{"gene":"CELSR1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2003,"finding":"Missense mutations in Celsr1 (spin cycle and crash alleles) disrupt planar cell polarity of inner ear hair cells and cause severe neural tube defects due to failure to initiate neural tube closure in mice, establishing Celsr1 as the first mammalian member of the flamingo/starry night PCP pathway.","method":"ENU mutagenesis, missense mutation identification, phenotypic analysis of heterozygous and homozygous mutants","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined loss-of-function alleles with specific cellular phenotypes, replicated across two independent ENU screens","pmids":["12842012"],"is_preprint":false},{"year":2011,"finding":"Missense variants in human CELSR1 associated with craniorachischisis abolish or diminish trafficking of CELSR1 protein to the plasma membrane, without affecting protein-protein interactions; comparable membrane trafficking defects were seen in crash and spin cycle mouse Celsr1 mutants.","method":"Subcellular protein localization assays, protein-protein interaction assays, sequencing of human CRN patients","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence, single lab, two orthogonal methods (interaction assay + localization assay)","pmids":["22095531"],"is_preprint":false},{"year":2010,"finding":"Celsr1 (Crash allele) is required for normal lung branching morphogenesis; mutant lungs show fewer branches, thickened mesenchyme, disrupted epithelial integrity, perturbed cytoskeletal remodelling, and failure of mutant endoderm to branch in response to FGF10; this phenotype is recapitulated by Rho kinase inhibition, placing Celsr1 upstream of Rho kinase in lung PCP signaling.","method":"Mouse mutant analysis (Celsr1Crsh), Rho kinase inhibitor treatment, ex vivo branching assay with FGF10","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, epistasis via pharmacological inhibition, single lab","pmids":["20223754"],"is_preprint":false},{"year":2013,"finding":"Celsr1 is recruited from endothelial filopodia to discrete membrane domains at cell-cell contacts during lymphatic valve morphogenesis and regulates dynamic endothelial cell movements by inhibiting stabilization of VE-cadherin and maturation of adherens junctions.","method":"Celsr1-deficient mouse analysis, live imaging of endothelial cell behaviors, localization studies of Celsr1 and VE-cadherin","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment tied to functional consequence, mechanistic link to VE-cadherin/adherens junction stabilization, multiple orthogonal methods","pmids":["23792146"],"is_preprint":false},{"year":2010,"finding":"Celsr1 functions non-cell-autonomously in facial branchiomotor (FBM) neuron migration: Celsr1 is expressed in FBM neuron precursors and the floor plate (not in migrating FBM neurons themselves), and its loss causes neurons to migrate rostrally instead of caudally. Celsr1 is epistatic to Celsr2 in this context.","method":"Knock-out and Crash allele mouse analysis, conditional inactivation, genetic epistasis (Celsr2 epistatic to Celsr1)","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO defining non-cell-autonomous function, genetic epistasis with multiple alleles, specific directional migration phenotype","pmids":["20631168"],"is_preprint":false},{"year":2014,"finding":"Celsr1 is required for multilevel polarity in the mouse oviduct: it is concentrated at specific cellular boundaries perpendicular to the ovary-uterus axis; its loss randomizes ciliary beat orientation, cell elongation/orientation, and epithelial fold directionality. Mosaic analysis shows that Celsr1 primarily regulates epithelial cell geometry, which secondarily aligns epithelial folds.","method":"Celsr1-deficient mouse analysis, mosaic analysis, immunofluorescence localization, ciliary motion assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with specific cellular phenotypes, mosaic analysis for epistasis, direct protein localization tied to function","pmids":["25406397"],"is_preprint":false},{"year":2014,"finding":"Two TG dinucleotide repeat variants in CELSR1 found in spina bifida patients change its subcellular localization and impair its physical association with VANGL2, diminishing the ability of CELSR1 to recruit VANGL2 to cell-cell contacts.","method":"In vitro subcellular localization assay, co-immunoprecipitation (physical interaction assay between CELSR1 and VANGL2)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, localization assay, single lab, two orthogonal methods","pmids":["24632739"],"is_preprint":false},{"year":2016,"finding":"Celsr1 functions non-cell-autonomously in FBM neuron migration: conditional inactivation specifically in the ventricular zone of rhombomeres r3-r5 (not in the floor plate) causes rostral migration of FBM neurons, indicating that Celsr1 in the adjacent neuroepithelium suppresses signals that could otherwise attract FBM neurons rostrally.","method":"Conditional (Cre-lox) inactivation of Celsr1 in specific cell types, dye fill experiments to trace neuron origins","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with cell-type specificity, dye-fill tracing confirming origin of rostrally migrating neurons","pmids":["27395006"],"is_preprint":false},{"year":2019,"finding":"The CELSR1 missense mutation P870L (c.2609G>A) is a gain-of-function mutation that upregulates both the PCP pathway and canonical WNT signaling in cells, and induces both neural tube defects and congenital heart defects in zebrafish embryos.","method":"In vitro cell-based assay for PCP and WNT pathway activity, zebrafish in vivo injection assay","journal":"Clinical science (London, England : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo zebrafish assay + in vitro pathway assays, single lab, two orthogonal methods","pmids":["27756857"],"is_preprint":false},{"year":2021,"finding":"Mouse Celsr1 engages in both trans- and cis-interactions, forming dense and highly stable punctate assemblies at junctions. The PCP-mutant variant Celsr1Crsh selectively impairs lateral cis-interactions, displays increased mobility, fails to engage in homophilic adhesion with wild-type protein, and consequently fails to organize Frizzled6 and Vangl2 into asymmetric junctional complexes, a defect rescuable by ectopic cis-dimerization.","method":"Biochemical assays, super-resolution microscopy, FRAP, co-immunoprecipitation with Fzd6 and Vangl2, ectopic cis-dimerization rescue experiment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (biochemistry, super-resolution imaging, FRAP, rescue by cis-dimerization) establishing mechanism","pmids":["33529151"],"is_preprint":false},{"year":2021,"finding":"In mouse oviduct multi-ciliated cells, CELSR1 is required for intercellular coordination