{"gene":"CELSR2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2010,"finding":"Celsr2 (and Celsr3) are required for ependymal ciliogenesis and planar organization of ependymal cilia; Celsr2-deficient mice show compromised cilia development and planar organization leading to defective CSF dynamics and hydrocephalus. The membrane distribution of PCP proteins Vangl2 and Fzd3 was disturbed in Celsr2 mutants, placing Celsr2 upstream of or parallel to Vangl2/Fzd3 in the PCP pathway.","method":"Celsr2 knockout mice, immunostaining for Vangl2/Fzd3 localization, histological and CSF dynamics analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular and organismal phenotype, replicated with double mutant, membrane localization of pathway components directly measured","pmids":["20473291"],"is_preprint":false},{"year":2006,"finding":"In zebrafish hindbrain, celsr2 expression in neuroepithelial cells is required to keep facial motor neurons near the pial surface during caudal migration; loss of celsr2 (off-road) causes aberrant radial processes and dorsomedial mismigration of nVII neurons, revealing a role in preventing differentiated neuron integration into the neuroepithelial layer.","method":"Zebrafish celsr2 (off-road) loss-of-function, imaging of neuronal migration in hindbrain","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in zebrafish ortholog with defined cellular migration phenotype, single lab","pmids":["17079269"],"is_preprint":false},{"year":2002,"finding":"Celsr2 protein localizes to intercellular boundaries in whisker follicles and to processes of hippocampal pyramidal cells, Purkinje cells, and olfactory neurons, consistent with a role in contact-mediated signaling at cell-cell interfaces.","method":"Immunohistochemistry and protein distribution analysis during mouse embryonic and postnatal development","journal":"Developmental dynamics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by IHC, single study, no direct functional consequence tested","pmids":["11891983"],"is_preprint":false},{"year":2014,"finding":"Celsr2 acts redundantly with Celsr3 in forebrain axon guidance: combined conditional knockout of Celsr2 and Celsr3 phenocopies Fzd3 inactivation in the same cell populations, placing Celsr2-3 and Fzd3 in the same pathway. Crucially, forebrain wiring is normal in Vangl1/Vangl2 double mutants, demonstrating that Celsr2/3-Fzd3-dependent axon guidance is Vangl-independent.","method":"Conditional knockout mice (Celsr2, Celsr3, Fzd3, Vangl1/2 single and combined), axon tract tracing, genetic epistasis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO combinations with epistasis analysis, orthogonal tract-tracing, clear pathway placement","pmids":["25002511"],"is_preprint":false},{"year":2006,"finding":"MEHP exposure rapidly induces serine/threonine phosphorylation of Celsr2 in transfected HeLa cells via protein kinase C and casein kinase 1 (but not PKA or MAPK), and concurrently alters Celsr2 subcellular localization in Sertoli cells in vivo (redistribution to basal aspect then diffuse pattern within 2 h).","method":"Phosphorylation assay in Celsr2-transfected HeLa cells with kinase inhibitors; immunolocalization in rat testis after MEHP exposure","journal":"Toxicological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assay with pharmacological inhibitors identifying PKC and CK1 as writers, plus in vivo localization change; single lab","pmids":["16484285"],"is_preprint":false},{"year":2020,"finding":"Celsr2 promotes Schwann cell proliferation and migration via the Wnt/β-catenin pathway: Celsr2 silencing reduced nuclear β-catenin, GSK3β phosphorylation, and downstream Cyclin D1 and MMP-7 expression, and these effects were rescued by Wnt/β-catenin activators (LiCl or mutant β-catenin S33Y).","method":"Celsr2 siRNA in primary Schwann cells; MTT, EdU, transwell, wound healing assays; luciferase reporter; western blot for β-catenin and downstream targets; rescue with LiCl/mutant β-catenin","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype, pathway reporter, and pharmacological rescue; single lab","pmids":["32988580"],"is_preprint":false},{"year":2021,"finding":"CELSR2 deficiency in hepatocytes suppresses lipid accumulation by reducing lipid synthesis enzyme expression, impairs physiological unfolded protein response (UPR) thereby disrupting ER homeostasis, and elevates reactive oxygen species (ROS) by decreasing antioxidant expression; ROS scavenging with N-acetylcysteine restores the decreased lipid accumulation phenotype of CELSR2-knockdown cells.","method":"CELSR2 knockdown in hepatocyte cell lines; lipid staining, western blot for UPR and antioxidant markers, ROS assay, NAC rescue experiment","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple orthogonal readouts (lipid, UPR, ROS) and pharmacological rescue; single lab","pmids":["34478580"],"is_preprint":false},{"year":2022,"finding":"Celsr2 negatively regulates motor axon regeneration and fasciculation: Celsr2 KO in spinal motor neurons promotes longer neurite outgrowth, larger growth cones, increased end-binding protein 3 expression, and higher calcium influx in cultured neurons, and improves axon regeneration and functional recovery after brachial plexus injury in vivo. Mechanistically, Celsr2 downregulation is accompanied by increased GTP-bound Rac1 and Cdc42, and elevated JNK and c-Jun levels.","method":"Celsr2 knockout mouse (constitutive and conditional in motor neurons); spinal explant cultures; brachial plexus injury model; neurite length/growth cone measurements; western blot for EB3, Rac1-GTP, Cdc42-GTP, JNK, c-Jun; calcium imaging; human motor neuron shRNA knockdown","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular and in vivo phenotype, multiple orthogonal methods (imaging, biochemistry, functional recovery), replicated in human neurons","pmids":["34983065"],"is_preprint":false},{"year":2023,"finding":"Celsr2 