{"gene":"CELSR3","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2005,"finding":"Celsr3 (ortholog of Drosophila flamingo/starry night) is required for development of major axonal fascicles in the mammalian CNS. Mice with Celsr3 inactivation show selective, marked anomalies of several major axonal tracts (anterior commissure, internal capsule, and longitudinal brainstem/spinal cord bundles), phenocopying Fzd3 inactivation, establishing Celsr3 as a core component of a PCP-like genetic pathway controlling axonal blueprint formation.","method":"Constitutive gene knockout in mice; in situ hybridization for co-expression; tract tracing","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined axonal phenotype, genetic epistasis with Fzd3, replicated and extended by multiple subsequent studies","pmids":["15778712"],"is_preprint":false},{"year":2008,"finding":"Conditional inactivation of Celsr3 in telencephalon, ventral forebrain, or cortex demonstrated that Celsr3 functions both cell-autonomously in neurons projecting axons and non-cell-autonomously in guidepost cells that channel growing axons through the internal capsule, establishing heterotypic axon–guidepost cell interactions as a key mechanism.","method":"Conditional (Cre/lox) Celsr3 knockout in specific forebrain regions; axonal tract tracing (DiI)","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — regionally restricted conditional KO with multiple Cre lines, clear dissection of cell-autonomous vs. non-autonomous roles, replicated phenotype","pmids":["18487195"],"is_preprint":false},{"year":2009,"finding":"Celsr3 is required for tangential and radial interneuron migration in the developing mouse forebrain. In Celsr3 knockout mice, calretinin-positive interneurons accumulate at the corticostriatal boundary and are reduced in the neocortex, while calbindin-positive cell lamination is altered; NRG1 and ErbB4 expression patterns are changed in Celsr3 mutants, implicating this pathway.","method":"Constitutive KO with GFP knock-in reporter; immunohistochemistry; expression analysis of NRG1/ErbB4","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype and pathway gene expression changes, single lab","pmids":["19332558"],"is_preprint":false},{"year":2009,"finding":"Celsr3 acts both in cortical projection neurons (cell-autonomous role in corticospinal axon growth) and in guidepost cells of the ventral forebrain (non-cell-autonomous role guiding axons through the internal capsule), as demonstrated by region-specific conditional inactivation.","method":"Conditional Celsr3 knockout (Foxg1-Cre, Emx1-Cre, Dlx-Cre); DiI tract tracing","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional alleles with orthogonal Cre drivers dissecting cell-autonomous and non-autonomous roles","pmids":["19349379"],"is_preprint":false},{"year":2010,"finding":"Celsr2 and Celsr3 together control ependymal ciliogenesis and planar organization of cilia. Double mutant ependyma shows markedly impaired ciliogenesis leading to lethal hydrocephalus. Celsr2 single mutants show defective planar organization of cilia and disturbed membrane distribution of Vangl2 and Fzd3; double mutants show even greater disruption of Vangl2/Fzd3 membrane asymmetry.","method":"Celsr2/Celsr3 single and double knockout mice; immunofluorescence for PCP proteins (Vangl2, Fzd3); cilia analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic double mutant epistasis with defined cellular phenotype (ciliogenesis defect), membrane localization of PCP components analyzed","pmids":["20473291"],"is_preprint":false},{"year":2012,"finding":"Celsr3 is required for hippocampal connectivity and pyramidal cell maturation. Conditional inactivation in the telencephalon (Foxg1-Cre) disrupts afferent and efferent hippocampal pathways and intrinsic connections, causes atrophic CA1 dendritic trees, decreased synapse density, altered LTP, and increased symmetric vs. asymmetric synapses; interneuron migration to hippocampus is preserved.","method":"Conditional KO (Celsr3|Foxg1 and Celsr3|Dlx); DiI tracing; electrophysiology (LTP); synapse electron microscopy; behavioral tests","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two conditional KO lines with multiple orthogonal readouts (tract