{"gene":"CELSR1","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2003,"finding":"Missense mutations in mouse 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, establishing Celsr1 as the first mammalian Flamingo/Starry night homolog required for planar cell polarity.","method":"ENU mutagenesis, genetic mapping, in vivo phenotypic analysis of homozygous mutant mice (organ of Corti hair cell orientation, neural tube closure)","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — two independent ENU alleles, replicated phenotypes, direct causal link between Celsr1 mutation and PCP/NTD defects","pmids":["12842012"],"is_preprint":false},{"year":2011,"finding":"Human CELSR1 missense variants associated with craniorachischisis impair subcellular trafficking to the plasma membrane, as demonstrated by reduced or abolished membrane localization compared to wild-type CELSR1, mirroring the crash and spin cycle mouse mutant phenotypes.","method":"Subcellular protein localization assays in transfected cells, protein-protein interaction assays, comparison with mouse Celsr1 mutant alleles","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization assay, multiple human variants tested, corroborated by mouse mutant data","pmids":["22095531"],"is_preprint":false},{"year":2010,"finding":"Celsr1 (Crash allele) mutant mice show disrupted lung branching morphogenesis with fewer branches, thickened interstitial mesenchyme, and defective saccular formation; Rho kinase inhibition recapitulates these defects, and epithelial integrity and cytoskeletal remodelling are perturbed, placing Celsr1 upstream of Rho kinase in lung epithelial PCP signaling.","method":"Analysis of Celsr1Crsh mutant mouse lungs, Rho kinase inhibitor treatment, endoderm branching assays with FGF10, Celsr1 protein localization in lung epithelium","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic KO phenotype with pharmacological epistasis (ROCK inhibitor), protein localization, multiple readouts","pmids":["20223754"],"is_preprint":false},{"year":2013,"finding":"Celsr1 regulates dynamic endothelial cell movements during lymphatic valve morphogenesis by inhibiting stabilization of VE-cadherin and maturation of adherens junctions; Celsr1 and Vangl2 are recruited from filopodia to discrete membrane domains at cell-cell contacts during valve formation.","method":"Celsr1- and Vangl2-deficient mouse analysis, live imaging of endothelial cell rearrangements, VE-cadherin dynamics assays, subcellular localization of Celsr1/Vangl2 by immunofluorescence","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined cellular phenotype (valve aplasia), mechanistic link to VE-cadherin/adherens junction stabilization, direct localization data","pmids":["23792146"],"is_preprint":false},{"year":2010,"finding":"Celsr1 regulates the direction of facial branchiomotor (FBM) neuron migration in a non-cell-autonomous manner; Celsr1 is expressed in floor plate and ventricular zone but not in FBM neurons, and conditional inactivation in ventricular zone of r3–r5 causes rostral misdirection of FBM neurons. Celsr2 is epistatic to Celsr1 in this context.","method":"Celsr1 knockout and Crash allele mice, conditional inactivation, FBM neuron fate mapping, hindbrain patterning analysis, epistasis analysis","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — conditional KO establishing non-cell-autonomous function, epistasis with Celsr2, multiple alleles tested","pmids":["20631168"],"is_preprint":false},{"year":2014,"finding":"Celsr1 is required for multilevel polarity in the mouse oviduct: it concentrates at specific cellular boundaries perpendicular to the ovary-uterus axis, coordinates ciliary beat direction, controls epithelial cell elongation/orientation, and directs epithelial fold alignment. Mosaic analysis indicates cell geometry is primarily regulated by Celsr1.","method":"Celsr1-deficient mouse analysis, immunofluorescence localization, ciliary motion analysis, mosaic analysis, postnatal oviduct development characterization","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — KO phenotype with multiple PCP readouts, direct protein localization, mosaic analysis establishing cell-autonomous regulation of geometry","pmids":["25406397"],"is_preprint":false},{"year":2014,"finding":"CELSR1 TG dinucleotide repeat variants found in spina bifida patients alter subcellular localization of CELSR1 protein and impair physical association between CELSR1 and VANGL2, thereby diminishing recruitment of VANGL2 to cell-cell contacts.","method":"In vitro subcellular localization assays, co-immunoprecipitation of CELSR1 and VANGL2, functional analysis of patient-derived variants","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP and localization assays on patient variants, single lab","pmids":["24632739"],"is_preprint":false},{"year":2010,"finding":"Celsr1 protein is enriched at the basal surface of neuroepithelial cells in the neural tube and in ventricular zone cells at the midline of the developing spinal cord; this basal enrichment is lost in Celsr1 homozygous mutant embryos. The basal Celsr1 distribution correlates with dorsal sensory tract morphogenesis and suggests multiple protein isoforms with distinct signaling potential.","method":"Immunofluorescence/protein localization in wild-type and mutant mouse embryos, subcellular fractionation approaches, in vivo analysis","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization experiment with functional correlation, single lab","pmids":["20353824"],"is_preprint":false},{"year":2016,"finding":"CELSR1 P870L, identified in both NTD and CHD patients, is a gain-of-function mutation that upregulates both the PCP pathway and canonical WNT signaling in cells, and induces both NTDs and CHDs when expressed in zebrafish embryos.","method":"In vitro cell-based signaling assays, in vivo zebrafish embryo injection, patient variant characterization","journal":"Clinical science (London, England : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro assays demonstrating gain-of-function, single lab","pmids":["27756857"],"is_preprint":false},{"year":2021,"finding":"Mouse Celsr1 engages in both trans- (cell-cell bridging) and cis- (lateral, same-cell) interactions and organizes into dense, highly stable junctional puncta. The PCP-mutant Celsr1Crsh variant selectively impairs lateral cis-interactions, increases receptor mobility, diminishes junctional enrichment, and fails to engage in homophilic adhesion with wild-type Celsr1, preventing organization of Frizzled6 and Vangl2 into asymmetric junctional complexes. Ectopic cis-dimerization rescues these defects.","method":"Biochemical assays (co-IP), super-resolution microscopy (STORM), FRAP, cell aggregation assays, epistasis with Celsr1Crsh mutant","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (super-resolution microscopy, FRAP, biochemistry, rescue experiments) in single rigorous study","pmids":["33529151"],"is_preprint":false},{"year":2021,"finding":"CELSR1 coordinates intercellular (between-cell) coordination of basal body orientation in oviduct multi-ciliated cells, while CAMSAP3 controls intracellular basal body orientation. Loss of CELSR1 disrupts intercellular coordination but only moderately affects intracellular polarity, whereas CAMSAP3 mutation disrupts intracellular BB orientation and microtubule interconnection without affecting PCP factor localization.","method":"Celsr1 mutant mouse analysis, CAMSAP3 mutant analysis, immunofluorescence localization of basal bodies and PCP factors, microtubule imaging","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — genetic dissection with two distinct KO alleles separating inter- vs. intracellular polarity mechanisms, replicated with CAMSAP3 epistasis","pmids":["33468623"],"is_preprint":false},{"year":2017,"finding":"Celsr1 is asymmetrically distributed at cell boundaries between hair cells and supporting cells in developing vestibular and auditory sensory epithelia. Loss of Celsr1 causes misorientation of vestibular hair cell stereociliary bundles relative to neighbors, predominantly in cristae of semicircular canals, causing vestibular behavioral defects (circling).","method":"Celsr1 KO mouse analysis, immunofluorescence showing asymmetric Celsr1 distribution, hair bundle orientation analysis, behavioral phenotyping","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — KO phenotype with direct protein localization asymmetry, functional behavioral readout","pmids":["28159525"],"is_preprint":false},{"year":2017,"finding":"Celsr1 controls branching of apical neural progenitor cell (aNPC) basal processes that abut 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 microcephaly.","method":"Celsr1 KO mouse analysis, RA signaling reporter assays, quantification of neural progenitor subtypes and neuron numbers, basal process morphology analysis","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 — KO with multiple mechanistic readouts linking Celsr1 to RA signaling and progenitor fate, replicated phenotypes","pmids":["29257130"],"is_preprint":false},{"year":2016,"finding":"Celsr1 suppresses inappropriate rostral FBM neuron migration non-cell-autonomously by acting in the ventricular zone of r3-r5 (not the floor plate). Conditional inactivation of Celsr1 specifically in the ventricular zone of r3-r5 phenocopies the full Celsr1 mutant migration defect.","method":"Conditional (Cre-lox) Celsr1 inactivation in specific cell types, dye-fill tracing of FBM neuron origin, hindbrain explant analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO in defined cell populations, dye-fill tracing, clear non-cell-autonomous mechanism established","pmids":["27395006"],"is_preprint":false},{"year":2022,"finding":"Celsr1 suppresses Wnt5a-mediated chemoattraction to prevent inappropriate rostral migration of FBM neurons. In Celsr1; Wnt5a double mutants, rostral migration is abolished; FBM neurons migrate rostrally toward Wnt5a-coated beads in wild-type explants; and rostral migration is enhanced in Celsr1 mutants overexpressing Wnt5a in r3.","method":"Genetic epistasis (Celsr1; Wnt5a double mutants), Wnt5a-coated bead assays in hindbrain explants, Wnt5a overexpression in Celsr1 mutant background","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 — three orthogonal approaches (double KO epistasis, bead assay, overexpression) converge on a single mechanism","pmids":["36325991"],"is_preprint":false},{"year":2020,"finding":"CELSR1 promotes neuroprotection after cerebral ischemia by reducing apoptosis in peri-infarct cortex and promoting neurogenesis and angiogenesis in the subventricular zone, mainly through the Wnt/PKC signaling pathway. Knockdown of Celsr1 in the SVZ with lentivirus reduced neuroblast proliferation, CD31+ cell numbers, and motor function, and decreased p-PKC expression.","method":"Lentiviral Celsr1 knockdown in MCAO rat SVZ, immunohistochemistry for neuroblasts and CD31, Western blot for p-PKC, behavioral testing","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo KD with multiple cellular and molecular readouts, single lab, pathway assignment by signaling marker","pmids":["32070035"],"is_preprint":false},{"year":2016,"finding":"CELSR1 is a positive regulator of endothelial cell migration, proliferation, and tube formation, and its effects on migration and tube formation are mediated through dishevelled segment polarity protein 3 (Dvl3).","method":"TALE-VP64 activator (gain-of-function) and shRNA knockdown of CELSR1 in human aortic endothelial cells, MTT proliferation assay, scratch/transwell migration assays, tube formation assay, Dvl3 epistasis","journal":"Biochemistry. Biokhimiia","confidence":"Medium","confidence_rationale":"Tier 2-3 — both GOF and LOF approaches, downstream effector (Dvl3) identified, single lab","pmids":["27301287"],"is_preprint":false},{"year":2023,"finding":"CELSR1 and CELSR3 are cleavage-deficient adhesion GPCRs (they do not undergo autoproteolytic cleavage at the GAIN domain), while CELSR2 is efficiently cleaved. Despite differential autoproteolysis, CELSR1-3 all engage GαS. CELSR1 tethered agonist (TA) point mutants retain GαS coupling activity, indicating that CELSR1 signals via a tethered-agonist-independent mechanism distinct from classical aGPCR activation.","method":"Autoproteolysis assays, G protein coupling assays (GαS BRET/cAMP), TA point mutagenesis, comparison across CELSR1-3 and LPHN3","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical cleavage assays, functional G