of basal body (BB) orientation, while CAMSAP3 (a microtubule minus-end regulator) controls intracellular BB orientation; CELSR1 loss disrupts intercellular but not intracellular polarity coordination, and does not affect CAMSAP3 localization.","method":"Celsr1-deficient and Camsap3-mutant mouse analysis, immunofluorescence, genetic epistasis (double mutant analysis)","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-mutant epistasis, direct localization experiments with functional consequence, mechanistic dissection of inter- vs. intracellular polarity","pmids":["33468623"],"is_preprint":false},{"year":2017,"finding":"Celsr1 controls branching of apical neural progenitor cell (aNPC) basal processes abutting the meninges and thereby regulates retinoic acid (RA)-dependent neurogenesis. Loss of Celsr1 decreases endfeet number, modifies RA-dependent transcriptional activity, and biases aNPC commitment toward self-renewal at the expense of basal progenitor and neuron production, resulting in cortical hypoplasia.","method":"Celsr1 loss-of-function mouse analysis, RA transcriptional activity assay, progenitor fate quantification","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, RA pathway assay, single lab, two orthogonal methods","pmids":["29257130"],"is_preprint":false},{"year":2017,"finding":"Celsr1 is asymmetrically distributed at cell boundaries between hair cells and neighboring supporting cells in developing vestibular and auditory sensory epithelia; loss of Celsr1 results in misoriented stereociliary bundles of vestibular hair cells, particularly in the cristae of the semicircular canals.","method":"Celsr1 knockout mouse analysis, immunofluorescence localization, behavioral analysis (circling)","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization tied to functional consequence, KO phenotype, single lab","pmids":["28159525"],"is_preprint":false},{"year":2023,"finding":"CELSR1 and CELSR3 are cleavage-deficient (lack autoproteolytic cleavage at the GAIN domain), while CELSR2 is efficiently cleaved. Despite this, CELSR1-3 all engage GαS. CELSR1 tethered agonist (TA) point mutants retain GαS coupling activity, indicating CELSR1 signals via a cleavage-independent mechanism distinct from the canonical tethered-agonist paradigm.","method":"G protein coupling assays, autoproteolysis assays, tethered agonist point mutant analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution of G protein coupling, mutagenesis of tethered agonist, multiple orthogonal assays, peer-reviewed","pmids":["37224017"],"is_preprint":false},{"year":2024,"finding":"CELSR1 tethered agonist (TA) point mutants retain GαS coupling activity; CELSR1 and CELSR3 are cleavage-deficient, while CELSR2 autoproteolysis enhances GαS coupling, yet acute TA exposure alone is insufficient for full activation.","method":"G protein coupling assays, autoproteolysis assays, tethered agonist point mutant analysis","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical assays with mutagenesis, preprint version of published peer-reviewed work (37224017), treated as supporting evidence","pmids":["37066404"],"is_preprint":true},{"year":2025,"finding":"Cryo-EM reconstruction of the mouse CELSR1 extracellular region (ECR) at 3.8 Å reveals 14 domains forming a compact module via conserved interactions between the CADH9 and C-terminal GAIN domains. In the presence of Ca2+, the CELSR1 ECR forms a dimer species via cadherin repeats putatively in antiparallel fashion. Cell-based assays show the N-terminal CADH1-8 repeat is required for cell-cell adhesion, while the C-terminal CADH9-GAIN compact module regulates cellular adhesion/signaling.","method":"Cryo-EM structure determination (3.8 Å), cell-based adhesion assays, domain deletion analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation by cell-based assays and domain mutagenesis","pmids":["40295529"],"is_preprint":false},{"year":2024,"finding":"Crystal structures of human CELSR1 EC1-4 and EC4-7 reveal typical cadherin folds with a non-canonical linker between EC5 and EC6. EC1-4 only dimerizes at high concentration in solution; EC7-MAD10 mediates dimerization; simulations and experiments indicate flexibility at EC5-6. Cell-based bead aggregation assays do not support strong adhesion by EC repeats alone, suggesting weak homophilic adhesion by CELSR1 cadherin repeats.","method":"X-ray crystallography (EC1-4 and EC4-7 crystal structures), bead aggregation assays, solution dimerization assays, molecular dynamics simulations","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional validation by bead aggregation and solution biochemistry, multiple orthogonal methods","pmids":["38307021"],"is_preprint":false},{"year":2023,"finding":"Celsr1 is the major Celsr family member driving epidermal planar cell polarity: removal of Celsr1 alone abolishes PCP protein asymmetry and hair follicle polarization, whereas loss of Celsr2 alone has no effect on epidermal PCP. FRAP assays show Celsr1 stably enriches at junctional interfaces while Celsr2 is much less efficiently recruited; both interact equivalently with Vangl2 and Fz6.","method":"CRISPR/Cas9 knockout of Celsr1 and Celsr2, FRAP, junctional enrichment assay, co-immunoprecipitation with Vangl2 and Fz6","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal KO comparison with multiple orthogonal methods (FRAP, Co-IP, PCP asymmetry assay), mechanistic dissection of Celsr1 vs Celsr2","pmids":["36712970"],"is_preprint":false},{"year":2022,"finding":"Celsr1 suppresses Wnt5a-mediated chemoattraction to direct caudal facial branchiomotor (FBM) neuron migration: in Celsr1;Wnt5a double mutants, FBM neurons never migrate rostrally; Wnt5a-coated beads attract FBM neurons rostrally in wild-type explants; and overexpression of Wnt5a in r3 of Celsr1 mutants greatly enhances rostral migration, establishing a genetic epistasis mechanism.","method":"Genetic epistasis (double mutant Celsr1;Wnt5a), bead implantation assay in hindbrain explants, Wnt5a overexpression in Celsr1 mutant background","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double mutant, bead assay, and overexpression rescue, three orthogonal experiments establishing mechanism","pmids":["36325991"],"is_preprint":false},{"year":2010,"finding":"Celsr1 protein is enriched at the basal surface of neuroepithelial cells within the early neural tube and in ventricular zone cells at the spinal cord midline, and this basal enrichment is lost in Celsr1 homozygous mutant embryos; this basal localization is spatiotemporally associated with dorsal sensory tract morphogenesis.","method":"Immunofluorescence localization in wild-type and Celsr1 mutant embryos, comparative analysis of protein distribution","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with