tracing, EM, electrophysiology, behavior)","pmids":["23035085"],"is_preprint":false},{"year":2014,"finding":"Celsr3 in motor neurons mediates pathfinding of peroneal nerve axons in the hindlimb by enabling sensitivity to attractive EphA-ephrinA reverse signaling. Celsr3-deficient motor axons respond normally to repulsive ephrinA-EphA forward signaling and GDNF but are insensitive to attractive EphA-ephrinA reverse signaling. By co-immunoprecipitation, Celsr3 physically interacts with ephrinA2, ephrinA5, Ret, GFRα1, and Frizzled3.","method":"Conditional KO (motor neuron-specific); retrograde axon tracing; co-immunoprecipitation in transfected cells; epistasis with Fzd3 and Vangl2 mutants","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with mechanistic dissection, co-IP identifying interactors, genetic epistasis with Fzd3 and Vangl2, multiple orthogonal methods","pmids":["25108913"],"is_preprint":false},{"year":2014,"finding":"Celsr2 acts redundantly with Celsr3 in forebrain axon guidance; combined Celsr2/Celsr3 inactivation mimics Fzd3 inactivation, placing all three in the same cellular pathway. Forebrain axon wiring is normal in Vangl1/Vangl2-deficient mice, demonstrating that Celsr2/3-Fzd3-dependent axon guidance is Vangl independent—mechanistically distinct from classical epithelial PCP.","method":"Conditional double KO (Celsr2/Celsr3) in multiple forebrain compartments; genetic epistasis with Vangl1/2 double KO; axon tracing","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional alleles, genetic epistasis with Fzd3 and Vangl1/2, replication across compartments","pmids":["25002511"],"is_preprint":false},{"year":2016,"finding":"Celsr3 and Fzd3 in Isl1-positive pioneer neurons are required to form a scaffold of early axonal projections crossing the diencephalon-telencephalon junction (DTJ). When Celsr3 or Fzd3 is inactivated in Isl1-expressing cells, pioneer projections fail to cross the DTJ, and later-growing thalamic and cortical axons cannot traverse this junction, demonstrating that Celsr3 organizes guidepost scaffold formation for thalamocortical connectivity.","method":"Conditional KO in Isl1-Cre cells; axon tracing (DiI); developmental time-course analysis","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type specific conditional KO identifying pioneer scaffold mechanism, developmental tracing at multiple time points","pmids":["27170656"],"is_preprint":false},{"year":2016,"finding":"Celsr3 and Fzd3 in immature cortical neurons (not progenitors) are required for neurons to respond to Wnt7 and upregulate Jag1, which activates Notch signaling in neural progenitor cells, thereby providing feedback that controls the timing of progenitor fate decisions (neurogenesis-to-gliogenesis transition).","method":"Conditional KO of Celsr3 and Fzd3 in neurons vs. progenitors; Notch pathway readouts; Jag1 expression analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO dissecting cell-type specificity, Wnt7-Jag1-Notch pathway placement, single lab","pmids":["26939553"],"is_preprint":false},{"year":2017,"finding":"Celsr3 and Vangl2 are localized at developing glutamatergic synapses (demonstrated by synaptosome fractionation and immunostaining) and co-immunoprecipitate with key synaptic proteins. Conditional KO of Celsr3 in hippocampus postnatally causes ~50% loss of glutamatergic synapses (but not inhibitory synapses) in vivo, impairs LTP-associated spatial learning and fear conditioning. Wnt5a inhibits Celsr3-mediated glutamatergic synapse formation. Conditional KO of Vangl2 has the opposite effect (increased synapse density), establishing opposing roles for Celsr3 and Vangl2 in synaptogenesis.","method":"Synaptosome fractionation; immunostaining; co-immunoprecipitation; conditional KO; mEPSC recording; electron microscopy; behavioral assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical fractionation, co-IP, electrophysiology, EM, behavior, genetic epistasis with Vangl2)","pmids":["28057866"],"is_preprint":false},{"year":2017,"finding":"Celsr3 in DRG neurons is dispensable for the initial patterning of central DRG axon projections into the spinal cord but is required for fine-mapping of sensory fiber termination: conditional inactivation (Wnt1-Cre) leads to decreased CGRP-positive fiber density in lamina I and increased Parvalbumin-positive