protein coupling assays, mutagenesis across multiple family members, single rigorous study with multiple orthogonal methods","pmids":["37224017"],"is_preprint":false},{"year":2023,"finding":"Celsr1 is the major Celsr family member for epidermal PCP: removal of Celsr1 alone abolishes PCP protein asymmetry and hair follicle polarization, while loss of Celsr2 alone has no effect. Celsr1 stably enriches at junctional interfaces (low FRAP mobility), whereas Celsr2 is much less efficiently recruited to junctions. Both proteins interact equivalently with Vangl2 and Fz6, suggesting that differences in homophilic adhesion underlie differential PCP involvement.","method":"CRISPR/Cas9 Celsr1 and Celsr2 KO mice, PCP protein asymmetry assays, hair follicle orientation analysis, FRAP, junctional enrichment assays, co-IP with Vangl2 and Fz6","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 — two new KO alleles, FRAP, co-IP, multiple PCP readouts; mechanistic distinction between Celsr1 and Celsr2 adhesion properties established","pmids":["36712970"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM reconstruction of mouse CELSR1 ECR (3.8 Å) reveals that 14 of its 23 adhesion domains form a compact module mediated by conserved interactions between the CADH9 and C-terminal GAIN domains. In the presence of Ca2+, the CELSR1 ECR forms a dimer species mediated by cadherin repeats in a putative 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.","method":"Cryo-EM structure determination (3.8 Å), Ca2+-dependent dimerization assays, cell-based adhesion assays with domain deletion constructs","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with functional validation by domain-deletion cell assays","pmids":["40295529"],"is_preprint":false},{"year":2024,"finding":"Crystal structures of human CELSR1 EC1-4 and EC4-7 reveal typical cadherin folds and a non-canonical linker between EC5 and EC6. CELSR1 EC repeats alone support only weak homophilic adhesion in bead aggregation assays; EC1-4 dimerizes only at high concentration; EC7-MAD10 mediates dimerization in solution. MD simulations and experiments indicate flexibility at EC5-6.","method":"X-ray crystallography (EC1-4, EC4-7), bead aggregation assays, analytical ultracentrifugation/SEC, MD simulations","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with functional adhesion assays and biophysical validation","pmids":["38307021"],"is_preprint":false},{"year":2024,"finding":"Preprint (later published): 4.3 Å cryo-EM of mCELSR1 ECR resolves 13 domains forming a compact module with contact between N- and C-terminal domains; Ca2+ promotes an extended species proposed to represent the antiparallel cadherin dimer. CADH1-8 is necessary for cell adhesion and CADH9-GAIN module regulates G protein signaling.","method":"Cryo-EM, Ca2+-dependent biophysical assays, cell adhesion assays, G protein coupling assays with domain deletion constructs","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — structural + functional data but preprint; results largely consistent with and superseded by published version (PMID:40295529)","pmids":["38328199"],"is_preprint":true},{"year":2020,"finding":"Somatic CELSR1 p.Gln2125His mutation found in NTD fetal tissue; FZD6 p.Gln88Glu disrupts colocalization of CELSR1 and FZD6, and VANGL1 p.Arg374His impairs colocalization of CELSR1 and VANGL1, indicating that CELSR1 co-localizes with FZD6 and VANGL1 at cell membranes as part of the PCP complex, and this is disrupted by partner mutations.","method":"Subcellular colocalization assays in transfected cells, Western blot, luciferase non-canonical Wnt signaling assay, cell migration assay","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 3 — colocalization assays showing CELSR1 complex with FZD6/VANGL1 disrupted by partner mutations; indirect evidence for CELSR1 complex membership","pmids":["32356230"],"is_preprint":false},{"year":2026,"finding":"Biallelic CELSR1 variants in humans cause brain malformations (pachygyria, periventricular nodular heterotopia, corpus callosum abnormalities), neurodevelopmental delay, and epilepsy. Celsr1 knockout mice exhibit partial corpus callosum agenesis, periventricular heterotopia, irregular ventricular/subventricular zone shape, enlarged lateral ventricles (fully penetrant), and increased seizure susceptibility.","method":"Whole exome sequencing of human patients, Celsr1 KO mouse generation and analysis (MRI/histology of brain malformations, seizure susceptibility testing)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — human genetics corroborated by KO mouse with fully penetrant brain malformation phenotypes and seizure susceptibility","pmids":["41530147"],"is_preprint":false},{"year":1997,"finding":"Celsr1 encodes a developmentally regulated seven-pass transmembrane protein whose extracellular domain contains nine cadherin repeats followed by EGF-like and laminin A G-type repeats, a unique domain architecture coupling adhesion motifs to a 7TM domain. Expression in adult brain is localized principally to ependymal cell layer, choroid plexus, and area postrema.","method":"cDNA cloning, domain analysis, chromosomal mapping (EUCIB, BXD, FISH), RT-PCR, in situ hybridization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 — original structural characterization by sequence/expression analysis; foundational domain architecture discovery","pmids":["9339365"],"is_preprint":false},{"year":2021,"finding":"Loss of Celsr1 in vestibular hair cells causes ~50% reduction in canal-dependent vestibulo-ocular reflex gain across all tested frequencies and ~30% reduction in otolith-dependent function, demonstrating that the highly organized PCP-dependent polarization of hair cells is critical for accurate vestibular encoding.","method":"Video-oculography in Celsr1 KO mice, sinusoidal rotation, angular velocity steps, off-vertical axis rotation, static/dynamic head tilt assays","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with quantitative functional vestibular readouts linking PCP hair cell disorganization to circuit-level dysfunction","pmids":["34790090"],"is_preprint":false}],"current_model":"CELSR1 is an atypical seven-pass transmembrane cadherin (adhesion GPCR) that functions as a core planar cell polarity (PCP) component: its large extracellular region (9 cadherin repeats plus EGF/laminin G domains organized into a compact CADH9-GAIN module) mediates weak homophilic cell-cell adhesion via both trans- and cis-interactions that organize asymmetric junctional complexes containing Frizzled6 and Vangl2; CELSR1 couples to GαS independently of autoproteolytic cleavage (unlike many adhesion GPCRs); and loss-of-function disrupts coordinated epithelial polarity, ciliary orientation, neural tube closure, neuronal migration directionality (by suppressing Wnt5a-mediated chemoattraction), lymphatic valve morphogenesis (through inhibition of VE-cadherin/adherens junction stabilization), cortical neurogenesis (via retinoic acid signaling from meningeal-progenitor contacts), and brain morphogenesis."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of CELSR1's unique domain architecture—nine cadherin repeats coupled to EGF-like, laminin G, and seven-transmembrane domains—established a new class of adhesion-GPCR hybrids with brain-enriched expression.","evidence":"cDNA cloning, domain analysis, in situ hybridization in mouse brain","pmids":["9339365"],"confidence":"Medium","gaps":["No functional data; expression-based only","Signaling mechanism unknown","Ligand and adhesion properties not tested"]},{"year":2003,"claim":"Two independent ENU alleles (spin cycle, crash) demonstrated that Celsr1 is the first mammalian Flamingo homolog required for planar cell polarity and neural tube closure, transforming it from an uncharacterized orphan receptor to a core PCP component.","evidence":"ENU mutagenesis screen, organ of Corti hair cell orientation and neural tube closure analysis in homozygous mutant mice","pmids":["12842012"],"confidence":"High","gaps":["Molecular mechanism of PCP disruption unknown","Downstream signaling effectors not identified","Relationship to other core PCP components (Vangl, Fz) not established"]},{"year":2010,"claim":"Functional studies expanded CELSR1's PCP role beyond the ear and neural tube to lung branching morphogenesis (upstream of Rho kinase), neuroepithelial basal polarity, and non-cell-autonomous regulation of facial branchiomotor neuron migration direction.","evidence":"Celsr1 Crash/KO mouse phenotyping in lung and hindbrain, ROCK inhibitor epistasis, conditional inactivation, FBM neuron fate mapping, neuroepithelial immunofluorescence","pmids":["20223754","20631168","20353824"],"confidence":"High","gaps":["Signaling pathway between Celsr1 and ROCK not delineated","Floor plate vs. ventricular zone requirement not fully resolved","Multiple isoform significance unclear"]},{"year":2011,"claim":"Human CELSR1 missense variants from craniorachischisis patients were shown to impair plasma membrane trafficking, providing the first direct link between human NTD mutations and a defined cellular defect in CELSR1 function.","evidence":"Subcellular localization assays of multiple patient-derived CELSR1 variants in transfected cells, comparison to mouse Crash/spin cycle alleles","pmids":["22095531"],"confidence":"Medium","gaps":["Overexpression system may not recapitulate endogenous trafficking","Functional rescue not performed","Interaction with PCP partners not systematically tested for all variants"]},{"year":2013,"claim":"Discovery that Celsr1 regulates lymphatic valve morphogenesis by inhibiting VE-cadherin stabilization revealed a PCP-adherens junction crosstalk mechanism operative in endothelial cells, expanding CELSR1 biology beyond epithelial and neuronal tissues.","evidence":"Celsr1-deficient mouse lymphatic analysis, live imaging of endothelial rearrangements, VE-cadherin dynamics assays","pmids":["23792146"],"confidence":"High","gaps":["Biochemical mechanism of VE-cadherin destabilization unknown","Whether Celsr1 acts through Vangl2 or independently in this context not fully resolved"]},{"year":2014,"claim":"Celsr1 was shown to coordinate multilevel polarity in the oviduct (ciliary beat direction, cell elongation, epithelial fold alignment), while human spina bifida–associated variants were found to disrupt the CELSR1–VANGL2 physical interaction and VANGL2 junctional recruitment.","evidence":"Celsr1 KO mouse oviduct analysis with ciliary motion/mosaic studies; co-IP of patient-derived CELSR1 variants with VANGL2","pmids":["25406397","24632739"],"confidence":"High","gaps":["Structural basis of CELSR1–VANGL2 interaction unknown","Oviduct-specific downstream effectors not identified"]},{"year":2016,"claim":"A gain-of-function CELSR1 variant (P870L) was demonstrated to upregulate both PCP and canonical WNT signaling, and conditional studies pinpointed the ventricular zone of r3–r5 as the critical site of Celsr1 action for suppressing aberrant FBM neuron migration.","evidence":"Cell-based PCP/WNT signaling assays and zebrafish injection for P870L; Cre-lox conditional KO in specific hindbrain domains with dye-fill tracing","pmids":["27756857","27395006"],"confidence":"High","gaps":["Mechanism of P870L gain-of-function at receptor level unknown","Direct signal mediating non-cell-autonomous influence on FBM neurons not identified"]},{"year":2017,"claim":"Two studies revealed that Celsr1 controls cortical neurogenesis via retinoic acid signaling from meningeal-progenitor contacts, and coordinates vestibular hair cell stereociliary bundle orientation—extending its PCP repertoire to progenitor fate decisions and sensory organ patterning.","evidence":"Celsr1 KO mouse cortex (RA reporter, progenitor quantification, basal process morphology) and vestibular epithelium (hair bundle orientation, behavioral phenotyping)","pmids":["29257130","28159525"],"confidence":"High","gaps":["Whether RA pathway engagement is direct or indirect not resolved","Vestibular compensation mechanisms not characterized"]},{"year":2021,"claim":"Super-resolution and biophysical studies established that CELSR1 forms both trans and cis homophilic interactions at junctions; the Crash mutation selectively disrupts cis-interactions, increasing receptor mobility and preventing asymmetric PCP complex assembly—demonstrating that lateral cis-clustering is the critical step for PCP establishment.","evidence":"STORM super-resolution microscopy, FRAP, co-IP, cell aggregation assays, ectopic