regulates morphological polarization and functional phenotype of reactive astrocytes: Celsr2 KO astrocytes show longer protrusions oriented toward lesion borders, elevated active Cdc42 and Rac1, and enhanced calcium influx; these morphological phenotypes are rescued by Cdc42 or Rac1 inhibitors. After spinal cord injury, astrocyte-specific Celsr2 conditional KO reduces lesion cavity and glial scar and improves functional recovery; inhibiting Cdc42/Rac1 reverses these benefits.","method":"Celsr2 KO and conditional KO in astrocytes; scratch assay; SCI model; time-lapse calcium imaging; western blot for Cdc42/Rac1; pharmacological rescue with Cdc42/Rac1 inhibitors","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-specific conditional KO, multiple orthogonal methods, pharmacological rescue confirming Cdc42/Rac1 as effectors, in vivo functional validation","pmids":["37186402"],"is_preprint":false},{"year":2023,"finding":"Celsr1 and Celsr2 exhibit distinct adhesive interactions: Celsr1 stably enriches at junctional interfaces (low FRAP recovery), whereas Celsr2 is much less efficiently recruited to and immobilized at junctions (higher FRAP recovery). Both interact with core PCP proteins Vangl2 and Fz6 equivalently. Celsr1 is the major family member driving epidermal PCP; loss of Celsr2 alone does not affect epidermal PCP.","method":"CRISPR/Cas9 Celsr1 and Celsr2 KO mice; FRAP; junctional enrichment assays; co-immunoprecipitation with Vangl2 and Fz6; hair follicle polarity assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP and junctional enrichment directly compare adhesive dynamics, co-IP with PCP partners, KO phenotype analysis; single lab","pmids":["36712970"],"is_preprint":false},{"year":2022,"finding":"Celsr2 is required for maintaining structural and functional integrity of adult cortical synapses: in vivo synaptic imaging in Celsr2-deficient adult mice revealed altered spinogenesis, reduced neuronal calcium activities, and anomalies in postsynaptic organization and presynaptic vesicles, associated with impaired motor learning. Adult-specific Celsr2 KO recapitulated these features.","method":"Celsr2 KO mice (developmental and adult-induced); in vivo synaptic imaging; calcium imaging; electron microscopy of pre/postsynaptic structures; motor learning behavioral tests","journal":"Progress in neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo imaging with adult-specific KO confirmation, multiple synaptic readouts; single lab","pmids":["36089108"],"is_preprint":false},{"year":2023,"finding":"Celsr2 knockout alleviates inhibitory synaptic stripping of injured motoneurons cell-autonomously: after brachial plexus avulsion, more inhibitory (F-bouton) synapses are maintained on motoneurons in Celsr2-/- mice than controls; MHC I molecule expression is upregulated around injured motoneurons in Celsr2-/- mice. Conditional KO of Celsr2 in astrocytes or oligodendrocytes does not replicate this synaptic preservation, indicating the effect is cell-autonomous to neurons or other cell types.","method":"Celsr2 KO and astrocyte/oligodendrocyte conditional KO mice; brachial plexus avulsion model; double immunostaining for synaptic vesicle markers; electron microscopy of F-boutons; RNAseq; MHC I immunostaining","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KOs used to assign cell autonomy, multiple morphological methods, RNAseq pathway analysis; single lab","pmids":["36593433"],"is_preprint":false},{"year":2025,"finding":"CELSR2 knockdown in glioma cells inhibits Wnt/β-catenin signaling and reduces cell proliferation with cell cycle arrest; WNT3A-induced glioma cell proliferation and downstream signaling are significantly reduced by CELSR2 knockdown, and the effect is rescued by GSK-3β inhibitor (activating β-catenin). Magnetic nanoparticles loaded with CELSR2-siRNA suppress tumor growth in a glioma orthotopic mouse model.","method":"CELSR2 siRNA/shRNA in glioma cell lines; proliferation and cell cycle assays; proteomic analysis; luciferase/western blot for Wnt/β-catenin; WNT3A stimulation and GSK-3β inhibitor rescue; in vivo orthotopic glioma model with nanoparticle delivery","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with pathway rescue, proteomic validation, and in vivo model; single lab","pmids":["41184253"],"is_preprint":false},{"year":2025,"finding":"A pilose antler peptide (LVLVEAELRE) directly binds Celsr2 (confirmed by CETSA, MST, and molecular docking) and upregulates Celsr2 expression; Celsr2 knockdown abolishes the peptide's neuroprotective effects (improvement of cognition, reduction of Aβ/p-Tau, restoration of AMPA receptor subunits, inhibition of neuronal senescence) in SAMP8 mice, while Celsr2 overexpression amplifies them.","method":"CETSA, microscale thermophoresis (MST), molecular docking; AAV-shCelsr2 knockdown and AAV-OECelsr2 overexpression in SAMP8 mice; behavioral tests; western blot for Aβ, p-Tau, AMPA subunits, senescence markers","journal":"Journal of ethnopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by two biophysical methods (CETSA and MST) plus bidirectional genetic manipulation in vivo; single lab","pmids":["41941989"],"is_preprint":false}],"current_model":"CELSR2 is a seven-pass transmembrane atypical cadherin that acts as a core planar cell polarity (PCP) component functioning upstream of or in concert with Vangl2 and Fzd3 to govern ependymal ciliogenesis, neuronal migration, and forebrain axon guidance (the latter in a Vangl-independent manner); it negatively regulates motor axon regeneration and astrocyte morphological polarization by restraining Rac1/Cdc42 and JNK/c-Jun signaling, maintains adult cortical synaptic integrity, promotes Schwann cell proliferation/migration via Wnt/β-catenin, and can be phosphorylated on serine/threonine residues by PKC and casein kinase 1 in response to cellular stimulation."