fiber invasion of the gray matter, resulting in reduced pain sensitivity and increased mechanical sensitivity.","method":"Conditional KO (Wnt1-Cre); DiI tracing; immunofluorescence; behavioral pain/mechanosensory tests","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined anatomical and behavioral phenotypes, single lab","pmids":["28754314"],"is_preprint":false},{"year":2021,"finding":"Celsr3 physically interacts with Kif2a (a microtubule-depolymerizing kinesin) and directs the tangential migration of neuroblasts from the SVZ to the olfactory bulb by orienting their leading process. Celsr3-deficient neuroblasts show aberrant leading process branching and decreased microtubule growth rate. Conditional inactivation of Kif2a in the forebrain recapitulates the Celsr3 KO migration phenotype, placing Celsr3 upstream of Kif2a-mediated MT dynamics.","method":"Conditional KO (forebrain-specific); co-immunoprecipitation (Celsr3–Kif2a interaction); live imaging of neuroblast migration; microtubule dynamics analysis; Kif2a conditional KO epistasis","journal":"Progress in neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP identifying binding partner, conditional KO epistasis with Kif2a, live imaging of cytoskeletal phenotype, multiple orthogonal methods","pmids":["34582949"],"is_preprint":false},{"year":2021,"finding":"Celsr3 is required for Purkinje cell maturation and postsynaptic plasticity in the cerebellum. Conditional KO in postnatal Purkinje cells causes atrophic dendrites, decreased synapse number, reduced mEPSC frequency, and defective LTP and LTD. LTP requires Wnt5a/cAMP signaling through Celsr3 and Fzd3; LTD requires mGluR1/PKCα signaling and is associated with downregulated mGluR1 expression in Celsr3 cKO.","method":"Conditional KO in Purkinje cells; whole-cell electrophysiology; Wnt5a perfusion; cAMP agonist/antagonist pharmacology; mGluR1 agonist application; immunofluorescence","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with electrophysiological and pharmacological dissection of LTP/LTD pathways, single lab","pmids":["34308297"],"is_preprint":false},{"year":2022,"finding":"Conditional inactivation of Celsr3 in the brainstem (En1-Cre) causes 83% reduction of rubrospinal axons and 30% decrease of corticospinal axons, increased branching of dopaminergic fibers in the ventral horn, and decreased spinal motoneurons and neuromuscular junctions, establishing a cell-non-autonomous role for Celsr3 in brainstem–spinal axon tract development.","method":"Conditional KO (En1-Cre); axonal tracing; transsynaptic tracing; EMG; calcium imaging; motor behavioral assays","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple anatomical and functional readouts, single lab","pmids":["35678978"],"is_preprint":false},{"year":2024,"finding":"In zebrafish, Celsr3 (but not Celsr2) is specifically required for axon guidance of Mauthner cells and spiral fiber neurons in the acoustic startle hindbrain circuit; Celsr3 loss disrupts Mauthner axon growth and symmetric spiral fiber innervation. Celsr3 acts via its binding partner Fzd3a. This contrasts with facial branchiomotor neuron migration which requires Celsr2 but not Celsr3, establishing distinct roles for individual PCP cadherins in different neuron populations.","method":"Zebrafish mutant analysis; genetic epistasis (Celsr2, Celsr3, Fzd3a loss-of-function); axon imaging; behavioral acoustic startle assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple loss-of-function mutants with defined circuit phenotypes and behavioral readouts, genetic epistasis, single lab","pmids":["39432544"],"is_preprint":false},{"year":2025,"finding":"Celsr3 deficiency in mice causes upregulation of Drd3 (dopamine D3 receptor) in striosomal D1-positive neurons with altered D3 receptor distribution (lower presynaptic, higher postsynaptic). Pharmacological activation or blockade of D3 receptors respectively amplifies or diminishes tic-like behaviors in Celsr3-deficient mice, placing D3 receptor dysregulation downstream of Celsr3 loss in a striatal circuit mediating tics. Spatial transcriptomics also reveals widespread extracellular matrix abnormalities in Celsr3 mutant striatum.","method":"Constitutive Celsr3 mutant mice; single-nucleus transcriptomics; spatial transcriptomics; in