection, while in epidermis intravital imaging confirmed nerve-dependent Lgr6 stem cell wound repair with compensatory hair follicle stem cell recruitment, and a Wnt/β-catenin–TCF7L2 positive feedback loop was identified in cervical cancer stem cells.\",\n      \"evidence\": \"AAA model with SMC-TGFβr2 knockout epistasis; intravital two-photon imaging with cell ablation and scRNA-seq; TOP/FOP reporter with ChIP at LGR6 promoter\",\n      \"pmids\": [\"34320253\", \"34102139\", \"34489551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TGF-β2 induction mechanism downstream of LGR6 undefined\", \"whether TCF7L2 feedback loop operates in normal tissue or only cancer stem cells unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple studies expanded LGR6's immune and skeletal roles: MaR1–LGR6 on Tregs resolves RSV-induced lung inflammation; MaR1–LGR6–CREB/JMJD3/IRF4 attenuates neuroinflammation; Lgr6-null osteoprogenitors show impaired fracture healing via attenuated Wnt signaling; and LGR6 is regulated by ZNRF3-mediated proteasomal degradation in myoblasts.\",\n      \"evidence\": \"Lgr6 knockout mice with RSV infection and immune profiling; SAH rat model with pathway inhibitors; Lgr6-null fracture model with microCT; C2C12 siRNA/overexpression with ZNRF3 knockdown\",\n      \"pmids\": [\"36595677\", \"38340785\", \"36708855\", \"37240382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ZNRF3-LGR6 ubiquitination sites and regulation not mapped\", \"whether JMJD3/IRF4 pathway is specific to microglia or generalizable unknown\", \"BMP–Wnt crosstalk through LGR6 only partially characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cardiac and vascular studies revealed LGR6 as a cardioprotective receptor: RSPO3–LGR6 activates STAT3/PGC1α to prevent ferroptosis in diabetic cardiomyopathy, suppresses STAT2/ZBP1-mediated necroptosis after I/R injury, and MaR1–LGR6 signals via CaMKII/Nrf2/HO-1 to attenuate hypertensive vascular remodeling; a human LGR6 frameshift variant linked receptor loss to impaired neutrophil phagocytosis and altered innate immunity.\",\n      \"evidence\": \"Cardiac-specific LGR6 KO/overexpression with RSPO3 rescue in diabetes and I/R models; LGR6 KO hypertension model; human variant analysis with functional immune assays in UK Biobank\",\n      \"pmids\": [\"39038735\", \"39471639\", \"38463394\", \"38718314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis for RSPO3 vs MaR1 pathway divergence at LGR6 unresolved\", \"human genetic confirmation of cardiac phenotypes lacking\", \"whether LGR6 frameshift variant affects Wnt signaling in human immune cells untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for dual ligand recognition (R-spondins vs MaR1), whether both ligand systems operate in the same cell simultaneously, the complete signaling intermediates linking LGR6 to cAMP production, and the extent of functional redundancy with LGR4 and LGR5 across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no crystal/cryo-EM structure of LGR6 with either ligand\", \"G protein coupling mechanism for MaR1 signaling undefined\", \"systematic comparison of LGR4/5/6 functional redundancy across tissues lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 10, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 11, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 10, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 10, 11, 13, 15, 21, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 4, 5, 7, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 14, 24, 27]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [21, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RSPO1\",\n      \"RSPO2\",\n      \"RSPO3\",\n      \"CTNNB1\",\n      \"LRP6\",\n      \"ZNRF3\",\n      \"TCF7L2\",\n      \"HNRNPK\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}