},"narrative":{"mechanistic_narrative":"CELSR2 is a seven-pass transmembrane atypical cadherin that functions as a core planar cell polarity (PCP) component governing ciliogenesis, neuronal migration, and axon guidance in the developing and adult nervous system [PMID:20473291, PMID:25002511]. It acts upstream of or in parallel with Vangl2 and Fzd3: loss of Celsr2 disrupts the membrane distribution of these PCP proteins and compromises planar organization of ependymal cilia, producing defective CSF dynamics and hydrocephalus [PMID:20473291], while combined Celsr2/Celsr3 loss phenocopies Fzd3 inactivation in forebrain axon guidance through a Vangl-independent route [PMID:25002511]. CELSR2 localizes to intercellular boundaries and neuronal processes, consistent with a contact-mediated signaling role [PMID:11891983], and engages Vangl2 and Fz6, though it is recruited to and immobilized at junctions far less efficiently than Celsr1 [PMID:36712970]. In injured neural tissue CELSR2 acts as a restraint on regenerative and reactive responses: it negatively regulates motor axon regeneration and astrocyte morphological polarization by limiting GTP-loading of Rac1 and Cdc42 and JNK/c-Jun signaling, such that Celsr2 loss enhances neurite outgrowth, glial polarization, and functional recovery after injury [PMID:34983065, PMID:37186402]. In the adult cortex CELSR2 is required to maintain synaptic structure and function and supports motor learning [PMID:36089108]. Beyond the nervous system, CELSR2 promotes Schwann cell and glioma cell proliferation through Wnt/β-catenin signaling [PMID:32988580, PMID:41184253] and supports hepatocyte lipid accumulation, UPR-dependent ER homeostasis, and redox balance [PMID:34478580]. CELSR2 is phosphorylated on serine/threonine residues by protein kinase C and casein kinase 1 upon cellular stimulation [PMID:16484285].","teleology":[{"year":2002,"claim":"Establishing where CELSR2 protein resides was the first step toward a function: its enrichment at cell-cell interfaces pointed to contact-mediated signaling rather than a diffusible role.","evidence":"Immunohistochemistry of Celsr2 distribution in developing mouse whisker follicles and neurons","pmids":["11891983"],"confidence":"Low","gaps":["Localization by IHC only with no functional consequence tested","No binding partners identified","Does not establish a molecular activity"]},{"year":2006,"claim":"Two parallel advances connected CELSR2 to neuronal positioning and to post-translational control: a zebrafish ortholog kept migrating motor neurons at the pial surface, while a phosphorylation assay identified the kinases that modify the receptor.","evidence":"Zebrafish celsr2 (off-road) loss-of-function imaging of nVII migration; phosphorylation assay in transfected HeLa cells with PKC/CK1/PKA/MAPK inhibitors plus rat testis immunolocalization","pmids":["17079269","16484285"],"confidence":"Medium","gaps":["The phosphorylation sites on CELSR2 are not mapped","Functional consequence of PKC/CK1 phosphorylation not tested","Migration mechanism in zebrafish not linked to specific signaling partners"]},{"year":2010,"claim":"This work placed CELSR2 firmly within the PCP pathway by showing it controls ependymal ciliogenesis and is required for correct membrane distribution of Vangl2 and Fzd3, defining it as upstream of or parallel to the core PCP module.","evidence":"Celsr2 knockout mice with immunostaining for Vangl2/Fzd3 localization, histology, and CSF dynamics analysis","pmids":["20473291"],"confidence":"High","gaps":["Direct physical interaction with Vangl2/Fzd3 not shown here","Mechanism by which Celsr2 positions PCP proteins unresolved","Redundancy with Celsr3 not dissected in this study"]},{"year":2014,"claim":"Genetic epistasis resolved how CELSR2 wires the forebrain, showing it acts redundantly with Celsr3 in the Fzd3 pathway but, unlike classic PCP, independently of Vangl1/2 for axon guidance.","evidence":"Conditional knockout combinations of Celsr2, Celsr3, Fzd3, and Vangl1/2 with axon tract tracing and genetic epistasis","pmids":["25002511"],"confidence":"High","gaps":["Molecular basis of Vangl-independence not defined","Downstream effectors of Celsr2/3-Fzd3 axon guidance not identified","Direct Celsr2-Fzd3 interaction not demonstrated"]},{"year":2020,"claim":"Beyond development, CELSR2 was linked to a defined intracellular cascade, driving Schwann cell proliferation and migration via Wnt/β-catenin signaling.","evidence":"Celsr2 siRNA in primary Schwann cells with proliferation/migration assays, luciferase reporter, western blot, and LiCl/mutant β-catenin rescue","pmids":["32988580"],"confidence":"Medium","gaps":["How CELSR2 couples to Wnt/β-catenin mechanistically is unknown","No direct partner linking receptor to GSK3β identified","Single cell type and single lab"]},{"year":2021,"claim":"A metabolic role emerged showing CELSR2 supports hepatocyte lipid accumulation, ER homeostasis via the UPR, and redox balance, with ROS scavenging rescuing the lipid phenotype.","evidence":"CELSR2 knockdown in hepatocyte cell lines with lipid staining, UPR/antioxidant western blots, ROS assay, and NAC rescue","pmids":["34478580"],"confidence":"Medium","gaps":["Signaling intermediates between CELSR2 and lipid/UPR/ROS pathways unknown","Whether the metabolic role uses PCP-type signaling untested","Single lab, cell-line based"]},{"year":2022,"claim":"Loss-of-function studies established CELSR2 as a negative regulator of motor axon regeneration and a maintainer of adult cortical synapses, defining its small-GTPase-restraining mechanism and an ongoing adult role.","evidence":"Constitutive and motor-neuron conditional Celsr2 KO with explant cultures, brachial plexus injury, growth cone imaging, Rac1/Cdc42/JNK/c-Jun western blots, calcium imaging, human neuron knockdown; separate adult-induced Celsr2 KO with in vivo synaptic and calcium imaging and EM","pmids":["34983065","36089108"],"confidence":"High","gaps":["How CELSR2 restrains Rac1/Cdc42 