situ hybridization; immunofluorescence; pharmacological D3 receptor manipulation; behavioral assays","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple transcriptomic and imaging methods plus pharmacological rescue establishing D3 pathway placement, single lab","pmids":["40155412"],"is_preprint":false},{"year":2025,"finding":"A human Tourette disorder-associated missense variant R774H (in the fifth cadherin repeat of CELSR3) introduced into mice causes altered cortical pyramidal neuron dendritic patterning and spine distribution, mild cholinergic interneuron hyperexcitability in the sensorimotor striatum, and sensorimotor gating deficits, without gross forebrain developmental anomalies, demonstrating that a single amino acid substitution in the cadherin domain is sufficient to perturb cortico-striatal circuit function.","method":"Knock-in mouse model (R774H); 3D morphometric dendritic analysis; patch-clamp electrophysiology; behavioral assays (prepulse inhibition)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific point mutation knock-in with electrophysiological and morphological phenotypes, single lab","pmids":["41226347"],"is_preprint":false}],"current_model":"CELSR3 is a seven-pass atypical cadherin and core planar cell polarity (PCP) component that functions as both a cell-autonomous receptor in growing axons and a non-cell-autonomous signal in guidepost cells to direct axonal tract formation throughout the CNS and PNS; it physically interacts with Fzd3 (co-receptor), ephrinA2/A5, Ret/GFRα1, and Kif2a to regulate cytoskeletal dynamics, acts independently of Vangl1/2 in axon guidance contexts, promotes glutamatergic synapse formation in opposition to Vangl2, controls ependymal ciliogenesis and interneuron migration, tunes progenitor fate via a Wnt7-Jag1-Notch feedback loop, and in striatal circuits its loss dysregulates D3 dopamine receptor distribution, collectively linking PCP signaling to diverse neurodevelopmental processes."},"narrative":{"mechanistic_narrative":"CELSR3 is a seven-pass atypical cadherin and core component of a planar-cell-polarity-like (PCP) genetic pathway that directs the formation of major axonal tracts throughout the CNS and PNS [PMID:15778712]. It operates through two complementary modes: cell-autonomously within projecting neurons and non-cell-autonomously in guidepost and pioneer cells that channel growing axons through choke points such as the internal capsule and the diencephalon-telencephalon junction [PMID:18487195, PMID:19349379, PMID:27170656]. CELSR3 acts in the same pathway as its co-receptor Fzd3 and redundantly with Celsr2, but independently of Vangl1/2, distinguishing this axon-guidance circuitry from classical epithelial PCP [PMID:25002511]. Mechanistically, CELSR3 physically associates with Fzd3, ephrinA2/ephrinA5, Ret and GFRα1 to confer responsiveness to attractive EphA-ephrinA reverse signaling during motor axon pathfinding [PMID:25108913], and it binds the microtubule-depolymerizing kinesin Kif2a to orient the leading process and tune microtubule dynamics during tangential neuroblast migration [PMID:34582949]. Beyond wiring, CELSR3 controls ependymal ciliogenesis and planar cilia organization together with Celsr2 [PMID:20473291], regulates interneuron migration [PMID:19332558], and promotes glutamatergic (but not inhibitory) synapse formation via Wnt5a-modulated signaling in opposition to Vangl2, shaping synaptic plasticity and learning [PMID:28057866, PMID:34308297]. A human Tourette-disorder-associated R774H missense variant in the fifth cadherin repeat perturbs cortico-striatal circuit function, and Celsr3 loss dysregulates D3 dopamine receptor distribution in striatal neurons to drive tic-like behaviors, linking CELSR3 to neurodevelopmental disease [PMID:40155412, PMID:41226347].","teleology":[{"year":2005,"claim":"Established that CELSR3 is a required core component of an axonal blueprint pathway, answering whether the mammalian flamingo/starry night ortholog controls CNS tract formation.","evidence":"Constitutive knockout in mice with tract tracing and co-expression analysis showing selective major tract anomalies phenocopying Fzd3 loss","pmids":["15778712"],"confidence":"High","gaps":["Does not resolve cell-autonomous vs. non-autonomous site of