mutant comparison, but functional consequence of basal enrichment not fully established","pmids":["20353824"],"is_preprint":false},{"year":2020,"finding":"Knockdown of Celsr1 in the subventricular zone (SVZ) after cerebral ischemia reduces neuroblast proliferation, CD31-positive cell number, and motor function, and increases apoptosis and infarct volume; these effects are associated with downregulation of p-PKC, placing Celsr1 upstream of Wnt/PKC signaling in post-ischemic neurogenesis and angiogenesis.","method":"Lentiviral Celsr1 knockdown in MCAO rat model, immunohistochemistry, functional behavioral assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular and behavioral phenotypes, PKC pathway readout, single lab","pmids":["32070035"],"is_preprint":false},{"year":2016,"finding":"CELSR1 promotes endothelial cell migration and tube formation through Dishevelled segment polarity protein 3 (Dvl3); gain- and loss-of-function of CELSR1 in human aortic endothelial cells bidirectionally regulate migration and angiogenic tube formation.","method":"TALE-VP64-mediated CELSR1 overexpression, shRNA knockdown, scratch/transwell migration assay, tube formation assay","journal":"Biochemistry. Biokhimiia","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain- and loss-of-function in cell culture with multiple phenotypic readouts, Dvl3 identified as downstream effector but interaction not directly confirmed by Co-IP","pmids":["27301287"],"is_preprint":false},{"year":2024,"finding":"De novo heterozygous CELSR1 missense variant p.(Cys1318Tyr) disrupts subcellular localization of CELSR1, affects cell-cell junctions, impairs planar cell polarity signaling, and lowers proliferation rate in vitro.","method":"In vitro subcellular localization assays, cell-cell junction assay, PCP signaling assay, proliferation assay","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro functional assays on patient variant, single lab","pmids":["38272662"],"is_preprint":false}],"current_model":"CELSR1 is a cleavage-deficient adhesion GPCR that functions as the core PCP organizer in mammalian epithelia and neural tissues: it forms stable homophilic trans- and cis-interactions through its cadherin ectodomain (structurally resolved by cryo-EM/X-ray), organizes Frizzled6 and Vangl2 into asymmetric junctional complexes via lateral cis-interactions, couples to GαS through a tethered-agonist-independent mechanism, recruits VANGL2 to cell-cell contacts, regulates adherens junction maturation (via VE-cadherin), directs collective cell polarity in skin, lung, oviduct, inner ear, and lymphatic valves, and controls neuronal migration directionality by suppressing Wnt5a-mediated chemoattraction in a non-cell-autonomous manner."},"narrative":{"mechanistic_narrative":"CELSR1 is the core mammalian planar cell polarity (PCP) organizer, the first vertebrate member of the flamingo/starry night pathway, required to coordinate cell orientation across diverse epithelia and to initiate neural tube closure [PMID:12842012]. It is a cleavage-deficient adhesion GPCR whose large cadherin ectodomain mediates homophilic adhesion: cryo-EM and crystallographic structures of the extracellular region show 14 domains in which an N-terminal CADH1-8 segment drives cell-cell adhesion while a C-terminal CADH9-GAIN compact module regulates adhesion and signaling, with Ca2+-dependent dimerization through the cadherin repeats [PMID:40295529, PMID:38307021]. CELSR1 forms dense, highly stable punctate junctional assemblies through both trans- and cis-interactions; the PCP-mutant Celsr1Crsh selectively loses lateral cis-interactions, becomes mobile, and fails to organize Frizzled6 and Vangl2 into asymmetric junctional complexes, a defect rescuable by ectopic cis-dimerization [PMID:33529151]. This stable junctional enrichment, rather than partner binding per se, distinguishes CELSR1 from CELSR2, since CELSR1 alone establishes epidermal PCP asymmetry despite both family members interacting equivalently with Vangl2 and Fz6 [PMID:36712970], and it recruits VANGL2 to cell-cell contacts [PMID:24632739]. Through this activity CELSR1 directs collective polarity in skin, lung, oviduct, inner ear, and lymphatic valve tissues, acting upstream of Rho kinase in lung branching [PMID:20223754], coordinating intercellular basal body orientation in multiciliated cells [PMID:33468623], and limiting VE-cadherin/adherens junction maturation to permit dynamic endothelial movements during valve formation [PMID:23792146]. CELSR1 also functions non-cell-autonomously in facial branchiomotor neuron migration, where neuroepithelial CELSR1 suppresses Wnt5a-mediated rostral chemoattraction to enforce caudal migration [PMID:27395006, PMID:36325991]. Biochemically, CELSR1 couples to GαS through a cleavage- and tethered-agonist-independent mechanism, since it lacks GAIN autoproteolysis yet tethered-agonist point mutants retain GαS coupling [PMID:37224017]. Human and mouse CELSR1 variants cause craniorachischisis and neural tube defects by disrupting plasma-membrane trafficking, junctional localization, VANGL2 recruitment, and PCP signaling [PMID:22095531, PMID:24632739, PMID:38272662].","teleology":[{"year":2003,"claim":"Established CELSR1 as the founding mammalian PCP-pathway gene by linking its mutation to the two diagnostic readouts of disrupted planar polarity and failed neural tube closure.","evidence":"ENU mutagenesis and phenotypic analysis of spin cycle and crash mouse alleles","pmids":["12842012"],"confidence":"High","gaps":["Molecular basis of how the missense alleles disrupt protein function not defined","Direct biochemical activity unaddressed"]},{"year":2010,"claim":"Extended CELSR1 PCP function to branching morphogenesis and to non-cell-autonomous control of directional neuron migration, broadening its role beyond epithelial polarity.","evidence":"Crash-allele and conditional mouse analysis, Rho kinase inhibition and FGF10 ex vivo branching assays (lung); conditional inactivation and genetic epistasis with Celsr2 (FBM neurons); immunofluorescence in neural tube","pmids":["20223754","20631168","20353824"],"confidence":"Medium","gaps":["Molecular link between CELSR1 and Rho kinase not biochemically resolved","Identity of the suppressed migratory signal not yet known","Functional consequence of basal neuroepithelial enrichment not established"]},{"year":2011,"claim":"Identified loss of plasma-membrane trafficking as the cellular defect underlying human craniorachischisis-associated CELSR1 variants, separating localization from protein-interaction capacity.","evidence":"Subcellular localization and protein-interaction assays of human CRN patient variants, compared to crash/spin cycle mutants","pmids":["22095531"],"confidence":"Medium","gaps":["Single lab","How