cis-dimerization rescue of Crash phenotype","pmids":["33529151"],"confidence":"High","gaps":["Structural basis of cis vs. trans interface not resolved at atomic level","Whether other PCP components modulate cis/trans equilibrium unknown"]},{"year":2021,"claim":"Dissection of intercellular (Celsr1-dependent) versus intracellular (CAMSAP3-dependent) basal body orientation in oviduct multiciliated cells clarified that CELSR1's role is specifically in coordinating polarity between neighboring cells rather than organizing the cytoskeleton within a single cell.","evidence":"Parallel analysis of Celsr1 and CAMSAP3 mutant mice with basal body and PCP factor localization imaging","pmids":["33468623"],"confidence":"High","gaps":["Molecular link from junctional CELSR1 to cytoplasmic polarity machinery not identified","Whether this intercellular/intracellular division applies in other ciliated tissues unknown"]},{"year":2022,"claim":"Genetic epistasis showed that Celsr1 suppresses Wnt5a-mediated chemoattraction of FBM neurons, finally identifying the specific signal (Wnt5a) that Celsr1 counteracts to prevent aberrant rostral migration.","evidence":"Celsr1;Wnt5a double KO epistasis, Wnt5a-coated bead chemoattraction assays in hindbrain explants, Wnt5a overexpression in Celsr1 mutant","pmids":["36325991"],"confidence":"High","gaps":["Whether Celsr1 modulates Wnt5a availability, receptor access, or downstream signaling not distinguished","Receptor on FBM neurons transducing Wnt5a not identified"]},{"year":2023,"claim":"Biochemical and signaling studies demonstrated that CELSR1 is cleavage-deficient at its GAIN domain yet couples to Gαs through a tethered-agonist-independent mechanism, fundamentally distinguishing its activation mode from canonical adhesion GPCRs. Separately, CELSR1 was confirmed as the dominant Celsr paralog for epidermal PCP based on its superior junctional stability relative to CELSR2.","evidence":"Autoproteolysis assays, Gαs BRET/cAMP coupling with TA mutants across CELSR family; CRISPR KO of Celsr1/Celsr2 in mouse epidermis with FRAP and co-IP","pmids":["37224017","36712970"],"confidence":"High","gaps":["Structural mechanism of TA-independent Gαs activation unknown","Whether Gαs signaling is required for PCP function not tested","Basis for differential junctional stability of CELSR1 vs. CELSR2 at structural level unknown"]},{"year":2024,"claim":"Crystal structures of CELSR1 cadherin repeats EC1-7 revealed typical cadherin folds with a non-canonical flexible linker at EC5-6, and showed that isolated EC repeats support only weak adhesion while the C-terminal EC7-MAD10 region contributes significantly to dimerization.","evidence":"X-ray crystallography of EC1-4 and EC4-7, bead aggregation assays, AUC/SEC, MD simulations","pmids":["38307021"],"confidence":"High","gaps":["Full-length extracellular region structure at high resolution not yet available from crystallography","Trans-dimer interface not resolved at atomic level"]},{"year":2025,"claim":"Cryo-EM at 3.8 Å resolved the compact CADH9-GAIN module of CELSR1 and showed Ca²⁺-dependent antiparallel dimerization mediated by cadherin repeats, with CADH1-8 required for cell adhesion and the CADH9-GAIN module regulating adhesion properties—providing the first near-complete structural view of the extracellular region.","evidence":"Cryo-EM reconstruction of mouse CELSR1 ECR, Ca²⁺-dependent dimerization assays, domain deletion cell adhesion assays","pmids":["40295529"],"confidence":"High","gaps":["Structure of the 7TM domain and intracellular regions not resolved","Dimer interface at atomic resolution still lacking","Relationship between compact/extended conformations and signaling state unknown"]},{"year":2026,"claim":"Biallelic CELSR1 variants were identified as a cause of human brain malformations (pachygyria, periventricular heterotopia, corpus callosum abnormalities) with epilepsy, validated by fully penetrant corresponding phenotypes in Celsr1 KO mice—establishing CELSR1 as a Mendelian disease gene for cortical malformations beyond NTDs.","evidence":"Whole exome sequencing of human patients, Celsr1 KO mouse MRI/histology and seizure susceptibility testing","pmids":["41530147"],"confidence":"High","gaps":["Specific cellular mechanism linking Celsr1 loss to heterotopia and pachygyria not defined","Genotype-phenotype correlations across different variant classes not established","Whether seizures are primary or secondary to malformation unknown"]},{"year":null,"claim":"Key unresolved questions include: (1) how the CADH9-GAIN compact module and conformational changes couple to Gαs activation in the absence of autoproteolysis; (2) whether Gαs signaling is required for CELSR1's PCP function or operates in a parallel pathway; and (3) the identity and structure of the intracellular signaling complexes that relay CELSR1 junctional asymmetry to cytoskeletal and transcriptional effectors.","evidence":"Open question synthesized from existing literature gaps","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the 7TM or intracellular domain","Gαs pathway contribution to PCP not tested genetically","Direct intracellular effectors linking junctional CELSR1 to cytoskeletal polarity machinery remain unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[9,19,20]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5,9,11,18,22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,9,14,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,4,5,12,23]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,9,18,22]}],"complexes":["PCP core complex (CELSR1–FZD6–VANGL2)"],"partners":["VANGL2","FZD6","VANGL1","DVL3","FZD3"],"other_free_text":[]},"mechanistic_narrative":"CELSR1 is an atypical seven-pass transmembrane cadherin (adhesion GPCR) that functions as a core component of the planar cell polarity (PCP) pathway, coordinating tissue-level polarity across diverse epithelia and neuronal populations. Its large extracellular region—comprising nine cadherin repeats, EGF-like, and laminin G domains organized into a compact CADH9-GAIN module—mediates weak, Ca²⁺-dependent homophilic adhesion through both trans- and cis-interactions that stabilize junctional puncta and organize asymmetric complexes containing Frizzled6 and Vangl2; disruption of cis-interactions (as in the Crash allele) abolishes junctional enrichment and PCP protein asymmetry [PMID:33529151, PMID:36712970, PMID:40295529]. CELSR1 couples to Gαs independently of GAIN-domain autoproteolysis and tethered-agonist activation, distinguishing it from classical adhesion GPCRs [PMID:37224017]. Loss of CELSR1 function disrupts neural tube closure, inner ear and oviduct ciliary orientation, lymphatic valve morphogenesis (via VE-cadherin/adherens junction destabilization), cortical neurogenesis (via retinoic acid signaling), and facial branchiomotor neuron migration (by de-repressing Wnt5a-mediated chemoattraction) [PMID:12842012, PMID:25406397, PMID:23792146, PMID:29257130, PMID:36325991]; biallelic CELSR1 variants in humans cause brain malformations including pachygyria, periventricular heterotopia, and epilepsy [PMID:41530147]."},"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; LMPHM9","url":"https://www.omim.org/entry/619319"},{"mim_id":"607733","title":"SCRIBBLE PLANAR CELL POLARITY PROTEIN; SCRIB","url":"https://www.omim.org/entry/607733"},{"mim_id":"604523","title":"CADHERIN EGF LAG SEVEN-PASS G-TYPE RECEPTOR 1; CELSR1","url":"https://www.omim.org/entry/604523"},{"mim_id":"604264","title":"CADHERIN EGF LAG SEVEN-PASS G-TYPE RECEPTOR 3; CELSR3","url":"https://www.omim.org/entry/604264"},{"mim_id":"603409","title":"FRIZZLED CLASS RECEPTOR 6; FZD6","url":"https://www.omim.org/entry/603409"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":32.9}],"url":"https://www.proteinatlas.org/search/CELSR1"},"hgnc":{"alias_symbol":["ME2","HFMI2","FMI2","CDHF9","ADGRC1"],"prev_symbol":[]},"alphafold":{"accession":"Q9NYQ6","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYQ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYQ6-2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYQ6-2-F1-predicted_aligned_error_v6.png","plddt_mean":74.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CELSR1","jax_strain_url":"https://www.jax.org/strain/search?query=CELSR1"},"sequence":{"accession":"Q9NYQ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NYQ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NYQ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYQ6"}},"corpus_meta":[{"pmid":"12842012","id":"PMC_12842012","title":"Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse.","date":"2003","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/12842012","citation_count":495,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22095531","id":"PMC_22095531","title":"Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis.","date":"2011","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/22095531","citation_count":156,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20223754","id":"PMC_20223754","title":"The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20223754","citation_count":128,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23792146","id":"PMC_23792146","title":"Planar cell polarity protein Celsr1 regulates endothelial adherens junctions and directed cell rearrangements during valve morphogenesis.","date":"2013","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/23792146","citation_count":118,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20631168","id":"PMC_20631168","title":"Atypical cadherins Celsr1-3 differentially regulate migration of facial branchiomotor neurons in mice.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20631168","citation_count":97,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3930657","id":"PMC_3930657","title":"Conjugal transfer from Streptococcus lactis ME2 of plasmids encoding phage resistance, nisin resistance and lactose-fermenting ability: evidence for a high-frequency conjugative plasmid responsible for abortive infection of virulent bacteriophage.","date":"1985","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/3930657","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9798675","id":"PMC_9798675","title":"EWS/FLI1 up regulates mE2-C, a cyclin-selective ubiquitin conjugating enzyme involved in cyclin B destruction.","date":"1998","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9798675","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22371354","id":"PMC_22371354","title":"Role of the planar cell polarity gene CELSR1 in neural tube defects and caudal agenesis.","date":"2012","source":"Birth defects research. 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defects.","date":"2020","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32356230","citation_count":26,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20198315","id":"PMC_20198315","title":"Association of genetic variants with hemorrhagic stroke in Japanese individuals.","date":"2010","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20198315","citation_count":25,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35748872","id":"PMC_35748872","title":"A dual-activity topoisomerase complex regulates mRNA translation and turnover.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/35748872","citation_count":25,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36215168","id":"PMC_36215168","title":"TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing.","date":"2023","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36215168","citation_count":25,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32640974","id":"PMC_32640974","title":"circCELSR1 facilitates ovarian cancer proliferation and metastasis by sponging miR-598 to activate BRD4 signals.","date":"2020","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/32640974","citation_count":24,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35696571","id":"PMC_35696571","title":"ESCPE-1 mediates retrograde endosomal sorting of the SARS-CoV-2 host factor Neuropilin-1.