action","Molecular signaling partners not identified"]},{"year":2008,"claim":"Resolved that CELSR3 acts both within projecting neurons and within guidepost cells, defining heterotypic axon-guidepost interactions as the operative mechanism.","evidence":"Region-specific Cre/lox conditional knockout in forebrain compartments with DiI tracing","pmids":["18487195"],"confidence":"High","gaps":["Molecular nature of the guidepost-axon interaction unresolved","Downstream cytoskeletal effectors not identified"]},{"year":2009,"claim":"Extended the dual-mode model to corticospinal projection and confirmed CELSR3 roles in interneuron migration, broadening its developmental scope.","evidence":"Conditional KO with orthogonal Cre drivers plus constitutive KO with immunohistochemistry and NRG1/ErbB4 expression analysis","pmids":["19349379","19332558"],"confidence":"High","gaps":["Mechanistic link between CELSR3 and NRG1/ErbB4 correlative only","Direct molecular partners still unknown"]},{"year":2010,"claim":"Showed CELSR3 functions with Celsr2 in ependymal ciliogenesis and planar cilia organization, demonstrating roles beyond axon guidance and connection to PCP protein membrane asymmetry.","evidence":"Single and double Celsr2/Celsr3 knockout mice with PCP protein immunofluorescence (Vangl2, Fzd3) and cilia analysis","pmids":["20473291"],"confidence":"High","gaps":["Mechanism by which CELSR3 controls Vangl2/Fzd3 membrane distribution not defined","Relationship between ciliary and axonal functions unclear"]},{"year":2014,"claim":"Identified the physical interactome and signaling logic of CELSR3 in motor axon guidance, answering how CELSR3 confers selective responsiveness to guidance cues.","evidence":"Motor-neuron-specific conditional KO, retrograde tracing, co-IP identifying ephrinA2/A5, Ret, GFRα1, Fzd3, and genetic epistasis with Fzd3/Vangl2","pmids":["25108913"],"confidence":"High","gaps":["Direct binding interfaces and stoichiometry not resolved","How reverse signaling is transduced intracellularly unknown"]},{"year":2014,"claim":"Demonstrated that Celsr2/3-Fzd3 axon guidance is Vangl-independent, establishing this pathway as mechanistically distinct from classical epithelial PCP.","evidence":"Conditional Celsr2/Celsr3 double KO across forebrain compartments with epistasis against Vangl1/2 double KO and axon tracing","pmids":["25002511"],"confidence":"High","gaps":["The intracellular effectors substituting for Vangl in axons not identified","Redundancy boundaries between Celsr2 and Celsr3 incompletely mapped"]},{"year":2016,"claim":"Defined a pioneer-scaffold and a progenitor-feedback mechanism, showing CELSR3 organizes early axon scaffolds and relays Wnt7-Jag1-Notch signaling to time progenitor fate.","evidence":"Cell-type-specific conditional KO (Isl1-Cre pioneers; neuron vs. progenitor) with tracing and Jag1/Notch pathway readouts","pmids":["27170656","26939553"],"confidence":"High","gaps":["How CELSR3 couples to Jag1 upregulation molecularly unknown","Whether pioneer-scaffold and feedback roles share effectors unresolved"]},{"year":2017,"claim":"Established CELSR3 as a synaptic regulator promoting glutamatergic synapse formation in opposition to Vangl2, and refined its role in sensory fiber fine-mapping.","evidence":"Synaptosome fractionation, co-IP, conditional KO, mEPSC/EM/behavior for synapses; Wnt1-Cre conditional KO with tracing and sensory behavior for DRG fibers","pmids":["28057866","28754314"],"confidence":"High","gaps":["Synaptic co-IP partners not validated as direct","Mechanism of Wnt5a inhibition of CELSR3 synaptogenesis undefined"]},{"year":2021,"claim":"Linked CELSR3 to cytoskeletal control via Kif2a and to cerebellar synaptic plasticity, providing a molecular effector for migration and connecting CELSR3 to LTP/LTD signaling.","evidence":"Conditional KO with Celsr3-Kif2a co-IP, live imaging of microtubule dynamics, Kif2a epistasis; Purkinje-cell cKO with electrophysiology and Wnt5a/cAMP and mGluR1/PKC pharmacology","pmids":["34582949","34308297"],"confidence":"High","gaps":["How CELSR3 regulates Kif2a activity biochemically unknown","Direct vs. indirect control of mGluR1 expression unresolved"]},{"year":2022,"claim":"Demonstrated a cell-non-autonomous CELSR3 requirement for brainstem-spinal tract development including rubrospinal