trafficking failure translates to PCP loss in vivo not shown"]},{"year":2013,"claim":"Revealed a junctional-dynamics function: CELSR1 restrains VE-cadherin/adherens junction maturation to enable the endothelial cell rearrangements of lymphatic valve formation.","evidence":"Celsr1-deficient mouse analysis, live imaging, and localization of Celsr1 and VE-cadherin","pmids":["23792146"],"confidence":"High","gaps":["Direct biochemical link between CELSR1 and VE-cadherin not defined","Signaling effector unknown"]},{"year":2014,"claim":"Tied CELSR1 asymmetric boundary localization to recruitment of VANGL2 and to organ-scale tissue polarity, and showed patient variants impair the CELSR1-VANGL2 interaction.","evidence":"Celsr1-deficient mouse with mosaic analysis (oviduct); Co-IP and localization assays of spina bifida TG-repeat variants with VANGL2","pmids":["25406397","24632739"],"confidence":"Medium","gaps":["Co-IP without reciprocal validation","Whether VANGL2 recruitment is direct not resolved"]},{"year":2016,"claim":"Localized the non-cell-autonomous migratory control to CELSR1 in the rhombomere neuroepithelium and identified Dvl3 as a downstream effector of CELSR1-driven endothelial migration.","evidence":"Cell-type-specific conditional inactivation with dye-fill tracing (FBM neurons); CELSR1 gain/loss-of-function with migration and tube-formation assays in endothelial cells","pmids":["27395006","27301287"],"confidence":"High","gaps":["CELSR1-Dvl3 interaction not confirmed by Co-IP","Identity of the suppressed neuroepithelial signal still unknown at this stage"]},{"year":2017,"claim":"Connected CELSR1 to progenitor-fate control and sensory-bundle orientation, linking its polarity activity to retinoic-acid-dependent neurogenesis and stereocilia alignment.","evidence":"Celsr1 loss-of-function mouse analysis with RA transcriptional assays and progenitor quantification (cortex); KO analysis with immunofluorescence and behavior (vestibular epithelia)","pmids":["29257130","28159525"],"confidence":"Medium","gaps":["Single lab for each context","Mechanism coupling endfoot branching to RA signaling not defined"]},{"year":2021,"claim":"Defined the molecular mechanism of CELSR1 PCP organization: stable cis/trans junctional assemblies are required to cluster Frizzled6 and Vangl2 asymmetrically, with the Crash mutation acting through loss of cis-interaction.","evidence":"Biochemistry, super-resolution microscopy, FRAP, Co-IP with Fzd6/Vangl2, and ectopic cis-dimerization rescue (epidermis/junctions); double-mutant epistasis with Camsap3 in oviduct ciliated cells","pmids":["33529151","33468623"],"confidence":"High","gaps":["Structural basis of cis vs trans contacts not resolved at this point","How junctional clustering couples to downstream signaling unaddressed"]},{"year":2022,"claim":"Identified the suppressed migratory signal as Wnt5a, establishing that CELSR1 enforces caudal neuron migration by blocking Wnt5a-mediated rostral chemoattraction.","evidence":"Celsr1;Wnt5a double mutants, Wnt5a bead implantation in hindbrain explants, and Wnt5a overexpression in Celsr1 mutant background","pmids":["36325991"],"confidence":"High","gaps":["Molecular mechanism by which CELSR1 suppresses Wnt5a signaling not defined","Receptor mediating Wnt5a chemoattraction not identified"]},{"year":2023,"claim":"Resolved the signaling mode and family specialization of CELSR1: it is a cleavage-deficient adhesion GPCR coupling to GαS independent of the tethered-agonist paradigm, and is the dominant Celsr driving epidermal PCP via stable junctional enrichment.","evidence":"G protein coupling, autoproteolysis, and tethered-agonist mutant assays; reciprocal Celsr1/Celsr2 CRISPR KO with FRAP, junctional enrichment, and Co-IP","pmids":["37224017","36712970"],"confidence":"High","gaps":["Physiological ligand/activation trigger of GαS coupling unknown","How GαS signaling integrates with PCP organization not established"]},{"year":2024,"claim":"Provided atomic-resolution structures of the cadherin ectodomain, assigning adhesion to N-terminal repeats and regulatory function to the CADH9-GAIN module, and confirmed pathogenicity of a de novo missense variant through PCP and junction assays.","evidence":"X-ray crystallography of EC1-4 and EC4-7 with bead aggregation and MD simulations; in vitro localization, junction, PCP, and proliferation assays of p.(Cys1318Tyr)","pmids":["38307021","38272662"],"confidence":"High","gaps":["Crystallography indicates only weak homophilic adhesion by isolated EC repeats","Full-length receptor architecture not captured by fragment structures"]},{"year":2025,"claim":"Delivered a near-complete cryo-EM model of the CELSR1 extracellular region, showing a compact 14-domain module formed by CADH9-GAIN contacts and Ca2+-dependent cadherin-mediated dimerization, unifying adhesion and signaling roles structurally.","evidence":"3.8 Å cryo-EM reconstruction with cell-based adhesion and domain-deletion assays","pmids":["40295529"],"confidence":"High","gaps":["Transmembrane/intracellular regions and GAIN-GPCR coupling not structurally resolved","Trans-dimer interface geometry remains putative"]},{"year":null,"claim":"How GAIN/GPCR-mediated GαS coupling is physiologically activated and mechanistically integrated with cadherin-based junctional clustering to drive asymmetric PCP complex assembly remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No identified activating ligand or trigger for GαS coupling","No structure of the full-length receptor or its intracellular signaling output","Mechanistic bridge between adhesion, G protein signaling, and Vangl2/Fzd6 clustering not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[13]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[15,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,9,22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,13,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[9,17,3]}],"complexes":["CELSR1-Frizzled6-Vangl2 asymmetric junctional PCP complex"],"partners":["VANGL2","FZD6","DVL3","WNT5A","CDH5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NYQ6","full_name":"Cadherin EGF LAG seven-pass G-type receptor 1","aliases":["Cadherin family member 9","Flamingo homolog 2","hFmi2"],"length_aa":3014,"mass_kda":329.5,"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/Q9NYQ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CELSR1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"HSPB11","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CELSR1","total_profiled":1310},"omim":[{"mim_id":"619319","title":"LYMPHATIC MALFORMATION 9; 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identification, phenotypic analysis of heterozygous and homozygous mutants\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined loss-of-function alleles with specific cellular phenotypes, replicated across two independent ENU screens\",\n      \"pmids\": [\"12842012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Missense variants in human CELSR1 associated with craniorachischisis abolish or diminish trafficking of CELSR1 protein to the plasma membrane, without affecting protein-protein interactions; comparable membrane trafficking defects were seen in crash and spin cycle mouse Celsr1 mutants.