GTP-loading is not defined","Link between PCP function and GTPase regulation unclear","Synaptic maintenance mechanism not molecularly resolved"]},{"year":2023,"claim":"Cell-type-specific deletions extended the GTPase-restraint mechanism to reactive astrocytes and assigned cell autonomy to CELSR2's effects on injured-neuron synapse preservation.","evidence":"Astrocyte-specific and constitutive Celsr2 KO with scratch/SCI models, calcium imaging, Cdc42/Rac1 western blots and pharmacological rescue; brachial plexus avulsion with synaptic EM, RNAseq, and MHC I staining; comparative junctional FRAP and co-IP of Celsr1/Celsr2 with Vangl2/Fz6","pmids":["37186402","36593433","36712970"],"confidence":"Medium","gaps":["The cell type mediating synaptic preservation not positively identified","Mechanism distinguishing Celsr1 from Celsr2 junctional immobilization unknown","Whether MHC I upregulation is causal for synapse preservation untested"]},{"year":2025,"claim":"CELSR2 was implicated as a pro-tumor and neuroprotective target, driving glioma proliferation through Wnt/β-catenin and serving as the direct binding target of a neuroprotective antler peptide.","evidence":"CELSR2 siRNA/shRNA glioma models with Wnt/β-catenin reporters, WNT3A and GSK-3β rescue, and orthotopic nanoparticle delivery; CETSA/MST/docking peptide binding with AAV knockdown/overexpression in SAMP8 mice","pmids":["41184253","41941989"],"confidence":"Medium","gaps":["Direct receptor-ligand mechanism of peptide-CELSR2 signaling unresolved","How CELSR2 activates Wnt/β-catenin in glioma mechanistically unknown","Single-lab findings without independent replication"]},{"year":null,"claim":"The molecular bridge connecting CELSR2's extracellular cadherin-PCP engagement to its intracellular control of Rac1/Cdc42, JNK/c-Jun, and Wnt/β-catenin signaling remains undefined.","evidence":"No discovery in the corpus identifies the cytoplasmic effectors or adaptors transducing CELSR2 signaling","pmids":[],"confidence":"Low","gaps":["No direct cytoplasmic effector or adaptor identified","No structural model of CELSR2 signaling","Mechanism unifying PCP, GTPase, and Wnt roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,9]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,7,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,9]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,8,12]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,10]}],"complexes":[],"partners":["VANGL2","FZD3","FZD6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HCU4","full_name":"Cadherin EGF LAG seven-pass G-type receptor 2","aliases":["Cadherin family member 10","Epidermal growth factor-like protein 2","EGF-like protein 2","Flamingo homolog 3","Multiple epidermal growth factor-like domains protein 3","Multiple EGF-like domains protein 3"],"length_aa":2923,"mass_kda":317.5,"function":"Receptor that may have an important role in cell/cell signaling during nervous system formation","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9HCU4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CELSR2","classification":"Not Classified","n_dependent_lines":69,"n_total_lines":1208,"dependency_fraction":0.057119205298013245},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CELSR2","total_profiled":1310},"omim":[{"mim_id":"613589","title":"LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 6; LDLCQ6","url":"https://www.omim.org/entry/613589"},{"mim_id":"604265","title":"CADHERIN EGF LAG SEVEN-PASS G-TYPE RECEPTOR 2; CELSR2","url":"https://www.omim.org/entry/604265"},{"mim_id":"602458","title":"SORTILIN; SORT1","url":"https://www.omim.org/entry/602458"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":24.4},{"tissue":"skin 1","ntpm":23.4}],"url":"https://www.proteinatlas.org/search/CELSR2"},"hgnc":{"alias_symbol":["KIAA0279","MEGF3","Flamingo1","CDHF10","ADGRC2"],"prev_symbol":["EGFL2"]},"alphafold":{"accession":"Q9HCU4","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCU4","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CELSR2","jax_strain_url":"https://www.jax.org/strain/search?query=CELSR2"},"sequence":{"accession":"Q9HCU4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HCU4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HCU4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCU4"}},"corpus_meta":[{"pmid":"20473291","id":"PMC_20473291","title":"Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus.","date":"2010","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20473291","citation_count":279,"is_preprint":false},{"pmid":"17079269","id":"PMC_17079269","title":"Frizzled3a and Celsr2 function in the neuroepithelium to regulate migration of facial motor neurons in the developing zebrafish hindbrain.","date":"2006","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17079269","citation_count":96,"is_preprint":false},{"pmid":"11891983","id":"PMC_11891983","title":"Differential expression of the seven-pass transmembrane cadherin genes Celsr1-3 and distribution of the Celsr2 protein during mouse development.","date":"2002","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/11891983","citation_count":79,"is_preprint":false},{"pmid":"18649068","id":"PMC_18649068","title":"The novel genetic variant predisposing to coronary artery disease in the region of the PSRC1 and CELSR2 genes on chromosome 1 associates with serum cholesterol.","date":"2008","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/18649068","citation_count":76,"is_preprint":false},{"pmid":"25002511","id":"PMC_25002511","title":"Genetic evidence that Celsr3 and Celsr2, together with Fzd3, regulate forebrain wiring in a Vangl-independent manner.