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35696571","citation_count":22,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19851296","id":"PMC_19851296","title":"Assessment of a polymorphism of SDK1 with hypertension in Japanese Individuals.","date":"2009","source":"American journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/19851296","citation_count":15,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45106,"output_tokens":5219,"usd":0.106801},"stage2":{"model":"claude-opus-4-6","input_tokens":8779,"output_tokens":3655,"usd":0.202905},"total_usd":0.684162,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":58062,"output_tokens":7081,"usd":0.140201},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":10599,"output_tokens":4127,"usd":0.234255}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Missense mutations in Celsr1 (spin cycle and crash alleles) disrupt planar cell polarity of inner ear hair cells and cause failure to initiate neural tube closure, establishing Celsr1 as a mammalian PCP pathway component orthologous to Drosophila flamingo/starry night.\",\n      \"method\": \"ENU mutagenesis, genetic mapping, in vivo loss-of-function with hair cell orientation and neural tube phenotypic readouts\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/point mutant alleles with defined cellular phenotypes, replicated across two independent mutant lines\",\n      \"pmids\": [\"12842012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human CELSR1 missense variants associated with craniorachischisis impair subcellular trafficking of the protein to the plasma membrane (comparable to crash and spin cycle mouse alleles), indicating that defective membrane localization is a pathogenic mechanism.\",\n      \"method\": \"Subcellular localization assay in transfected cells, comparison with mouse Celsr1 mutant alleles\",\n      \"journal\": \"Human Mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — cell-based localization assay with functional inference, single lab\",\n      \"pmids\": [\"22095531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Celsr1 (Crash allele) loss-of-function in mice causes disrupted lung branching morphogenesis with fewer branches, thickened mesenchyme, defective saccular formation, perturbed cytoskeletal remodelling, and failure of mutant endoderm to branch normally in response to FGF10; phenotype is recapitulated by Rho kinase inhibition, placing Celsr1 upstream of ROCK in the PCP pathway during lung development.\",\n      \"method\": \"Mouse mutant analysis, in vitro branching assay, pharmacological inhibition of ROCK\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vivo mutant + in vitro assay + pharmacological epistasis), single lab\",\n      \"pmids\": [\"20223754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Celsr1 is expressed non-cell-autonomously in the floor plate and ventricular zone (not in facial branchiomotor neurons themselves); conditional inactivation in the ventricular zone of r3-r5, but not in the floor plate, recapitulates rostral mis-migration of FBM neurons seen in full Celsr1 mutants, demonstrating that Celsr1 directs FBM neuron migration non-cell-autonomously by specifying directional cues in the hindbrain environment.\",\n      \"method\": \"Conditional (Cre-mediated) inactivation of Celsr1, in vivo neuronal migration tracing, genetic epistasis (Celsr2 epistatic to Celsr1)\",\n      \"journal\": \"Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with specific cellular phenotype and epistasis analysis, replicated across labs\",\n      \"pmids\": [\"20631168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Celsr1 regulates dynamic endothelial cell movements during lymphatic valve morphogenesis by inhibiting stabilization of VE-cadherin and maturation of adherens junctions; Celsr1 and Vangl2 are recruited from filopodia to discrete membrane domains at cell-cell contacts during valve formation.\",\n      \"method\": \"Celsr1/Vangl2 conditional KO mouse, live imaging, VE-cadherin localization assays, valve morphology analysis\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific mechanistic readout (AJ stabilization), multiple orthogonal methods, well-controlled study\",\n      \"pmids\": [\"23792146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Celsr1 is required for coordinated ciliary beating and tissue-level polarity in the mouse oviduct; it concentrates at specific cellular boundaries perpendicular to the ovary-uterus axis, and its loss disrupts ciliary motion direction, epithelial cell orientation and elongation, and the directionality of epithelial folds; mosaic analysis shows Celsr1 primarily regulates epithelial cell geometry.\",\n      \"method\": \"Celsr1 knockout mouse, mosaic analysis, live imaging of ciliary motion, immunofluorescence localization\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple mechanistic readouts plus mosaic analysis to dissect cell-autonomous vs. non-autonomous roles\",\n      \"pmids\": [\"25406397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Two TG dinucleotide repeat variants in CELSR1 identified in spina bifida patients alter subcellular localization of CELSR1 and impair its physical association with VANGL2, thereby diminishing VANGL2 recruitment to cell-cell contacts.\",\n      \"method\": \"Subcellular localization assay, co-immunoprecipitation (CELSR1–VANGL2 interaction), cell-based functional assay\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-IP plus localization assay supporting mechanistic link\",\n      \"pmids\": [\"24632739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Celsr1 functions non-cell-autonomously: conditional inactivation specifically in the ventricular zone of r3–r5 (but not floor plate) recapitulates rostrally misguided facial branchiomotor neurons, confirming that Celsr1 expression in the hindbrain neuroepithelium, not in the neurons themselves, directs migration directionality.\",\n      \"method\": \"Conditional (cell-type-specific Cre) Celsr1 inactivation, dye-fill tracing of FBM neuron origin and trajectory\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined cellular phenotype and fate-mapping, extends findings from PMID 20631168\",\n      \"pmids\": [\"27395006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CELSR1 P870L is a gain-of-function mutation that up-regulates both the PCP pathway and canonical WNT signalling in cells and induces NTDs and CHDs in zebrafish embryos.\",\n      \"method\": \"In vitro cell-based PCP and WNT pathway reporter assays, zebrafish in vivo overexpression model\",\n      \"journal\": \"Clinical Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro signalling assays plus in vivo zebrafish model, single lab\",\n      \"pmids\": [\"27756857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Celsr1 is asymmetrically distributed at cell boundaries between hair cells and supporting cells in vestibular sensory epithelia; loss of Celsr1 causes misorientation of stereociliary bundles of vestibular hair cells and vestibular behavioral phenotypes (circling), demonstrating Celsr1 organizes intercellular planar polarity complexes in the inner ear.\",\n      \"method\": \"Celsr1 KO mouse, immunofluorescence for asymmetric protein distribution, behavioral analysis\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular (asymmetric localization) and functional (behavioral) phenotypes\",\n      \"pmids\": [\"28159525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Celsr1 controls branching of apical neural progenitor cell basal processes abutting the meninges, regulating retinoic acid-dependent neurogenesis; loss of Celsr1 decreases endfeet number, alters RA-dependent transcriptional activity, and biases progenitor commitment toward self-renewal at the expense of neuron production, causing cortical hypoplasia and microcephaly.\",\n      \"method\": \"Celsr1 KO mouse, immunofluorescence, RA signaling reporter assays, progenitor fate analysis\",\n      \"journal\": \"Molecular Psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with mechanistic pathway placement (RA signaling) and multiple orthogonal readouts\",\n      \"pmids\": [\"29257130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mouse Celsr1 engages in both homophilic trans-adhesion and lateral cis-interactions; the PCP-mutant Celsr1Crsh variant selectively impairs cis-interactions, increases protein mobility, reduces junctional enrichment, and fails to organize Frizzled6 and Vangl2 into asymmetric junctional complexes, while retaining trans-adhesion capacity.\",\n      \"method\": \"Biochemical interaction assays, super-resolution microscopy, FRAP, ectopic cis-dimerization rescue, co-immunoprecipitation with Fzd6 and Vangl2\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (biochemistry, super-resolution imaging, FRAP, rescue) in a single rigorous study\",\n      \"pmids\": [\"33529151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CELSR1 coordinates intercellular cilia orientation in multi-ciliated oviduct cells; its loss disrupts intercellular coordination of basal body orientation without abolishing intracellular polarity, whereas CAMSAP3 controls intracellular basal body orientation independently of PCP factor localization.\",\n      \"method\": \"Celsr1 KO and Camsap3 mutant mouse analysis, immunofluorescence for basal body and PCP factor distribution\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined mechanistic dissection of inter- vs. intracellular polarity roles, orthogonal genetic models\",\n      \"pmids\": [\"33468623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Celsr1 suppresses Wnt5a-mediated chemoattraction that would otherwise drive inappropriate rostral migration of facial branchiomotor neurons; in Celsr1;Wnt5a double mutants, rostral migration is abolished, and Wnt5a-coated beads attract FBM neurons rostrally in wild-type explants, placing Celsr1 as a suppressor of Wnt5a chemoattraction.\",\n      \"method\": \"Genetic epistasis (Celsr1;Wnt5a double mutant), bead assay with Wnt5a protein in hindbrain explants, Wnt5a overexpression in Celsr1 mutant background\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple orthogonal experimental approaches (double mutant, explant bead assay, overexpression)\",\n      \"pmids\": [\"36325991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CELSR1 and CELSR3 are cleavage-deficient (do not undergo autoproteolytic cleavage), while CELSR2 is efficiently cleaved; despite differential autoproteolysis, CELSR1-3 all engage GαS; CELSR1 and CELSR3 tethered-agonist point mutants retain GαS coupling activity, indicating CELSR1 signals through a tethered-agonist-independent mechanism distinct from classical adhesion GPCR activation.\",\n      \"method\": \"Autoproteolysis assays, G protein coupling (GαS) assays in mammalian cells, tethered-agonist point mutagenesis\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical cleavage assays plus G protein coupling assays with mutagenesis, multiple CELSR family members compared\",\n      \"pmids\": [\"37224017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Celsr1 is the major Celsr family member driving epidermal PCP: removal of Celsr1 alone abolishes PCP protein asymmetry and hair follicle polarization, whereas loss of Celsr2 has no effect; FRAP and junctional enrichment assays show Celsr1 stably enriches at junctions while Celsr2 is much less efficiently recruited and immobilized.\",\n      \"method\": \"CRISPR/Cas9 Celsr1 and Celsr2 KO mice, FRAP, junctional enrichment assays, PCP protein asymmetry immunofluorescence, Vangl2/Fz6 co-interaction assays\",\n      \"journal\": \"Frontiers in Cell and Developmental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — new CRISPR KO lines with multiple orthogonal methods (FRAP, localization, interaction assays) in a rigorous comparative study\",\n      \"pmids\": [\"36712970\"],\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; EC5-6 is flexible; EC7-MAD10 mediates dimerization; EC repeats alone support only weak homophilic adhesion (bead aggregation assay does not detect strong adhesion by EC repeats alone, and EC1-4 dimerizes only at high concentration).\",\n      \"method\": \"X-ray crystallography of EC1-4 and EC4-7, bead aggregation adhesion assays, solution dimerization experiments, molecular dynamics simulations\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with functional validation by adhesion assays and solution biochemistry\",\n      \"pmids\": [\"38307021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM reconstruction (3.8 Å) of mouse CELSR1 ECR reveals 14 domains forming a compact module mediated by conserved interactions between CADH9 and the C-terminal GAIN domain; in the presence of Ca2+, the CELSR1 ECR forms a dimer species via cadherin repeats putatively in antiparallel fashion; the N-terminal CADH1-8 module is required for cell-cell adhesion, and the C-terminal CADH9-GAIN module regulates cellular adhesion/signaling.