\",\n      \"method\": \"Subcellular protein localization assays, protein-protein interaction assays, sequencing of human CRN patients\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence, single lab, two orthogonal methods (interaction assay + localization assay)\",\n      \"pmids\": [\"22095531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Celsr1 (Crash allele) is required for normal lung branching morphogenesis; mutant lungs show fewer branches, thickened mesenchyme, disrupted epithelial integrity, perturbed cytoskeletal remodelling, and failure of mutant endoderm to branch in response to FGF10; this phenotype is recapitulated by Rho kinase inhibition, placing Celsr1 upstream of Rho kinase in lung PCP signaling.\",\n      \"method\": \"Mouse mutant analysis (Celsr1Crsh), Rho kinase inhibitor treatment, ex vivo branching assay with FGF10\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, epistasis via pharmacological inhibition, single lab\",\n      \"pmids\": [\"20223754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Celsr1 is recruited from endothelial filopodia to discrete membrane domains at cell-cell contacts during lymphatic valve morphogenesis and regulates dynamic endothelial cell movements by inhibiting stabilization of VE-cadherin and maturation of adherens junctions.\",\n      \"method\": \"Celsr1-deficient mouse analysis, live imaging of endothelial cell behaviors, localization studies of Celsr1 and VE-cadherin\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment tied to functional consequence, mechanistic link to VE-cadherin/adherens junction stabilization, multiple orthogonal methods\",\n      \"pmids\": [\"23792146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Celsr1 functions non-cell-autonomously in facial branchiomotor (FBM) neuron migration: Celsr1 is expressed in FBM neuron precursors and the floor plate (not in migrating FBM neurons themselves), and its loss causes neurons to migrate rostrally instead of caudally. Celsr1 is epistatic to Celsr2 in this context.\",\n      \"method\": \"Knock-out and Crash allele mouse analysis, conditional inactivation, genetic epistasis (Celsr2 epistatic to Celsr1)\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO defining non-cell-autonomous function, genetic epistasis with multiple alleles, specific directional migration phenotype\",\n      \"pmids\": [\"20631168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Celsr1 is required for multilevel polarity in the mouse oviduct: it is concentrated at specific cellular boundaries perpendicular to the ovary-uterus axis; its loss randomizes ciliary beat orientation, cell elongation/orientation, and epithelial fold directionality. Mosaic analysis shows that Celsr1 primarily regulates epithelial cell geometry, which secondarily aligns epithelial folds.\",\n      \"method\": \"Celsr1-deficient mouse analysis, mosaic analysis, immunofluorescence localization, ciliary motion assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with specific cellular phenotypes, mosaic analysis for epistasis, direct protein localization tied to function\",\n      \"pmids\": [\"25406397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Two TG dinucleotide repeat variants in CELSR1 found in spina bifida patients change its subcellular localization and impair its physical association with VANGL2, diminishing the ability of CELSR1 to recruit VANGL2 to cell-cell contacts.\",\n      \"method\": \"In vitro subcellular localization assay, co-immunoprecipitation (physical interaction assay between CELSR1 and VANGL2)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, localization assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"24632739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Celsr1 functions non-cell-autonomously in FBM neuron migration: conditional inactivation specifically in the ventricular zone of rhombomeres r3-r5 (not in the floor plate) causes rostral migration of FBM neurons, indicating that Celsr1 in the adjacent neuroepithelium suppresses signals that could otherwise attract FBM neurons rostrally.\",\n      \"method\": \"Conditional (Cre-lox) inactivation of Celsr1 in specific cell types, dye fill experiments to trace neuron origins\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with cell-type specificity, dye-fill tracing confirming origin of rostrally migrating neurons\",\n      \"pmids\": [\"27395006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The CELSR1 missense mutation P870L (c.2609G>A) is a gain-of-function mutation that upregulates both the PCP pathway and canonical WNT signaling in cells, and induces both neural tube defects and congenital heart defects in zebrafish embryos.\",\n      \"method\": \"In vitro cell-based assay for PCP and WNT pathway activity, zebrafish in vivo injection assay\",\n      \"journal\": \"Clinical science (London, England : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo zebrafish assay + in vitro pathway assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"27756857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mouse Celsr1 engages in both trans- and cis-interactions, forming dense and highly stable punctate assemblies at junctions. The PCP-mutant variant Celsr1Crsh selectively impairs lateral cis-interactions, displays increased mobility, fails to engage in homophilic adhesion with wild-type protein, and consequently fails to organize Frizzled6 and Vangl2 into asymmetric junctional complexes, a defect rescuable by ectopic cis-dimerization.\",\n      \"method\": \"Biochemical assays, super-resolution microscopy, FRAP, co-immunoprecipitation with Fzd6 and Vangl2, ectopic cis-dimerization rescue experiment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (biochemistry, super-resolution imaging, FRAP, rescue by cis-dimerization) establishing mechanism\",\n      \"pmids\": [\"33529151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In mouse oviduct multi-ciliated cells, CELSR1 is required for intercellular coordination of basal body (BB) orientation, while CAMSAP3 (a microtubule minus-end regulator) controls intracellular BB orientation; CELSR1 loss disrupts intercellular but not intracellular polarity coordination, and does not affect CAMSAP3 localization.