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25002511","citation_count":68,"is_preprint":false},{"pmid":"28052552","id":"PMC_28052552","title":"CELSR2, encoding a planar cell polarity protein, is a putative gene in Joubert syndrome with cortical heterotopia, microophthalmia, and growth hormone deficiency.","date":"2017","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/28052552","citation_count":30,"is_preprint":false},{"pmid":"26464717","id":"PMC_26464717","title":"Association of variants in CELSR2-PSRC1-SORT1 with risk of serum lipid traits, coronary artery disease and ischemic stroke.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26464717","citation_count":25,"is_preprint":false},{"pmid":"34478580","id":"PMC_34478580","title":"CELSR2 deficiency suppresses lipid accumulation in hepatocyte by impairing the UPR and elevating ROS level.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34478580","citation_count":23,"is_preprint":false},{"pmid":"34983065","id":"PMC_34983065","title":"Inactivating Celsr2 promotes motor axon fasciculation and regeneration in mouse and human.","date":"2022","source":"Brain : a 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PSRC1, CELSR2, and SORT1 Gene Polymorphisms on the Variability of Warfarin Dosage and Susceptibility to Cardiovascular Disease.","date":"2020","source":"Pharmacogenomics and personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33235484","citation_count":16,"is_preprint":false},{"pmid":"36089108","id":"PMC_36089108","title":"Planar cell polarity protein Celsr2 maintains structural and functional integrity of adult cortical synapses.","date":"2022","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/36089108","citation_count":14,"is_preprint":false},{"pmid":"36975855","id":"PMC_36975855","title":"Association between Genetic Variants of CELSR2-PSRC1-SORT1 and Cardiovascular Diseases: A Systematic Review and Meta-Analysis.","date":"2023","source":"Journal of cardiovascular development and disease","url":"https://pubmed.ncbi.nlm.nih.gov/36975855","citation_count":13,"is_preprint":false},{"pmid":"32988580","id":"PMC_32988580","title":"Silencing Celsr2 inhibits 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Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/16484285","citation_count":10,"is_preprint":false},{"pmid":"33810964","id":"PMC_33810964","title":"rs629301 CELSR2 polymorphism confers a ten-year equivalent risk of critical stenosis assessed by coronary angiography.","date":"2021","source":"Nutrition, metabolism, and cardiovascular diseases : NMCD","url":"https://pubmed.ncbi.nlm.nih.gov/33810964","citation_count":7,"is_preprint":false},{"pmid":"36593433","id":"PMC_36593433","title":"Celsr2 Knockout Alleviates Inhibitory Synaptic Stripping and Benefits Motoneuron Survival and Axon Regeneration After Branchial Plexus Avulsion.","date":"2023","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/36593433","citation_count":5,"is_preprint":false},{"pmid":"40373963","id":"PMC_40373963","title":"Targeting mesenchymal monocyte-derived macrophages to enhance the sensitivity of glioblastoma to temozolomide by inhibiting TNF/CELSR2/p65/Kla-HDAC1/EPAS1 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The membrane distribution of PCP proteins Vangl2 and Fzd3 was disturbed in Celsr2 mutants, placing Celsr2 upstream of or parallel to Vangl2/Fzd3 in the PCP pathway.\",\n      \"method\": \"Celsr2 knockout mice, immunostaining for Vangl2/Fzd3 localization, histological and CSF dynamics analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular and organismal phenotype, replicated with double mutant, membrane localization of pathway components directly measured\",\n      \"pmids\": [\"20473291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In zebrafish hindbrain, celsr2 expression in neuroepithelial cells is required to keep facial motor neurons near the pial surface during caudal migration; loss of celsr2 (off-road) causes aberrant radial processes and dorsomedial mismigration of nVII neurons, revealing a role in preventing differentiated neuron integration into the neuroepithelial layer.\",\n      \"method\": \"Zebrafish celsr2 (off-road) loss-of-function, imaging of neuronal migration in hindbrain\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in zebrafish ortholog with defined cellular migration phenotype, single lab\",\n      \"pmids\": [\"17079269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Celsr2 protein localizes to intercellular boundaries in whisker follicles and to processes of hippocampal pyramidal cells, Purkinje cells, and olfactory neurons, consistent with a role in contact-mediated signaling at cell-cell interfaces.\",\n      \"method\": \"Immunohistochemistry and protein distribution analysis during mouse embryonic and postnatal development\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by IHC, single study, no direct functional consequence tested\",\n      \"pmids\": [\"11891983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Celsr2 acts redundantly with Celsr3 in forebrain axon guidance: combined conditional knockout of Celsr2 and Celsr3 phenocopies Fzd3 inactivation in the same cell populations, placing Celsr2-3 and Fzd3 in the same pathway. Crucially, forebrain wiring is normal in Vangl1/Vangl2 double mutants, demonstrating that Celsr2/3-Fzd3-dependent axon guidance is Vangl-independent.\",\n      \"method\": \"Conditional knockout mice (Celsr2, Celsr3, Fzd3, Vangl1/2 single and combined), axon tract tracing, genetic epistasis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO combinations with epistasis analysis, orthogonal tract-tracing, clear pathway placement\",\n      \"pmids\": [\"25002511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MEHP exposure rapidly induces serine/threonine phosphorylation of Celsr2 in transfected HeLa cells via protein kinase C and casein kinase 1 (but not PKA or MAPK), and concurrently alters Celsr2 subcellular localization in Sertoli cells in vivo (redistribution to basal aspect then diffuse pattern within 2 h).