\",\n      \"method\": \"Cryo-EM structure determination, cell-based adhesion assays, Ca2+-dependent dimerization assay\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with functional domain dissection by cell-based assays\",\n      \"pmids\": [\"40295529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"De novo heterozygous CELSR1 missense variant p.(Cys1318Tyr) disrupts subcellular localization of the protein, impairs cell-cell junction formation, impairs PCP signalling, and lowers cell proliferation rate in vitro.\",\n      \"method\": \"In vitro subcellular localization assay, cell-junction assay, PCP signalling reporter assay, proliferation assay in transfected cells\",\n      \"journal\": \"Journal of Medical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple cell-based assays, single lab, patient-derived variant study\",\n      \"pmids\": [\"38272662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Celsr1 protein is enriched at the basal surface of neuroepithelial cells in the early neural tube and in ventricular zone cells at the spinal cord midline; this basal enrichment is lost in Celsr1 homozygous mutant embryos and correlates spatiotemporally with dorsal sensory tract morphogenesis, suggesting a novel apico-basal distribution distinct from classical planar junctional localization.\",\n      \"method\": \"Immunofluorescence and subcellular fractionation in mouse neuroepithelium, comparison between wild-type and Celsr1 mutant embryos\",\n      \"journal\": \"Molecular and Cellular Neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization experiment with genetic control (mutant loss of signal), single lab\",\n      \"pmids\": [\"20353824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of Celsr1 in the subventricular zone of MCAO rats reduces neuroblast proliferation, angiogenesis (CD31+ cells), and p-PKC expression, and increases infarct volume and apoptosis; these data implicate CELSR1 in neuroprotection and neurogenesis via a Wnt/PKC signalling pathway.\",\n      \"method\": \"Lentiviral shRNA knockdown of Celsr1 in rat SVZ, MCAO model, immunofluorescence, behavioral analysis\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — in vivo knockdown with pathway inferred from p-PKC changes, single lab\",\n      \"pmids\": [\"32070035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Celsr1 knockout mice exhibit partial agenesis of the corpus callosum, periventricular heterotopia, irregular ventricular/subventricular zone shape, enlarged lateral ventricles, and increased seizure susceptibility, establishing CELSR1 as required for polarity-dependent processes during brain morphogenesis including corpus callosum formation and neuronal migration to the cortex.\",\n      \"method\": \"Celsr1 knockout mouse generation, brain MRI/histology, EEG seizure susceptibility testing\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with fully penetrant brain malformation phenotypes validated across multiple structural readouts\",\n      \"pmids\": [\"41530147\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CELSR1 is a core planar cell polarity (PCP) adhesion GPCR that organizes tissue polarity through homophilic trans- and cis-interactions at cell junctions — forming a compact extracellular module resolved by cryo-EM — and signals via GαS in a tethered-agonist-independent manner; it non-cell-autonomously directs neuronal migration by suppressing Wnt5a chemoattraction, regulates adherens junction dynamics and collective cell rearrangements in vascular and epithelial morphogenesis, controls coordinated ciliary orientation, and directs neural progenitor fate via retinoic acid signaling, with its junctional cis-interactions essential for organizing the asymmetric Frizzled6/Vangl2 complexes that propagate polarity across epithelia.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEPT papers.\n\n**Classification summary:**\n- Papers about CELSR1 (canonical protein): KEEP — [1],[2],[3],[4],[5],[8],[9],[10],[13],[14],[15],[16],[19],[21],[23],[24],[28],[29],[30],[33],[37],[39],[41],[47],[48],[50],[51],[53],[55],[58],[59],[64],[66],[68],[70],[71],[74],[75],[79],[80],[81],[83],[85],[86],[93],[95],[96]\n- Papers about circ_CELSR1/circCELSR1 (alt-locus product): EXCLUDE — [35],[28 additional corpus]\n- Papers about ME2 (malic enzyme 2, unrelated gene): EXCLUDE — [7],[12],[17],[18],[20],[25],[26],[27],[31],[32],[34],[36],[38],[40],[42],[43],[44],[46],[49],[52],[54],[56],[57],[60],[61],[62],[63],[65],[67],[72],[76],[77],[84],[87],[89],[90],[91],[92],[94],[98],[99],[100]\n- Other unrelated: EXCLUDE — [6],[11],[22],[31],[69],[82],[88],[97]\n- Additional corpus: most are proteomics/genomics resources not specific to CELSR1 mechanism; gene2pubmed [28] (circCELSR1) EXCLUDE; [24] (somatic PCP mutations) KEEP\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Missense mutations in mouse 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, establishing Celsr1 as the first mammalian Flamingo/Starry night homolog required for planar cell polarity.\",\n      \"method\": \"ENU mutagenesis, genetic mapping, in vivo phenotypic analysis of homozygous mutant mice (organ of Corti hair cell orientation, neural tube closure)\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent ENU alleles, replicated phenotypes, direct causal link between Celsr1 mutation and PCP/NTD defects\",\n      \"pmids\": [\"12842012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human CELSR1 missense variants associated with craniorachischisis impair subcellular trafficking to the plasma membrane, as demonstrated by reduced or abolished membrane localization compared to wild-type CELSR1, mirroring the crash and spin cycle mouse mutant phenotypes.\",\n      \"method\": \"Subcellular protein localization assays in transfected cells, protein-protein interaction assays, comparison with mouse Celsr1 mutant alleles\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization assay, multiple human variants tested, corroborated by mouse mutant data\",\n      \"pmids\": [\"22095531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Celsr1 (Crash allele) mutant mice show disrupted lung branching morphogenesis with fewer branches, thickened interstitial mesenchyme, and defective saccular formation; Rho kinase inhibition recapitulates these defects, and epithelial integrity and cytoskeletal remodelling are perturbed, placing Celsr1 upstream of Rho kinase in lung epithelial PCP signaling.\",\n      \"method\": \"Analysis of Celsr1Crsh mutant mouse lungs, Rho kinase inhibitor treatment, endoderm branching assays with FGF10, Celsr1 protein localization in lung epithelium\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO phenotype with pharmacological epistasis (ROCK inhibitor), protein localization, multiple readouts\",\n      \"pmids\": [\"20223754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Celsr1 regulates dynamic endothelial cell movements during lymphatic valve morphogenesis by inhibiting stabilization of VE-cadherin and maturation of adherens junctions; Celsr1 and Vangl2 are recruited from filopodia to discrete membrane domains at cell-cell contacts during valve formation.\",\n      \"method\": \"Celsr1- and Vangl2-deficient mouse analysis, live imaging of endothelial cell rearrangements, VE-cadherin dynamics assays, subcellular localization of Celsr1/Vangl2 by immunofluorescence\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular phenotype (valve aplasia), mechanistic link to VE-cadherin/adherens junction stabilization, direct localization data\",\n      \"pmids\": [\"23792146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Celsr1 regulates the direction of facial branchiomotor (FBM) neuron migration in a non-cell-autonomous manner; Celsr1 is expressed in floor plate and ventricular zone but not in FBM neurons, and conditional inactivation in ventricular zone of r3–r5 causes rostral misdirection of FBM neurons. Celsr2 is epistatic to Celsr1 in this context.\",\n      \"method\": \"Celsr1 knockout and Crash allele mice, conditional inactivation, FBM neuron fate mapping, hindbrain patterning analysis, epistasis analysis\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO establishing non-cell-autonomous function, epistasis with Celsr2, multiple alleles tested\",\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 concentrates at specific cellular boundaries perpendicular to the ovary-uterus axis, coordinates ciliary beat direction, controls epithelial cell elongation/orientation, and directs epithelial fold alignment. Mosaic analysis indicates cell geometry is primarily regulated by Celsr1.\",\n      \"method\": \"Celsr1-deficient mouse analysis, immunofluorescence localization, ciliary motion analysis, mosaic analysis, postnatal oviduct development characterization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO phenotype with multiple PCP readouts, direct protein localization, mosaic analysis establishing cell-autonomous regulation of geometry\",\n      \"pmids\": [\"25406397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CELSR1 TG dinucleotide repeat variants found in spina bifida patients alter subcellular localization of CELSR1 protein and impair physical association between CELSR1 and VANGL2, thereby diminishing recruitment of VANGL2 to cell-cell contacts.\",\n      \"method\": \"In vitro subcellular localization assays, co-immunoprecipitation of CELSR1 and VANGL2, functional analysis of patient-derived variants\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP and localization assays on patient variants, single lab\",\n      \"pmids\": [\"24632739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Celsr1 protein is enriched at the basal surface of neuroepithelial cells in the neural tube and in ventricular zone cells at the midline of the developing spinal cord; this basal enrichment is lost in Celsr1 homozygous mutant embryos. The basal Celsr1 distribution correlates with dorsal sensory tract morphogenesis and suggests multiple protein isoforms with distinct signaling potential.\",\n      \"method\": \"Immunofluorescence/protein localization in wild-type and mutant mouse embryos, subcellular fractionation approaches, in vivo analysis\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization experiment with functional correlation, single lab\",\n      \"pmids\": [\"20353824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CELSR1 P870L, identified in both NTD and CHD patients, is a gain-of-function mutation that upregulates both the PCP pathway and canonical WNT signaling in cells, and induces both NTDs and CHDs when expressed in zebrafish embryos.\",\n      \"method\": \"In vitro cell-based signaling assays, in vivo zebrafish embryo injection, patient variant characterization\",\n      \"journal\": \"Clinical science (London, England : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro assays demonstrating gain-of-function, single lab\",\n      \"pmids\": [\"27756857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mouse Celsr1 engages in both trans- (cell-cell bridging) and cis- (lateral, same-cell) interactions and organizes into dense, highly stable junctional puncta. The PCP-mutant Celsr1Crsh variant selectively impairs lateral cis-interactions, increases receptor mobility, diminishes junctional enrichment, and fails to engage in homophilic adhesion with wild-type Celsr1, preventing organization of Frizzled6 and Vangl2 into asymmetric junctional complexes. Ectopic cis-dimerization rescues these defects.\",\n      \"method\": \"Biochemical assays (co-IP), super-resolution microscopy (STORM), FRAP, cell aggregation assays, epistasis with Celsr1Crsh mutant\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (super-resolution microscopy, FRAP, biochemistry, rescue experiments) in single rigorous study\",\n      \"pmids\": [\"33529151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CELSR1 coordinates intercellular (between-cell) coordination of basal body orientation in oviduct multi-ciliated cells, while CAMSAP3 controls intracellular basal body orientation. Loss of CELSR1 disrupts intercellular coordination but only moderately affects intracellular polarity, whereas CAMSAP3 mutation disrupts intracellular BB orientation and microtubule interconnection without affecting PCP factor localization.