\",\n      \"method\": \"Celsr1-deficient and Camsap3-mutant mouse analysis, immunofluorescence, genetic epistasis (double mutant analysis)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-mutant epistasis, direct localization experiments with functional consequence, mechanistic dissection of inter- vs. intracellular polarity\",\n      \"pmids\": [\"33468623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Celsr1 controls branching of apical neural progenitor cell (aNPC) basal processes abutting the meninges and thereby regulates retinoic acid (RA)-dependent neurogenesis. Loss of Celsr1 decreases endfeet number, modifies RA-dependent transcriptional activity, and biases aNPC commitment toward self-renewal at the expense of basal progenitor and neuron production, resulting in cortical hypoplasia.\",\n      \"method\": \"Celsr1 loss-of-function mouse analysis, RA transcriptional activity assay, progenitor fate quantification\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, RA pathway assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"29257130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Celsr1 is asymmetrically distributed at cell boundaries between hair cells and neighboring supporting cells in developing vestibular and auditory sensory epithelia; loss of Celsr1 results in misoriented stereociliary bundles of vestibular hair cells, particularly in the cristae of the semicircular canals.\",\n      \"method\": \"Celsr1 knockout mouse analysis, immunofluorescence localization, behavioral analysis (circling)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization tied to functional consequence, KO phenotype, single lab\",\n      \"pmids\": [\"28159525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CELSR1 and CELSR3 are cleavage-deficient (lack autoproteolytic cleavage at the GAIN domain), while CELSR2 is efficiently cleaved. Despite this, CELSR1-3 all engage GαS. CELSR1 tethered agonist (TA) point mutants retain GαS coupling activity, indicating CELSR1 signals via a cleavage-independent mechanism distinct from the canonical tethered-agonist paradigm.\",\n      \"method\": \"G protein coupling assays, autoproteolysis assays, tethered agonist point mutant analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution of G protein coupling, mutagenesis of tethered agonist, multiple orthogonal assays, peer-reviewed\",\n      \"pmids\": [\"37224017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CELSR1 tethered agonist (TA) point mutants retain GαS coupling activity; CELSR1 and CELSR3 are cleavage-deficient, while CELSR2 autoproteolysis enhances GαS coupling, yet acute TA exposure alone is insufficient for full activation.\",\n      \"method\": \"G protein coupling assays, autoproteolysis assays, tethered agonist point mutant analysis\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical assays with mutagenesis, preprint version of published peer-reviewed work (37224017), treated as supporting evidence\",\n      \"pmids\": [\"37066404\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM reconstruction of the mouse CELSR1 extracellular region (ECR) at 3.8 Å reveals 14 domains forming a compact module via conserved interactions between the CADH9 and C-terminal GAIN domains. In the presence of Ca2+, the CELSR1 ECR forms a dimer species via cadherin repeats putatively in antiparallel fashion. Cell-based assays show the N-terminal CADH1-8 repeat is required for cell-cell adhesion, while the C-terminal CADH9-GAIN compact module regulates cellular adhesion/signaling.\",\n      \"method\": \"Cryo-EM structure determination (3.8 Å), cell-based adhesion assays, domain deletion analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation by cell-based assays and domain mutagenesis\",\n      \"pmids\": [\"40295529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Crystal structures of human CELSR1 EC1-4 and EC4-7 reveal typical cadherin folds with a non-canonical linker between EC5 and EC6. EC1-4 only dimerizes at high concentration in solution; EC7-MAD10 mediates dimerization; simulations and experiments indicate flexibility at EC5-6. Cell-based bead aggregation assays do not support strong adhesion by EC repeats alone, suggesting weak homophilic adhesion by CELSR1 cadherin repeats.\",\n      \"method\": \"X-ray crystallography (EC1-4 and EC4-7 crystal structures), bead aggregation assays, solution dimerization assays, molecular dynamics simulations\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional validation by bead aggregation and solution biochemistry, multiple orthogonal methods\",\n      \"pmids\": [\"38307021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Celsr1 is the major Celsr family member driving epidermal planar cell polarity: removal of Celsr1 alone abolishes PCP protein asymmetry and hair follicle polarization, whereas loss of Celsr2 alone has no effect on epidermal PCP. FRAP assays show Celsr1 stably enriches at junctional interfaces while Celsr2 is much less efficiently recruited; both interact equivalently with Vangl2 and Fz6.\",\n      \"method\": \"CRISPR/Cas9 knockout of Celsr1 and Celsr2, FRAP, junctional enrichment assay, co-immunoprecipitation with Vangl2 and Fz6\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal KO comparison with multiple orthogonal methods (FRAP, Co-IP, PCP asymmetry assay), mechanistic dissection of Celsr1 vs Celsr2\",\n      \"pmids\": [\"36712970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Celsr1 suppresses Wnt5a-mediated chemoattraction to direct caudal facial branchiomotor (FBM) neuron migration: in Celsr1;Wnt5a double mutants, FBM neurons never migrate rostrally; Wnt5a-coated beads attract FBM neurons rostrally in wild-type explants; and overexpression of Wnt5a in r3 of Celsr1 mutants greatly enhances rostral migration, establishing a genetic epistasis mechanism.\",\n      \"method\": \"Genetic epistasis (double mutant Celsr1;Wnt5a), bead implantation assay in hindbrain explants, Wnt5a overexpression in Celsr1 mutant background\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double mutant, bead assay, and overexpression rescue, three orthogonal experiments establishing mechanism\",\n      \"pmids\": [\"36325991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Celsr1 protein is enriched at the basal surface of neuroepithelial cells within the early neural tube and in ventricular zone cells at the spinal cord midline, and this basal enrichment is lost in Celsr1 homozygous mutant embryos; this basal localization is spatiotemporally associated with dorsal sensory tract morphogenesis.