\",\n      \"method\": \"Phosphorylation assay in Celsr2-transfected HeLa cells with kinase inhibitors; immunolocalization in rat testis after MEHP exposure\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assay with pharmacological inhibitors identifying PKC and CK1 as writers, plus in vivo localization change; single lab\",\n      \"pmids\": [\"16484285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Celsr2 promotes Schwann cell proliferation and migration via the Wnt/β-catenin pathway: Celsr2 silencing reduced nuclear β-catenin, GSK3β phosphorylation, and downstream Cyclin D1 and MMP-7 expression, and these effects were rescued by Wnt/β-catenin activators (LiCl or mutant β-catenin S33Y).\",\n      \"method\": \"Celsr2 siRNA in primary Schwann cells; MTT, EdU, transwell, wound healing assays; luciferase reporter; western blot for β-catenin and downstream targets; rescue with LiCl/mutant β-catenin\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype, pathway reporter, and pharmacological rescue; single lab\",\n      \"pmids\": [\"32988580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CELSR2 deficiency in hepatocytes suppresses lipid accumulation by reducing lipid synthesis enzyme expression, impairs physiological unfolded protein response (UPR) thereby disrupting ER homeostasis, and elevates reactive oxygen species (ROS) by decreasing antioxidant expression; ROS scavenging with N-acetylcysteine restores the decreased lipid accumulation phenotype of CELSR2-knockdown cells.\",\n      \"method\": \"CELSR2 knockdown in hepatocyte cell lines; lipid staining, western blot for UPR and antioxidant markers, ROS assay, NAC rescue experiment\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple orthogonal readouts (lipid, UPR, ROS) and pharmacological rescue; single lab\",\n      \"pmids\": [\"34478580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Celsr2 negatively regulates motor axon regeneration and fasciculation: Celsr2 KO in spinal motor neurons promotes longer neurite outgrowth, larger growth cones, increased end-binding protein 3 expression, and higher calcium influx in cultured neurons, and improves axon regeneration and functional recovery after brachial plexus injury in vivo. Mechanistically, Celsr2 downregulation is accompanied by increased GTP-bound Rac1 and Cdc42, and elevated JNK and c-Jun levels.\",\n      \"method\": \"Celsr2 knockout mouse (constitutive and conditional in motor neurons); spinal explant cultures; brachial plexus injury model; neurite length/growth cone measurements; western blot for EB3, Rac1-GTP, Cdc42-GTP, JNK, c-Jun; calcium imaging; human motor neuron shRNA knockdown\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular and in vivo phenotype, multiple orthogonal methods (imaging, biochemistry, functional recovery), replicated in human neurons\",\n      \"pmids\": [\"34983065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Celsr2 regulates morphological polarization and functional phenotype of reactive astrocytes: Celsr2 KO astrocytes show longer protrusions oriented toward lesion borders, elevated active Cdc42 and Rac1, and enhanced calcium influx; these morphological phenotypes are rescued by Cdc42 or Rac1 inhibitors. After spinal cord injury, astrocyte-specific Celsr2 conditional KO reduces lesion cavity and glial scar and improves functional recovery; inhibiting Cdc42/Rac1 reverses these benefits.\",\n      \"method\": \"Celsr2 KO and conditional KO in astrocytes; scratch assay; SCI model; time-lapse calcium imaging; western blot for Cdc42/Rac1; pharmacological rescue with Cdc42/Rac1 inhibitors\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-specific conditional KO, multiple orthogonal methods, pharmacological rescue confirming Cdc42/Rac1 as effectors, in vivo functional validation\",\n      \"pmids\": [\"37186402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Celsr1 and Celsr2 exhibit distinct adhesive interactions: Celsr1 stably enriches at junctional interfaces (low FRAP recovery), whereas Celsr2 is much less efficiently recruited to and immobilized at junctions (higher FRAP recovery). Both interact with core PCP proteins Vangl2 and Fz6 equivalently. Celsr1 is the major family member driving epidermal PCP; loss of Celsr2 alone does not affect epidermal PCP.\",\n      \"method\": \"CRISPR/Cas9 Celsr1 and Celsr2 KO mice; FRAP; junctional enrichment assays; co-immunoprecipitation with Vangl2 and Fz6; hair follicle polarity assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP and junctional enrichment directly compare adhesive dynamics, co-IP with PCP partners, KO phenotype analysis; single lab\",\n      \"pmids\": [\"36712970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Celsr2 is required for maintaining structural and functional integrity of adult cortical synapses: in vivo synaptic imaging in Celsr2-deficient adult mice revealed altered spinogenesis, reduced neuronal calcium activities, and anomalies in postsynaptic organization and presynaptic vesicles, associated with impaired motor learning. Adult-specific Celsr2 KO recapitulated these features.\",\n      \"method\": \"Celsr2 KO mice (developmental and adult-induced); in vivo synaptic imaging; calcium imaging; electron microscopy of pre/postsynaptic structures; motor learning behavioral tests\",\n      \"journal\": \"Progress in neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo imaging with adult-specific KO confirmation, multiple synaptic readouts; single lab\",\n      \"pmids\": [\"36089108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Celsr2 knockout alleviates inhibitory synaptic stripping of injured motoneurons cell-autonomously: after brachial plexus avulsion, more inhibitory (F-bouton) synapses are maintained on motoneurons in Celsr2-/- mice than controls; MHC I molecule expression is upregulated around injured motoneurons in Celsr2-/- mice. Conditional KO of Celsr2 in astrocytes or oligodendrocytes does not replicate this synaptic preservation, indicating the effect is cell-autonomous to neurons or other cell types.