and corticospinal pathways and motoneuron/NMJ integrity.","evidence":"En1-Cre conditional KO with axonal/transsynaptic tracing, EMG, calcium imaging, and motor behavior","pmids":["35678978"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","Identity of the non-autonomous cellular source not pinpointed"]},{"year":2024,"claim":"Showed CELSR3-specific, Celsr2-independent requirement in a defined zebrafish startle circuit acting through Fzd3a, establishing paralog-specific roles across neuron populations.","evidence":"Zebrafish loss-of-function mutants with genetic epistasis (Celsr2/Celsr3/Fzd3a), axon imaging, and acoustic startle behavior","pmids":["39432544"],"confidence":"Medium","gaps":["Single-lab finding","Molecular basis of paralog selectivity not defined"]},{"year":2025,"claim":"Connected CELSR3 to human Tourette disorder mechanistically, showing a cadherin-domain point mutation perturbs cortico-striatal circuits and that CELSR3 loss dysregulates D3 dopamine receptor signaling driving tic-like behavior.","evidence":"R774H knock-in mouse with morphometry and patch-clamp; constitutive mutant with single-nucleus/spatial transcriptomics and pharmacological D3 receptor manipulation","pmids":["41226347","40155412"],"confidence":"Medium","gaps":["Single-lab findings","How CELSR3 loss leads to Drd3 upregulation mechanistically unknown","Extracellular matrix abnormalities not mechanistically linked"]},{"year":null,"claim":"How CELSR3's extracellular cadherin/seven-pass receptor architecture transduces guidance and synaptic signals intracellularly, and what effectors substitute for Vangl in the axonal pathway, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CELSR3 signaling complexes","Intracellular signal transduction cascade downstream of CELSR3 undefined","Direct biochemical mechanism of partner regulation (Kif2a, Fzd3) unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,6,10]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10,13]}],"complexes":[],"partners":["FZD3","EFNA2","EFNA5","RET","GFRA1","KIF2A","VANGL2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NYQ7","full_name":"Cadherin EGF LAG seven-pass G-type receptor 3","aliases":["Cadherin family member 11","Epidermal growth factor-like protein 1","EGF-like protein 1","Flamingo homolog 1","hFmi1","Multiple epidermal growth factor-like domains protein 2","Multiple EGF-like domains protein 2"],"length_aa":3312,"mass_kda":358.2,"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/Q9NYQ7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CELSR3","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CELSR3","total_profiled":1310},"omim":[{"mim_id":"618501","title":"CEREBELLAR ATROPHY WITH SEIZURES AND VARIABLE DEVELOPMENTAL DELAY; CASVDD","url":"https://www.omim.org/entry/618501"},{"mim_id":"607082","title":"CALCIUM CHANNEL, VOLTAGE-DEPENDENT, ALPHA-2/DELTA SUBUNIT 2; CACNA2D2","url":"https://www.omim.org/entry/607082"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":15.4},{"tissue":"pituitary gland","ntpm":6.8}],"url":"https://www.proteinatlas.org/search/CELSR3"},"hgnc":{"alias_symbol":["MEGF2","HFMI1","FMI1","CDHF11","ADGRC3"],"prev_symbol":["EGFL1"]},"alphafold":{"accession":"Q9NYQ7","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYQ7","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CELSR3","jax_strain_url":"https://www.jax.org/strain/search?query=CELSR3"},"sequence":{"accession":"Q9NYQ7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NYQ7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NYQ7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYQ7"}},"corpus_meta":[{"pmid":"20473291","id":"PMC_20473291","title":"Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus.","date":"2010","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20473291","citation_count":279,"is_preprint":false},{"pmid":"15778712","id":"PMC_15778712","title":"Protocadherin Celsr3 is crucial in axonal tract development.","date":"2005","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15778712","citation_count":208,"is_preprint":false},{"pmid":"18487195","id":"PMC_18487195","title":"Early forebrain wiring: genetic dissection using conditional Celsr3 mutant mice.","date":"2008","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18487195","citation_count":147,"is_preprint":false},{"pmid":"20876647","id":"PMC_20876647","title":"The Flamingo ortholog FMI-1 controls pioneer-dependent navigation of follower axons in C. elegans.","date":"2010","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20876647","citation_count":77,"is_preprint":false},{"pmid":"25002511","id":"PMC_25002511","title":"Genetic evidence that Celsr3 and Celsr2, together with Fzd3, regulate forebrain wiring in a Vangl-independent manner.