\",\n      \"method\": \"Immunofluorescence localization in wild-type and Celsr1 mutant embryos, comparative analysis of protein distribution\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with mutant comparison, but functional consequence of basal enrichment not fully established\",\n      \"pmids\": [\"20353824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of Celsr1 in the subventricular zone (SVZ) after cerebral ischemia reduces neuroblast proliferation, CD31-positive cell number, and motor function, and increases apoptosis and infarct volume; these effects are associated with downregulation of p-PKC, placing Celsr1 upstream of Wnt/PKC signaling in post-ischemic neurogenesis and angiogenesis.\",\n      \"method\": \"Lentiviral Celsr1 knockdown in MCAO rat model, immunohistochemistry, functional behavioral assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular and behavioral phenotypes, PKC pathway readout, single lab\",\n      \"pmids\": [\"32070035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CELSR1 promotes endothelial cell migration and tube formation through Dishevelled segment polarity protein 3 (Dvl3); gain- and loss-of-function of CELSR1 in human aortic endothelial cells bidirectionally regulate migration and angiogenic tube formation.\",\n      \"method\": \"TALE-VP64-mediated CELSR1 overexpression, shRNA knockdown, scratch/transwell migration assay, tube formation assay\",\n      \"journal\": \"Biochemistry. Biokhimiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain- and loss-of-function in cell culture with multiple phenotypic readouts, Dvl3 identified as downstream effector but interaction not directly confirmed by Co-IP\",\n      \"pmids\": [\"27301287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"De novo heterozygous CELSR1 missense variant p.(Cys1318Tyr) disrupts subcellular localization of CELSR1, affects cell-cell junctions, impairs planar cell polarity signaling, and lowers proliferation rate in vitro.\",\n      \"method\": \"In vitro subcellular localization assays, cell-cell junction assay, PCP signaling assay, proliferation assay\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro functional assays on patient variant, single lab\",\n      \"pmids\": [\"38272662\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CELSR1 is a cleavage-deficient adhesion GPCR that functions as the core PCP organizer in mammalian epithelia and neural tissues: it forms stable homophilic trans- and cis-interactions through its cadherin ectodomain (structurally resolved by cryo-EM/X-ray), organizes Frizzled6 and Vangl2 into asymmetric junctional complexes via lateral cis-interactions, couples to GαS through a tethered-agonist-independent mechanism, recruits VANGL2 to cell-cell contacts, regulates adherens junction maturation (via VE-cadherin), directs collective cell polarity in skin, lung, oviduct, inner ear, and lymphatic valves, and controls neuronal migration directionality by suppressing Wnt5a-mediated chemoattraction in a non-cell-autonomous manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CELSR1 is the core mammalian planar cell polarity (PCP) organizer, the first vertebrate member of the flamingo/starry night pathway, required to coordinate cell orientation across diverse epithelia and to initiate neural tube closure [#0]. It is a cleavage-deficient adhesion GPCR whose large cadherin ectodomain mediates homophilic adhesion: cryo-EM and crystallographic structures of the extracellular region show 14 domains in which an N-terminal CADH1-8 segment drives cell-cell adhesion while a C-terminal CADH9-GAIN compact module regulates adhesion and signaling, with Ca2+-dependent dimerization through the cadherin repeats [#15, #16]. CELSR1 forms dense, highly stable punctate junctional assemblies through both trans- and cis-interactions; the PCP-mutant Celsr1Crsh selectively loses lateral cis-interactions, becomes mobile, and fails to organize Frizzled6 and Vangl2 into asymmetric junctional complexes, a defect rescuable by ectopic cis-dimerization [#9]. This stable junctional enrichment, rather than partner binding per se, distinguishes CELSR1 from CELSR2, since CELSR1 alone establishes epidermal PCP asymmetry despite both family members interacting equivalently with Vangl2 and Fz6 [#17], and it recruits VANGL2 to cell-cell contacts [#6]. Through this activity CELSR1 directs collective polarity in skin, lung, oviduct, inner ear, and lymphatic valve tissues, acting upstream of Rho kinase in lung branching [#2], coordinating intercellular basal body orientation in multiciliated cells [#10], and limiting VE-cadherin/adherens junction maturation to permit dynamic endothelial movements during valve formation [#3]. CELSR1 also functions non-cell-autonomously in facial branchiomotor neuron migration, where neuroepithelial CELSR1 suppresses Wnt5a-mediated rostral chemoattraction to enforce caudal migration [#7, #18]. Biochemically, CELSR1 couples to G\\u03b1S through a cleavage- and tethered-agonist-independent mechanism, since it lacks GAIN autoproteolysis yet tethered-agonist point mutants retain G\\u03b1S coupling [#13]. Human and mouse CELSR1 variants cause craniorachischisis and neural tube defects by disrupting plasma-membrane trafficking, junctional localization, VANGL2 recruitment, and PCP signaling [#1, #6, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established CELSR1 as the founding mammalian PCP-pathway gene by linking its mutation to the two diagnostic readouts of disrupted planar polarity and failed neural tube closure.\",\n      \"evidence\": \"ENU mutagenesis and phenotypic analysis of spin cycle and crash mouse alleles\",\n      \"pmids\": [\"12842012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of how the missense alleles disrupt protein function not defined\", \"Direct biochemical activity unaddressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended CELSR1 PCP function to branching morphogenesis and to non-cell-autonomous control of directional neuron migration, broadening its role beyond epithelial polarity.\",\n      \"evidence\": \"Crash-allele and conditional mouse analysis, Rho kinase inhibition and FGF10 ex vivo branching assays (lung); conditional inactivation and genetic epistasis with Celsr2 (FBM neurons); immunofluorescence in neural tube\",\n      \"pmids\": [\"20223754\", \"20631168\", \"20353824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between CELSR1 and Rho kinase not biochemically resolved\", \"Identity of the suppressed migratory signal not yet known\", \"Functional consequence of basal neuroepithelial enrichment not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified loss of plasma-membrane trafficking as the cellular defect underlying human craniorachischisis-associated CELSR1 variants, separating localization from protein-interaction capacity.