\",\n      \"method\": \"Celsr1 mutant mouse analysis, CAMSAP3 mutant analysis, immunofluorescence localization of basal bodies and PCP factors, microtubule imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic dissection with two distinct KO alleles separating inter- vs. intracellular polarity mechanisms, replicated with CAMSAP3 epistasis\",\n      \"pmids\": [\"33468623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Celsr1 is asymmetrically distributed at cell boundaries between hair cells and supporting cells in developing vestibular and auditory sensory epithelia. Loss of Celsr1 causes misorientation of vestibular hair cell stereociliary bundles relative to neighbors, predominantly in cristae of semicircular canals, causing vestibular behavioral defects (circling).\",\n      \"method\": \"Celsr1 KO mouse analysis, immunofluorescence showing asymmetric Celsr1 distribution, hair bundle orientation analysis, behavioral phenotyping\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO phenotype with direct protein localization asymmetry, functional behavioral readout\",\n      \"pmids\": [\"28159525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Celsr1 controls branching of apical neural progenitor cell (aNPC) basal processes that abut 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 microcephaly.\",\n      \"method\": \"Celsr1 KO mouse analysis, RA signaling reporter assays, quantification of neural progenitor subtypes and neuron numbers, basal process morphology analysis\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple mechanistic readouts linking Celsr1 to RA signaling and progenitor fate, replicated phenotypes\",\n      \"pmids\": [\"29257130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Celsr1 suppresses inappropriate rostral FBM neuron migration non-cell-autonomously by acting in the ventricular zone of r3-r5 (not the floor plate). Conditional inactivation of Celsr1 specifically in the ventricular zone of r3-r5 phenocopies the full Celsr1 mutant migration defect.\",\n      \"method\": \"Conditional (Cre-lox) Celsr1 inactivation in specific cell types, dye-fill tracing of FBM neuron origin, hindbrain explant analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO in defined cell populations, dye-fill tracing, clear non-cell-autonomous mechanism established\",\n      \"pmids\": [\"27395006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Celsr1 suppresses Wnt5a-mediated chemoattraction to prevent inappropriate rostral migration of FBM neurons. In Celsr1; Wnt5a double mutants, rostral migration is abolished; FBM neurons migrate rostrally toward Wnt5a-coated beads in wild-type explants; and rostral migration is enhanced in Celsr1 mutants overexpressing Wnt5a in r3.\",\n      \"method\": \"Genetic epistasis (Celsr1; Wnt5a double mutants), Wnt5a-coated bead assays in hindbrain explants, Wnt5a overexpression in Celsr1 mutant background\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — three orthogonal approaches (double KO epistasis, bead assay, overexpression) converge on a single mechanism\",\n      \"pmids\": [\"36325991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CELSR1 promotes neuroprotection after cerebral ischemia by reducing apoptosis in peri-infarct cortex and promoting neurogenesis and angiogenesis in the subventricular zone, mainly through the Wnt/PKC signaling pathway. Knockdown of Celsr1 in the SVZ with lentivirus reduced neuroblast proliferation, CD31+ cell numbers, and motor function, and decreased p-PKC expression.\",\n      \"method\": \"Lentiviral Celsr1 knockdown in MCAO rat SVZ, immunohistochemistry for neuroblasts and CD31, Western blot for p-PKC, behavioral testing\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo KD with multiple cellular and molecular readouts, single lab, pathway assignment by signaling marker\",\n      \"pmids\": [\"32070035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CELSR1 is a positive regulator of endothelial cell migration, proliferation, and tube formation, and its effects on migration and tube formation are mediated through dishevelled segment polarity protein 3 (Dvl3).\",\n      \"method\": \"TALE-VP64 activator (gain-of-function) and shRNA knockdown of CELSR1 in human aortic endothelial cells, MTT proliferation assay, scratch/transwell migration assays, tube formation assay, Dvl3 epistasis\",\n      \"journal\": \"Biochemistry. Biokhimiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — both GOF and LOF approaches, downstream effector (Dvl3) identified, single lab\",\n      \"pmids\": [\"27301287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CELSR1 and CELSR3 are cleavage-deficient adhesion GPCRs (they do not undergo autoproteolytic cleavage at the GAIN domain), while CELSR2 is efficiently cleaved. Despite differential autoproteolysis, CELSR1-3 all engage GαS. CELSR1 tethered agonist (TA) point mutants retain GαS coupling activity, indicating that CELSR1 signals via a tethered-agonist-independent mechanism distinct from classical aGPCR activation.\",\n      \"method\": \"Autoproteolysis assays, G protein coupling assays (GαS BRET/cAMP), TA point mutagenesis, comparison across CELSR1-3 and LPHN3\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical cleavage assays, functional G protein coupling assays, mutagenesis across multiple family members, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"37224017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Celsr1 is the major Celsr family member for epidermal PCP: removal of Celsr1 alone abolishes PCP protein asymmetry and hair follicle polarization, while loss of Celsr2 alone has no effect. Celsr1 stably enriches at junctional interfaces (low FRAP mobility), whereas Celsr2 is much less efficiently recruited to junctions. Both proteins interact equivalently with Vangl2 and Fz6, suggesting that differences in homophilic adhesion underlie differential PCP involvement.\",\n      \"method\": \"CRISPR/Cas9 Celsr1 and Celsr2 KO mice, PCP protein asymmetry assays, hair follicle orientation analysis, FRAP, junctional enrichment assays, co-IP with Vangl2 and Fz6\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two new KO alleles, FRAP, co-IP, multiple PCP readouts; mechanistic distinction between Celsr1 and Celsr2 adhesion properties established\",\n      \"pmids\": [\"36712970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM reconstruction of mouse CELSR1 ECR (3.8 Å) reveals that 14 of its 23 adhesion domains form a compact module mediated by conserved interactions between the CADH9 and C-terminal GAIN domains. In the presence of Ca2+, the CELSR1 ECR forms a dimer species mediated by cadherin repeats in a putative 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.\",\n      \"method\": \"Cryo-EM structure determination (3.8 Å), Ca2+-dependent dimerization assays, cell-based adhesion assays with domain deletion constructs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with functional validation by domain-deletion cell assays\",\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 and a non-canonical linker between EC5 and EC6. CELSR1 EC repeats alone support only weak homophilic adhesion in bead aggregation assays; EC1-4 dimerizes only at high concentration; EC7-MAD10 mediates dimerization in solution. MD simulations and experiments indicate flexibility at EC5-6.\",\n      \"method\": \"X-ray crystallography (EC1-4, EC4-7), bead aggregation assays, analytical ultracentrifugation/SEC, MD simulations\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with functional adhesion assays and biophysical validation\",\n      \"pmids\": [\"38307021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Preprint (later published): 4.3 Å cryo-EM of mCELSR1 ECR resolves 13 domains forming a compact module with contact between N- and C-terminal domains; Ca2+ promotes an extended species proposed to represent the antiparallel cadherin dimer. CADH1-8 is necessary for cell adhesion and CADH9-GAIN module regulates G protein signaling.\",\n      \"method\": \"Cryo-EM, Ca2+-dependent biophysical assays, cell adhesion assays, G protein coupling assays with domain deletion constructs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural + functional data but preprint; results largely consistent with and superseded by published version (PMID:40295529)\",\n      \"pmids\": [\"38328199\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Somatic CELSR1 p.Gln2125His mutation found in NTD fetal tissue; FZD6 p.Gln88Glu disrupts colocalization of CELSR1 and FZD6, and VANGL1 p.Arg374His impairs colocalization of CELSR1 and VANGL1, indicating that CELSR1 co-localizes with FZD6 and VANGL1 at cell membranes as part of the PCP complex, and this is disrupted by partner mutations.\",\n      \"method\": \"Subcellular colocalization assays in transfected cells, Western blot, luciferase non-canonical Wnt signaling assay, cell migration assay\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — colocalization assays showing CELSR1 complex with FZD6/VANGL1 disrupted by partner mutations; indirect evidence for CELSR1 complex membership\",\n      \"pmids\": [\"32356230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Biallelic CELSR1 variants in humans cause brain malformations (pachygyria, periventricular nodular heterotopia, corpus callosum abnormalities), neurodevelopmental delay, and epilepsy. Celsr1 knockout mice exhibit partial corpus callosum agenesis, periventricular heterotopia, irregular ventricular/subventricular zone shape, enlarged lateral ventricles (fully penetrant), and increased seizure susceptibility.\",\n      \"method\": \"Whole exome sequencing of human patients, Celsr1 KO mouse generation and analysis (MRI/histology of brain malformations, seizure susceptibility testing)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetics corroborated by KO mouse with fully penetrant brain malformation phenotypes and seizure susceptibility\",\n      \"pmids\": [\"41530147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Celsr1 encodes a developmentally regulated seven-pass transmembrane protein whose extracellular domain contains nine cadherin repeats followed by EGF-like and laminin A G-type repeats, a unique domain architecture coupling adhesion motifs to a 7TM domain. Expression in adult brain is localized principally to ependymal cell layer, choroid plexus, and area postrema.\",\n      \"method\": \"cDNA cloning, domain analysis, chromosomal mapping (EUCIB, BXD, FISH), RT-PCR, in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — original structural characterization by sequence/expression analysis; foundational domain architecture discovery\",\n      \"pmids\": [\"9339365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of Celsr1 in vestibular hair cells causes ~50% reduction in canal-dependent vestibulo-ocular reflex gain across all tested frequencies and ~30% reduction in otolith-dependent function, demonstrating that the highly organized PCP-dependent polarization of hair cells is critical for accurate vestibular encoding.\",\n      \"method\": \"Video-oculography in Celsr1 KO mice, sinusoidal rotation, angular velocity steps, off-vertical axis rotation, static/dynamic head tilt assays\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with quantitative functional vestibular readouts linking PCP hair cell disorganization to circuit-level dysfunction\",\n      \"pmids\": [\"34790090\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CELSR1 is an atypical seven-pass transmembrane cadherin (adhesion GPCR) that functions as a core planar cell polarity (PCP) component: its large extracellular region (9 cadherin repeats plus EGF/laminin G domains organized into a compact CADH9-GAIN module) mediates weak homophilic cell-cell adhesion via both trans- and cis-interactions that organize asymmetric junctional complexes containing Frizzled6 and Vangl2; CELSR1 couples to GαS independently of autoproteolytic cleavage (unlike many adhesion GPCRs); and loss-of-function disrupts coordinated epithelial polarity, ciliary orientation, neural tube closure, neuronal migration directionality (by suppressing Wnt5a-mediated chemoattraction), lymphatic valve morphogenesis (through inhibition of VE-cadherin/adherens junction stabilization), cortical neurogenesis (via retinoic acid signaling from meningeal-progenitor contacts), and brain morphogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CELSR1 is a core planar cell polarity (PCP) adhesion GPCR that organizes tissue-level polarity across diverse epithelia and the developing nervous system. It engages in Ca²⁺-dependent homophilic trans-adhesion via its N-terminal cadherin repeats and lateral cis-interactions that are essential for stably enriching at cell junctions and organizing asymmetric Frizzled6/Vangl2 complexes; disruption of cis-interactions (as in the Crsh allele) abolishes PCP protein asymmetry without eliminating trans-adhesion [PMID:33529151, PMID:36712970]. Structurally, its extracellular region forms a compact 14-domain module in which CADH9 contacts the C-terminal GAIN domain, and it signals through Gαs via a tethered-agonist-independent mechanism [PMID:40295529, PMID:37224017]. Loss of CELSR1 causes craniorachischisis and spina bifida through defective neural tube closure, disrupts coordinated ciliary orientation, impairs lymphatic valve morphogenesis by destabilizing adherens junction dynamics, non-cell-autonomously directs facial branchiomotor neuron migration by suppressing Wnt5a chemoattraction, and biases neural progenitor fate toward self-renewal via retinoic acid signaling, with knockout mice exhibiting corpus callosum agenesis, periventricular heterotopia, and seizure susceptibility [PMID:12842012, PMID:36325991, PMID:23792146, PMID:29257130, PMID:41530147].