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25002511","citation_count":68,"is_preprint":false},{"pmid":"28057866","id":"PMC_28057866","title":"Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28057866","citation_count":61,"is_preprint":false},{"pmid":"25108913","id":"PMC_25108913","title":"Celsr3 is required in motor neurons to steer their axons in the hindlimb.","date":"2014","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25108913","citation_count":58,"is_preprint":false},{"pmid":"22442082","id":"PMC_22442082","title":"Caenorhabditis elegans flamingo cadherin fmi-1 regulates GABAergic neuronal development.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22442082","citation_count":43,"is_preprint":false},{"pmid":"19332558","id":"PMC_19332558","title":"The protocadherin gene Celsr3 is required for interneuron migration in the mouse forebrain.","date":"2009","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19332558","citation_count":37,"is_preprint":false},{"pmid":"26939553","id":"PMC_26939553","title":"Feedback regulation of apical progenitor fate by immature neurons through Wnt7-Celsr3-Fzd3 signalling.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26939553","citation_count":37,"is_preprint":false},{"pmid":"27170656","id":"PMC_27170656","title":"Celsr3 and Fzd3 Organize a Pioneer Neuron Scaffold to Steer Growing Thalamocortical Axons.","date":"2016","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/27170656","citation_count":33,"is_preprint":false},{"pmid":"25813877","id":"PMC_25813877","title":"Celsr3 and Fzd3 in axon guidance.","date":"2015","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25813877","citation_count":30,"is_preprint":false},{"pmid":"23035085","id":"PMC_23035085","title":"A role for atypical cadherin Celsr3 in hippocampal maturation and connectivity.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23035085","citation_count":30,"is_preprint":false},{"pmid":"21852962","id":"PMC_21852962","title":"Celsr3 is required for normal development of GABA circuits in the inner retina.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21852962","citation_count":25,"is_preprint":false},{"pmid":"19349379","id":"PMC_19349379","title":"Role of the atypical cadherin Celsr3 during development of the internal capsule.","date":"2009","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/19349379","citation_count":25,"is_preprint":false},{"pmid":"15614764","id":"PMC_15614764","title":"Expression of the Celsr/flamingo homologue, c-fmi1, in the early avian embryo indicates a conserved role in neural tube closure and additional roles in asymmetry and somitogenesis.","date":"2005","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/15614764","citation_count":23,"is_preprint":false},{"pmid":"25113559","id":"PMC_25113559","title":"Regulation of the protocadherin Celsr3 gene and its role in globus pallidus development and connectivity.","date":"2014","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25113559","citation_count":21,"is_preprint":false},{"pmid":"34951123","id":"PMC_34951123","title":"CELSR3 variants are associated with febrile seizures and epilepsy with antecedent febrile seizures.","date":"2021","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34951123","citation_count":15,"is_preprint":false},{"pmid":"26838213","id":"PMC_26838213","title":"Involvement of CELSR3 Hypermethylation in Primary Oral Squamous Cell Carcinoma.","date":"2016","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/26838213","citation_count":14,"is_preprint":false},{"pmid":"33811453","id":"PMC_33811453","title":"Systematic expression analysis of the CELSR family reveals the importance of CELSR3 in human lung adenocarcinoma.