\",\n      \"evidence\": \"Subcellular localization and protein-interaction assays of human CRN patient variants, compared to crash/spin cycle mutants\",\n      \"pmids\": [\"22095531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How trafficking failure translates to PCP loss in vivo not shown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a junctional-dynamics function: CELSR1 restrains VE-cadherin/adherens junction maturation to enable the endothelial cell rearrangements of lymphatic valve formation.\",\n      \"evidence\": \"Celsr1-deficient mouse analysis, live imaging, and localization of Celsr1 and VE-cadherin\",\n      \"pmids\": [\"23792146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between CELSR1 and VE-cadherin not defined\", \"Signaling effector unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Tied CELSR1 asymmetric boundary localization to recruitment of VANGL2 and to organ-scale tissue polarity, and showed patient variants impair the CELSR1-VANGL2 interaction.\",\n      \"evidence\": \"Celsr1-deficient mouse with mosaic analysis (oviduct); Co-IP and localization assays of spina bifida TG-repeat variants with VANGL2\",\n      \"pmids\": [\"25406397\", \"24632739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP without reciprocal validation\", \"Whether VANGL2 recruitment is direct not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Localized the non-cell-autonomous migratory control to CELSR1 in the rhombomere neuroepithelium and identified Dvl3 as a downstream effector of CELSR1-driven endothelial migration.\",\n      \"evidence\": \"Cell-type-specific conditional inactivation with dye-fill tracing (FBM neurons); CELSR1 gain/loss-of-function with migration and tube-formation assays in endothelial cells\",\n      \"pmids\": [\"27395006\", \"27301287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CELSR1-Dvl3 interaction not confirmed by Co-IP\", \"Identity of the suppressed neuroepithelial signal still unknown at this stage\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected CELSR1 to progenitor-fate control and sensory-bundle orientation, linking its polarity activity to retinoic-acid-dependent neurogenesis and stereocilia alignment.\",\n      \"evidence\": \"Celsr1 loss-of-function mouse analysis with RA transcriptional assays and progenitor quantification (cortex); KO analysis with immunofluorescence and behavior (vestibular epithelia)\",\n      \"pmids\": [\"29257130\", \"28159525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab for each context\", \"Mechanism coupling endfoot branching to RA signaling not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the molecular mechanism of CELSR1 PCP organization: stable cis/trans junctional assemblies are required to cluster Frizzled6 and Vangl2 asymmetrically, with the Crash mutation acting through loss of cis-interaction.\",\n      \"evidence\": \"Biochemistry, super-resolution microscopy, FRAP, Co-IP with Fzd6/Vangl2, and ectopic cis-dimerization rescue (epidermis/junctions); double-mutant epistasis with Camsap3 in oviduct ciliated cells\",\n      \"pmids\": [\"33529151\", \"33468623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cis vs trans contacts not resolved at this point\", \"How junctional clustering couples to downstream signaling unaddressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the suppressed migratory signal as Wnt5a, establishing that CELSR1 enforces caudal neuron migration by blocking Wnt5a-mediated rostral chemoattraction.\",\n      \"evidence\": \"Celsr1;Wnt5a double mutants, Wnt5a bead implantation in hindbrain explants, and Wnt5a overexpression in Celsr1 mutant background\",\n      \"pmids\": [\"36325991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which CELSR1 suppresses Wnt5a signaling not defined\", \"Receptor mediating Wnt5a chemoattraction not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the signaling mode and family specialization of CELSR1: it is a cleavage-deficient adhesion GPCR coupling to G\\u03b1S independent of the tethered-agonist paradigm, and is the dominant Celsr driving epidermal PCP via stable junctional enrichment.\",\n      \"evidence\": \"G protein coupling, autoproteolysis, and tethered-agonist mutant assays; reciprocal Celsr1/Celsr2 CRISPR KO with FRAP, junctional enrichment, and Co-IP\",\n      \"pmids\": [\"37224017\", \"36712970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological ligand/activation trigger of G\\u03b1S coupling unknown\", \"How G\\u03b1S signaling integrates with PCP organization not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided atomic-resolution structures of the cadherin ectodomain, assigning adhesion to N-terminal repeats and regulatory function to the CADH9-GAIN module, and confirmed pathogenicity of a de novo missense variant through PCP and junction assays.\",\n      \"evidence\": \"X-ray crystallography of EC1-4 and EC4-7 with bead aggregation and MD simulations; in vitro localization, junction, PCP, and proliferation assays of p.(Cys1318Tyr)\",\n      \"pmids\": [\"38307021\", \"38272662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystallography indicates only weak homophilic adhesion by isolated EC repeats\", \"Full-length receptor architecture not captured by fragment structures\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Delivered a near-complete cryo-EM model of the CELSR1 extracellular region, showing a compact 14-domain module formed by CADH9-GAIN contacts and Ca2+-dependent cadherin-mediated dimerization, unifying adhesion and signaling roles structurally.\",\n      \"evidence\": \"3.8 \\u00c5 cryo-EM reconstruction with cell-based adhesion and domain-deletion assays\",\n      \"pmids\": [\"40295529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transmembrane/intracellular regions and GAIN-GPCR coupling not structurally resolved\", \"Trans-dimer interface geometry remains putative\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GAIN/GPCR-mediated G\\u03b1S coupling is physiologically activated and mechanistically integrated with cadherin-based junctional clustering to drive asymmetric PCP complex assembly remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No identified activating ligand or trigger for G\\u03b1S coupling\", \"No structure of the full-length receptor or its intracellular signaling output\", \"Mechanistic bridge between adhesion, G protein signaling, and Vangl2/Fzd6 clustering not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [15, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 9, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 13, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [9, 17, 3]}\n    ],\n    \"complexes\": [\"CELSR1-Frizzled6-Vangl2 asymmetric junctional PCP complex\"],\n    \"partners\": [\"VANGL2\", \"FZD6\", \"DVL3\", \"WNT5A\", \"CDH5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}