\",\n      \"method\": \"Celsr2 KO and astrocyte/oligodendrocyte conditional KO mice; brachial plexus avulsion model; double immunostaining for synaptic vesicle markers; electron microscopy of F-boutons; RNAseq; MHC I immunostaining\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KOs used to assign cell autonomy, multiple morphological methods, RNAseq pathway analysis; single lab\",\n      \"pmids\": [\"36593433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CELSR2 knockdown in glioma cells inhibits Wnt/β-catenin signaling and reduces cell proliferation with cell cycle arrest; WNT3A-induced glioma cell proliferation and downstream signaling are significantly reduced by CELSR2 knockdown, and the effect is rescued by GSK-3β inhibitor (activating β-catenin). Magnetic nanoparticles loaded with CELSR2-siRNA suppress tumor growth in a glioma orthotopic mouse model.\",\n      \"method\": \"CELSR2 siRNA/shRNA in glioma cell lines; proliferation and cell cycle assays; proteomic analysis; luciferase/western blot for Wnt/β-catenin; WNT3A stimulation and GSK-3β inhibitor rescue; in vivo orthotopic glioma model with nanoparticle delivery\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with pathway rescue, proteomic validation, and in vivo model; single lab\",\n      \"pmids\": [\"41184253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A pilose antler peptide (LVLVEAELRE) directly binds Celsr2 (confirmed by CETSA, MST, and molecular docking) and upregulates Celsr2 expression; Celsr2 knockdown abolishes the peptide's neuroprotective effects (improvement of cognition, reduction of Aβ/p-Tau, restoration of AMPA receptor subunits, inhibition of neuronal senescence) in SAMP8 mice, while Celsr2 overexpression amplifies them.\",\n      \"method\": \"CETSA, microscale thermophoresis (MST), molecular docking; AAV-shCelsr2 knockdown and AAV-OECelsr2 overexpression in SAMP8 mice; behavioral tests; western blot for Aβ, p-Tau, AMPA subunits, senescence markers\",\n      \"journal\": \"Journal of ethnopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by two biophysical methods (CETSA and MST) plus bidirectional genetic manipulation in vivo; single lab\",\n      \"pmids\": [\"41941989\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CELSR2 is a seven-pass transmembrane atypical cadherin that acts as a core planar cell polarity (PCP) component functioning upstream of or in concert with Vangl2 and Fzd3 to govern ependymal ciliogenesis, neuronal migration, and forebrain axon guidance (the latter in a Vangl-independent manner); it negatively regulates motor axon regeneration and astrocyte morphological polarization by restraining Rac1/Cdc42 and JNK/c-Jun signaling, maintains adult cortical synaptic integrity, promotes Schwann cell proliferation/migration via Wnt/β-catenin, and can be phosphorylated on serine/threonine residues by PKC and casein kinase 1 in response to cellular stimulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CELSR2 is a seven-pass transmembrane atypical cadherin that functions as a core planar cell polarity (PCP) component governing ciliogenesis, neuronal migration, and axon guidance in the developing and adult nervous system [#0, #3]. It acts upstream of or in parallel with Vangl2 and Fzd3: loss of Celsr2 disrupts the membrane distribution of these PCP proteins and compromises planar organization of ependymal cilia, producing defective CSF dynamics and hydrocephalus [#0], while combined Celsr2/Celsr3 loss phenocopies Fzd3 inactivation in forebrain axon guidance through a Vangl-independent route [#3]. CELSR2 localizes to intercellular boundaries and neuronal processes, consistent with a contact-mediated signaling role [#2], and engages Vangl2 and Fz6, though it is recruited to and immobilized at junctions far less efficiently than Celsr1 [#9]. In injured neural tissue CELSR2 acts as a restraint on regenerative and reactive responses: it negatively regulates motor axon regeneration and astrocyte morphological polarization by limiting GTP-loading of Rac1 and Cdc42 and JNK/c-Jun signaling, such that Celsr2 loss enhances neurite outgrowth, glial polarization, and functional recovery after injury [#7, #8]. In the adult cortex CELSR2 is required to maintain synaptic structure and function and supports motor learning [#10]. Beyond the nervous system, CELSR2 promotes Schwann cell and glioma cell proliferation through Wnt/\\u03b2-catenin signaling [#5, #12] and supports hepatocyte lipid accumulation, UPR-dependent ER homeostasis, and redox balance [#6]. CELSR2 is phosphorylated on serine/threonine residues by protein kinase C and casein kinase 1 upon cellular stimulation [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing where CELSR2 protein resides was the first step toward a function: its enrichment at cell-cell interfaces pointed to contact-mediated signaling rather than a diffusible role.\",\n      \"evidence\": \"Immunohistochemistry of Celsr2 distribution in developing mouse whisker follicles and neurons\",\n      \"pmids\": [\"11891983\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Localization by IHC only with no functional consequence tested\", \"No binding partners identified\", \"Does not establish a molecular activity\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Two parallel advances connected CELSR2 to neuronal positioning and to post-translational control: a zebrafish ortholog kept migrating motor neurons at the pial surface, while a phosphorylation assay identified the kinases that modify the receptor.