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of Celsr1 as a mammalian PCP gene resolved the question of whether the Drosophila flamingo/starry night pathway is conserved in vertebrates, establishing that Celsr1 is required for both inner ear hair cell orientation and neural tube closure.\",\n      \"evidence\": \"ENU-induced missense alleles (spin cycle, crash) in mouse with hair cell polarity and neural tube closure phenotypes\",\n      \"pmids\": [\"12842012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors not identified\", \"Mechanism of intercellular polarity propagation unknown\", \"Structural basis of Celsr1 function not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Conditional inactivation revealed that Celsr1 directs facial branchiomotor neuron migration non-cell-autonomously from the neuroepithelium, fundamentally distinguishing it from cell-intrinsic guidance receptors.\",\n      \"evidence\": \"Cell-type-specific Cre-mediated Celsr1 inactivation in ventricular zone vs. floor plate with neuronal migration tracing in mouse\",\n      \"pmids\": [\"20631168\", \"27395006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signal transduced non-cell-autonomously not identified\", \"Relationship to Wnt chemoattraction not yet tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that Celsr1 acts upstream of ROCK during lung branching morphogenesis placed it within an FGF10-responsive PCP-Rho kinase signaling axis governing organ development beyond the neural tube.\",\n      \"evidence\": \"Celsr1 Crash mutant mouse lung analysis, in vitro branching assay, ROCK inhibitor epistasis\",\n      \"pmids\": [\"20223754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between Celsr1 and RhoA/ROCK not demonstrated\", \"Specificity to PCP vs. other Rho-activating pathways not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing that human CELSR1 variants associated with craniorachischisis impair plasma membrane trafficking established defective surface localization as a pathogenic mechanism, linking mouse PCP phenotypes to human neural tube defects.\",\n      \"evidence\": \"Subcellular localization assay of human variants in transfected cells compared with mouse crash/spin cycle alleles\",\n      \"pmids\": [\"22095531\", \"24632739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Patient variants not tested for PCP signaling in vivo\", \"Functional redundancy with CELSR2/3 in human NTDs not assessed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that Celsr1 regulates lymphatic valve morphogenesis by inhibiting VE-cadherin stabilization extended its role to vascular biology and revealed a specific mechanism—modulation of adherens junction dynamics—through which PCP controls collective cell rearrangements.\",\n      \"evidence\": \"Celsr1/Vangl2 conditional KO mouse, live imaging, VE-cadherin junctional maturation assays\",\n      \"pmids\": [\"23792146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism linking Celsr1 to VE-cadherin turnover unknown\", \"Whether Celsr1 acts through Rho-ROCK in endothelial cells not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Celsr1 was shown to coordinate intercellular ciliary orientation in multi-ciliated oviduct epithelium while being dispensable for intracellular basal body alignment, delineating its role as an intercellular polarity coordinator rather than an intracellular organizer.\",\n      \"evidence\": \"Celsr1 KO and Camsap3 mutant mouse oviduct analysis, mosaic analysis, live ciliary imaging\",\n      \"pmids\": [\"25406397\", \"33468623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Celsr1 transmits directional information to basal bodies not identified\", \"Contribution of cilia dysfunction to fertility phenotype not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that Celsr1 controls branching of neural progenitor basal processes and retinoic acid-dependent neurogenesis revealed a novel mechanism by which PCP signaling regulates cortical progenitor fate decisions, explaining microcephaly in Celsr1 mutants.\",\n      \"evidence\": \"Celsr1 KO mouse cortex analysis, RA signaling reporters, progenitor fate quantification\",\n      \"pmids\": [\"29257130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between Celsr1 and RA receptor/transporter machinery not identified\", \"Whether meningeal contact per se or RA access is the critical variable not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Biochemical and imaging dissection of Celsr1 cis- vs. trans-interactions resolved how polarity is organized: homophilic trans-adhesion connects opposing cells while lateral cis-interactions immobilize Celsr1 at junctions and scaffold asymmetric Fzd6/Vangl2 complexes; the PCP-disrupting Crsh mutation selectively impairs cis-interactions.\",\n      \"evidence\": \"Super-resolution microscopy, FRAP, biochemical cis/trans interaction assays, ectopic cis-dimerization rescue, co-IP with Fzd6/Vangl2\",\n      \"pmids\": [\"33529151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cis-interaction not determined at atomic resolution\", \"Whether cis-interactions require additional cofactors in vivo unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic epistasis revealed that Celsr1 non-cell-autonomously suppresses Wnt5a-mediated chemoattraction of FBM neurons, finally identifying the molecular signal whose action Celsr1 counteracts during directional neuronal migration.\",\n      \"evidence\": \"Celsr1;Wnt5a double mutant mouse, Wnt5a-coated bead chemoattraction assay in hindbrain explants\",\n      \"pmids\": [\"36325991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Celsr1 suppresses Wnt5a signaling (sequestration, receptor competition, or transcriptional) not determined\", \"Whether this suppressive relationship operates in other Celsr1-dependent tissues untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstration that CELSR1 is cleavage-deficient yet couples to Gαs through a tethered-agonist-independent mechanism established that CELSR1 signals as an adhesion GPCR via a non-canonical activation mode distinct from classical GAIN-domain autoproteolysis.\",\n      \"evidence\": \"Autoproteolysis assays, Gαs coupling assays, tethered-agonist point mutagenesis across CELSR1-3 in mammalian cells\",\n      \"pmids\": [\"37224017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of Gαs coupling by CELSR1 in PCP context not identified\", \"Whether Gαs signaling is required for any established Celsr1 phenotype not tested in vivo\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Comparative analysis of Celsr1 vs. Celsr2 in epidermis established Celsr1 as the dominant PCP-organizing paralog, attributable to its superior junctional enrichment and stability; Celsr2 cannot substitute despite sequence similarity.\",\n      \"evidence\": \"CRISPR KO mice for Celsr1 and Celsr2, FRAP, junctional enrichment, PCP asymmetry immunofluorescence\",\n      \"pmids\": [\"36712970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants conferring Celsr1's superior junctional retention over Celsr2 not mapped\", \"Whether Celsr3 can compensate in epidermal PCP not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Crystal structures of CELSR1 EC1-7 revealed typical cadherin folds with a non-canonical flexible linker at EC5-6 and showed that EC repeats alone mediate only weak homophilic adhesion, implying that additional domains are needed for robust adhesion.\",\n      \"evidence\": \"X-ray crystallography of EC1-4 and EC4-7, bead aggregation assays, solution dimerization, MD simulations\",\n      \"pmids\": [\"38307021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length extracellular structure not yet available at crystallographic resolution\", \"Functional significance of EC5-6 flexibility not tested in vivo\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM of the complete CELSR1 extracellular region revealed a compact 14-domain architecture with an intramolecular CADH9-GAIN contact and Ca²⁺-dependent antiparallel dimerization, providing the first near-complete structural framework for understanding how adhesion and signaling are coupled in this receptor.\",\n      \"evidence\": \"3.8 Å cryo-EM reconstruction, cell-based adhesion and Ca²⁺-dependent dimerization assays\",\n      \"pmids\": [\"40295529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the seven-transmembrane domain and intracellular region not resolved\", \"Structural basis of cis-interaction still unknown\", \"How CADH9-GAIN interaction regulates signaling not mechanistically defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Celsr1 knockout mice were shown to exhibit corpus callosum agenesis, periventricular heterotopia, and seizure susceptibility, establishing CELSR1 as necessary for brain morphogenesis beyond neural tube closure.\",\n      \"evidence\": \"Celsr1 KO mouse, brain MRI/histology, EEG seizure susceptibility\",\n      \"pmids\": [\"41530147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether brain malformations are secondary to migration defects or independent PCP roles not dissected\", \"Human patients with CELSR1 brain phenotypes not yet systematically characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of Celsr1 cis-interactions, the in vivo relevance of Gαs coupling to established PCP phenotypes, the mechanism by which Celsr1 suppresses Wnt5a signaling, and the structure of the transmembrane and intracellular domains.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Structural basis of cis-interaction not resolved\", \"In vivo role of Gαs coupling not tested\", \"Mechanism of Wnt5a suppression not defined\", \"No structure of TM/intracellular region\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 11, 16, 17]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5, 9, 11, 15, 18]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 11, 13, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 4, 5, 10, 21]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 7, 13, 21]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 11, 17]}\n    ],\n    \"complexes\": [\n      \"PCP core complex (Celsr1–Frizzled6–Vangl2)\"\n    ],\n    \"partners\": [\n      \"VANGL2\",\n      \"FZD6\",\n      \"GNAS\",\n      \"WNT5A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"CELSR1 is an atypical seven-pass transmembrane cadherin (adhesion GPCR) that functions as a core component of the planar cell polarity (PCP) pathway, coordinating tissue-level polarity across diverse epithelia and neuronal populations. Its large extracellular region—comprising nine cadherin repeats, EGF-like, and laminin G domains organized into a compact CADH9-GAIN module—mediates weak, Ca²⁺-dependent homophilic adhesion through both trans- and cis-interactions that stabilize junctional puncta and organize asymmetric complexes containing Frizzled6 and Vangl2; disruption of cis-interactions (as in the Crash allele) abolishes junctional enrichment and PCP protein asymmetry [PMID:33529151, PMID:36712970, PMID:40295529]. CELSR1 couples to Gαs independently of GAIN-domain autoproteolysis and tethered-agonist activation, distinguishing it from classical adhesion GPCRs [PMID:37224017]. Loss of CELSR1 function disrupts neural tube closure, inner ear and oviduct ciliary orientation, lymphatic valve morphogenesis (via VE-cadherin/adherens junction destabilization), cortical neurogenesis (via retinoic acid signaling), and facial branchiomotor neuron migration (by de-repressing Wnt5a-mediated chemoattraction) [PMID:12842012, PMID:25406397, PMID:23792146, PMID:29257130, PMID:36325991]; biallelic CELSR1 variants in humans cause brain malformations including pachygyria, periventricular heterotopia, and epilepsy [PMID:41530147].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of CELSR1's unique domain architecture—nine cadherin repeats coupled to EGF-like, laminin G, and seven-transmembrane domains—established a new class of adhesion-GPCR hybrids with brain-enriched expression.\",\n      \"evidence\": \"cDNA cloning, domain analysis, in situ hybridization in mouse brain\",\n      \"pmids\": [\"9339365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional data; expression-based only\", \"Signaling mechanism unknown\", \"Ligand and adhesion properties not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Two independent ENU alleles (spin cycle, crash) demonstrated that Celsr1 is the first mammalian Flamingo homolog required for planar cell polarity and neural tube closure, transforming it from an uncharacterized orphan receptor to a core PCP component.\",\n      \"evidence\": \"ENU mutagenesis screen, organ of Corti hair cell orientation and neural tube closure analysis in homozygous mutant mice\",\n      \"pmids\": [\"12842012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of PCP disruption unknown\", \"Downstream signaling effectors not identified\", \"Relationship to other core PCP components (Vangl, Fz) not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Functional studies expanded CELSR1's PCP role beyond the ear and neural tube to lung branching morphogenesis (upstream of Rho kinase), neuroepithelial basal polarity, and non-cell-autonomous regulation of facial branchiomotor neuron migration direction.\",\n      \"evidence\": \"Celsr1 Crash/KO mouse phenotyping in lung and hindbrain, ROCK inhibitor epistasis, conditional inactivation, FBM neuron fate mapping, neuroepithelial immunofluorescence\",\n      \"pmids\": [\"20223754\", \"20631168\", \"20353824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway between Celsr1 and ROCK not delineated\", \"Floor plate vs. ventricular zone requirement not fully resolved\", \"Multiple isoform significance unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Human CELSR1 missense variants from craniorachischisis patients were shown to impair plasma membrane trafficking, providing the first direct link between human NTD mutations and a defined cellular defect in CELSR1 function.\",\n      \"evidence\": \"Subcellular localization assays of multiple patient-derived CELSR1 variants in transfected cells, comparison to mouse Crash/spin cycle alleles\",\n      \"pmids\": [\"22095531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression system may not recapitulate endogenous trafficking\", \"Functional rescue not performed\", \"Interaction with PCP partners not systematically tested for all variants\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that Celsr1 regulates lymphatic valve morphogenesis by inhibiting VE-cadherin stabilization revealed a PCP-adherens junction crosstalk mechanism operative in endothelial cells, expanding CELSR1 biology beyond epithelial and neuronal tissues.\",\n      \"evidence\": \"Celsr1-deficient mouse lymphatic analysis, live imaging of endothelial rearrangements, VE-cadherin dynamics assays\",\n      \"pmids\": [\"23792146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism of VE-cadherin destabilization unknown\", \"Whether Celsr1 acts through Vangl2 or independently in this context not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Celsr1 was shown to coordinate multilevel polarity in the oviduct (ciliary beat direction, cell elongation, epithelial fold alignment), while human spina bifida–associated variants were found to disrupt the CELSR1–VANGL2 physical interaction and VANGL2 junctional recruitment.\",\n      \"evidence\": \"Celsr1 KO mouse oviduct analysis with ciliary motion/mosaic studies; co-IP of patient-derived CELSR1 variants with VANGL2\",\n      \"pmids\": [\"25406397\", \"24632739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CELSR1–VANGL2 interaction unknown\", \"Oviduct-specific downstream effectors not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A gain-of-function CELSR1 variant (P870L) was demonstrated to upregulate both PCP and canonical WNT signaling, and conditional studies pinpointed the ventricular zone of r3–r5 as the critical site of Celsr1 action for suppressing aberrant FBM neuron migration.\",\n      \"evidence\": \"Cell-based PCP/WNT signaling assays and zebrafish injection for P870L; Cre-lox conditional KO in specific hindbrain domains with dye-fill tracing\",\n      \"pmids\": [\"27756857\", \"27395006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of P870L gain-of-function at receptor level unknown\", \"Direct signal mediating non-cell-autonomous influence on FBM neurons not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies revealed that Celsr1 controls cortical neurogenesis via retinoic acid signaling from meningeal-progenitor contacts, and coordinates vestibular hair cell stereociliary bundle orientation—extending its PCP repertoire to progenitor fate decisions and sensory organ patterning.\",\n      \"evidence\": \"Celsr1 KO mouse cortex (RA reporter, progenitor quantification, basal process morphology) and vestibular epithelium (hair bundle orientation, behavioral phenotyping)\",\n      \"pmids\": [\"29257130\", \"28159525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RA pathway engagement is direct or indirect not resolved\", \"Vestibular compensation mechanisms not characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Super-resolution and biophysical studies established that CELSR1 forms both trans and cis homophilic interactions at junctions; the Crash mutation selectively disrupts cis-interactions, increasing receptor mobility and preventing asymmetric PCP complex assembly—demonstrating that lateral cis-clustering is the critical step for PCP establishment.\",\n      \"evidence\": \"STORM super-resolution microscopy, FRAP, co-IP, cell aggregation assays, ectopic cis-dimerization rescue of Crash phenotype\",\n      \"pmids\": [\"33529151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cis vs. trans interface not resolved at atomic level\", \"Whether other PCP components modulate cis/trans equilibrium unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Dissection of intercellular (Celsr1-dependent) versus intracellular (CAMSAP3-dependent) basal body orientation in oviduct multiciliated cells clarified that CELSR1's role is specifically in coordinating polarity between neighboring cells rather than organizing the cytoskeleton within a single cell.\",\n      \"evidence\": \"Parallel analysis of Celsr1 and CAMSAP3 mutant mice with basal body and PCP factor localization imaging\",\n      \"pmids\": [\"33468623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link from junctional CELSR1 to cytoplasmic polarity machinery not identified\", \"Whether this intercellular/intracellular division applies in other ciliated tissues unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic epistasis showed that Celsr1 suppresses Wnt5a-mediated chemoattraction of FBM neurons, finally identifying the specific signal (Wnt5a) that Celsr1 counteracts to prevent aberrant rostral migration.\",\n      \"evidence\": \"Celsr1;Wnt5a double KO epistasis, Wnt5a-coated bead chemoattraction assays in hindbrain explants, Wnt5a overexpression in Celsr1 mutant\",\n      \"pmids\": [\"36325991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Celsr1 modulates Wnt5a availability, receptor access, or downstream signaling not distinguished\", \"Receptor on FBM neurons transducing Wnt5a not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Biochemical and signaling studies demonstrated that CELSR1 is cleavage-deficient at its GAIN domain yet couples to Gαs through a tethered-agonist-independent mechanism, fundamentally distinguishing its activation mode from canonical adhesion GPCRs. Separately, CELSR1 was confirmed as the dominant Celsr paralog for epidermal PCP based on its superior junctional stability relative to CELSR2.\",\n      \"evidence\": \"Autoproteolysis assays, Gαs BRET/cAMP coupling with TA mutants across CELSR family; CRISPR KO of Celsr1/Celsr2 in mouse epidermis with FRAP and co-IP\",\n      \"pmids\": [\"37224017\", \"36712970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of TA-independent Gαs activation unknown\", \"Whether Gαs signaling is required for PCP function not tested\", \"Basis for differential junctional stability of CELSR1 vs. CELSR2 at structural level unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Crystal structures of CELSR1 cadherin repeats EC1-7 revealed typical cadherin folds with a non-canonical flexible linker at EC5-6, and showed that isolated EC repeats support only weak adhesion while the C-terminal EC7-MAD10 region contributes significantly to dimerization.\",\n      \"evidence\": \"X-ray crystallography of EC1-4 and EC4-7, bead aggregation assays, AUC/SEC, MD simulations\",\n      \"pmids\": [\"38307021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length extracellular region structure at high resolution not yet available from crystallography\", \"Trans-dimer interface not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM at 3.8 Å resolved the compact CADH9-GAIN module of CELSR1 and showed Ca²⁺-dependent antiparallel dimerization mediated by cadherin repeats, with CADH1-8 required for cell adhesion and the CADH9-GAIN module regulating adhesion properties—providing the first near-complete structural view of the extracellular region.\",\n      \"evidence\": \"Cryo-EM reconstruction of mouse CELSR1 ECR, Ca²⁺-dependent dimerization assays, domain deletion cell adhesion assays\",\n      \"pmids\": [\"40295529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the 7TM domain and intracellular regions not resolved\", \"Dimer interface at atomic resolution still lacking\", \"Relationship between compact/extended conformations and signaling state unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Biallelic CELSR1 variants were identified as a cause of human brain malformations (pachygyria, periventricular heterotopia, corpus callosum abnormalities) with epilepsy, validated by fully penetrant corresponding phenotypes in Celsr1 KO mice—establishing CELSR1 as a Mendelian disease gene for cortical malformations beyond NTDs.\",\n      \"evidence\": \"Whole exome sequencing of human patients, Celsr1 KO mouse MRI/histology and seizure susceptibility testing\",\n      \"pmids\": [\"41530147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific cellular mechanism linking Celsr1 loss to heterotopia and pachygyria not defined\", \"Genotype-phenotype correlations across different variant classes not established\", \"Whether seizures are primary or secondary to malformation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) how the CADH9-GAIN compact module and conformational changes couple to Gαs activation in the absence of autoproteolysis; (2) whether Gαs signaling is required for CELSR1's PCP function or operates in a parallel pathway; and (3) the identity and structure of the intracellular signaling complexes that relay CELSR1 junctional asymmetry to cytoskeletal and transcriptional effectors.\",\n      \"evidence\": \"Open question synthesized from existing literature gaps\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of the 7TM or intracellular domain\", \"Gαs pathway contribution to PCP not tested genetically\", \"Direct intracellular effectors linking junctional CELSR1 to cytoskeletal polarity machinery remain unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [9, 19, 20]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5, 9, 11, 18, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 9, 14, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 4, 5, 12, 23]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 9, 18, 22]}\n    ],\n    \"complexes\": [\n      \"PCP core complex (CELSR1–FZD6–VANGL2)\"\n    ],\n    \"partners\": [\n      \"VANGL2\",\n      \"FZD6\",\n      \"VANGL1\",\n      \"DVL3\",\n      \"FZD3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}