\",\n      \"evidence\": \"Zebrafish celsr2 (off-road) loss-of-function imaging of nVII migration; phosphorylation assay in transfected HeLa cells with PKC/CK1/PKA/MAPK inhibitors plus rat testis immunolocalization\",\n      \"pmids\": [\"17079269\", \"16484285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The phosphorylation sites on CELSR2 are not mapped\", \"Functional consequence of PKC/CK1 phosphorylation not tested\", \"Migration mechanism in zebrafish not linked to specific signaling partners\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"This work placed CELSR2 firmly within the PCP pathway by showing it controls ependymal ciliogenesis and is required for correct membrane distribution of Vangl2 and Fzd3, defining it as upstream of or parallel to the core PCP module.\",\n      \"evidence\": \"Celsr2 knockout mice with immunostaining for Vangl2/Fzd3 localization, histology, and CSF dynamics analysis\",\n      \"pmids\": [\"20473291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction with Vangl2/Fzd3 not shown here\", \"Mechanism by which Celsr2 positions PCP proteins unresolved\", \"Redundancy with Celsr3 not dissected in this study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic epistasis resolved how CELSR2 wires the forebrain, showing it acts redundantly with Celsr3 in the Fzd3 pathway but, unlike classic PCP, independently of Vangl1/2 for axon guidance.\",\n      \"evidence\": \"Conditional knockout combinations of Celsr2, Celsr3, Fzd3, and Vangl1/2 with axon tract tracing and genetic epistasis\",\n      \"pmids\": [\"25002511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of Vangl-independence not defined\", \"Downstream effectors of Celsr2/3-Fzd3 axon guidance not identified\", \"Direct Celsr2-Fzd3 interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Beyond development, CELSR2 was linked to a defined intracellular cascade, driving Schwann cell proliferation and migration via Wnt/\\u03b2-catenin signaling.\",\n      \"evidence\": \"Celsr2 siRNA in primary Schwann cells with proliferation/migration assays, luciferase reporter, western blot, and LiCl/mutant \\u03b2-catenin rescue\",\n      \"pmids\": [\"32988580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CELSR2 couples to Wnt/\\u03b2-catenin mechanistically is unknown\", \"No direct partner linking receptor to GSK3\\u03b2 identified\", \"Single cell type and single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A metabolic role emerged showing CELSR2 supports hepatocyte lipid accumulation, ER homeostasis via the UPR, and redox balance, with ROS scavenging rescuing the lipid phenotype.\",\n      \"evidence\": \"CELSR2 knockdown in hepatocyte cell lines with lipid staining, UPR/antioxidant western blots, ROS assay, and NAC rescue\",\n      \"pmids\": [\"34478580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling intermediates between CELSR2 and lipid/UPR/ROS pathways unknown\", \"Whether the metabolic role uses PCP-type signaling untested\", \"Single lab, cell-line based\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Loss-of-function studies established CELSR2 as a negative regulator of motor axon regeneration and a maintainer of adult cortical synapses, defining its small-GTPase-restraining mechanism and an ongoing adult role.\",\n      \"evidence\": \"Constitutive and motor-neuron conditional Celsr2 KO with explant cultures, brachial plexus injury, growth cone imaging, Rac1/Cdc42/JNK/c-Jun western blots, calcium imaging, human neuron knockdown; separate adult-induced Celsr2 KO with in vivo synaptic and calcium imaging and EM\",\n      \"pmids\": [\"34983065\", \"36089108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CELSR2 restrains Rac1/Cdc42 GTP-loading is not defined\", \"Link between PCP function and GTPase regulation unclear\", \"Synaptic maintenance mechanism not molecularly resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cell-type-specific deletions extended the GTPase-restraint mechanism to reactive astrocytes and assigned cell autonomy to CELSR2's effects on injured-neuron synapse preservation.\",\n      \"evidence\": \"Astrocyte-specific and constitutive Celsr2 KO with scratch/SCI models, calcium imaging, Cdc42/Rac1 western blots and pharmacological rescue; brachial plexus avulsion with synaptic EM, RNAseq, and MHC I staining; comparative junctional FRAP and co-IP of Celsr1/Celsr2 with Vangl2/Fz6\",\n      \"pmids\": [\"37186402\", \"36593433\", \"36712970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The cell type mediating synaptic preservation not positively identified\", \"Mechanism distinguishing Celsr1 from Celsr2 junctional immobilization unknown\", \"Whether MHC I upregulation is causal for synapse preservation untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CELSR2 was implicated as a pro-tumor and neuroprotective target, driving glioma proliferation through Wnt/\\u03b2-catenin and serving as the direct binding target of a neuroprotective antler peptide.\",\n      \"evidence\": \"CELSR2 siRNA/shRNA glioma models with Wnt/\\u03b2-catenin reporters, WNT3A and GSK-3\\u03b2 rescue, and orthotopic nanoparticle delivery; CETSA/MST/docking peptide binding with AAV knockdown/overexpression in SAMP8 mice\",\n      \"pmids\": [\"41184253\", \"41941989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor-ligand mechanism of peptide-CELSR2 signaling unresolved\", \"How CELSR2 activates Wnt/\\u03b2-catenin in glioma mechanistically unknown\", \"Single-lab findings without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular bridge connecting CELSR2's extracellular cadherin-PCP engagement to its intracellular control of Rac1/Cdc42, JNK/c-Jun, and Wnt/\\u03b2-catenin signaling remains undefined.\",\n      \"evidence\": \"No discovery in the corpus identifies the cytoplasmic effectors or adaptors transducing CELSR2 signaling\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct cytoplasmic effector or adaptor identified\", \"No structural model of CELSR2 signaling\", \"Mechanism unifying PCP, GTPase, and Wnt roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 8, 12]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VANGL2\", \"FZD3\", \"FZD6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}