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33811453","citation_count":14,"is_preprint":false},{"pmid":"34139980","id":"PMC_34139980","title":"miR-1-3p/CELSR3 Participates in Regulating Malignant Phenotypes of Lung Adenocarcinoma Cells.","date":"2021","source":"Current gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34139980","citation_count":13,"is_preprint":false},{"pmid":"34308297","id":"PMC_34308297","title":"Celsr3 is required for Purkinje cell maturation and regulates cerebellar postsynaptic plasticity.","date":"2021","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/34308297","citation_count":12,"is_preprint":false},{"pmid":"32226501","id":"PMC_32226501","title":"Effect of CELSR3 on the Cell Cycle and Apoptosis of Hepatocellular Carcinoma Cells.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32226501","citation_count":12,"is_preprint":false},{"pmid":"32631831","id":"PMC_32631831","title":"Caenorhabditis elegans Flamingo FMI-1 controls dendrite self-avoidance through F-actin assembly.","date":"2020","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32631831","citation_count":12,"is_preprint":false},{"pmid":"34582949","id":"PMC_34582949","title":"The Celsr3-Kif2a axis directs neuronal migration in the postnatal brain.","date":"2021","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/34582949","citation_count":11,"is_preprint":false},{"pmid":"37546702","id":"PMC_37546702","title":"The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer.","date":"2023","source":"Cancer research communications","url":"https://pubmed.ncbi.nlm.nih.gov/37546702","citation_count":9,"is_preprint":false},{"pmid":"27619161","id":"PMC_27619161","title":"Deregulation of the planar cell polarity genes CELSR3 and FZD3 in Hirschsprung disease.","date":"2016","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27619161","citation_count":9,"is_preprint":false},{"pmid":"28754314","id":"PMC_28754314","title":"The role of Celsr3 in the development of central somatosensory projections from dorsal root ganglia.","date":"2017","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28754314","citation_count":8,"is_preprint":false},{"pmid":"40155412","id":"PMC_40155412","title":"Tic-related behaviors in Celsr3 mutant mice are contributed by alterations of striatal D3 dopamine receptors.","date":"2025","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/40155412","citation_count":7,"is_preprint":false},{"pmid":"38429302","id":"PMC_38429302","title":"Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies.","date":"2024","source":"NPJ genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38429302","citation_count":6,"is_preprint":false},{"pmid":"18494256","id":"PMC_18494256","title":"The atypical cadherin Celsr3 regulates the development of the axonal blueprint.","date":"2007","source":"Novartis Foundation symposium","url":"https://pubmed.ncbi.nlm.nih.gov/18494256","citation_count":5,"is_preprint":false},{"pmid":"35678978","id":"PMC_35678978","title":"Celsr3 Inactivation in the Brainstem Impairs Rubrospinal Tract Development and Mouse Behaviors in Motor Coordination and Mechanic-Induced Response.","date":"2022","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35678978","citation_count":5,"is_preprint":false},{"pmid":"39432544","id":"PMC_39432544","title":"Celsr3 drives development and connectivity of the acoustic startle hindbrain circuit.","date":"2024","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39432544","citation_count":4,"is_preprint":false},{"pmid":"38378098","id":"PMC_38378098","title":"The adhesion GPCR and PCP component flamingo (FMI-1) alters body size and regulates the composition of the extracellular matrix.","date":"2024","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/38378098","citation_count":4,"is_preprint":false},{"pmid":"25479044","id":"PMC_25479044","title":"Identification of amacrine subtypes that express the atypical cadherin celsr3.","date":"2014","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/25479044","citation_count":3,"is_preprint":false},{"pmid":"38903756","id":"PMC_38903756","title":"Rare exonic CELSR3 variants identified in Bladder Exstrophy Epispadias Complex.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38903756","citation_count":3,"is_preprint":false},{"pmid":"34582697","id":"PMC_34582697","title":"Clinical Significance and Underlying Mechanisms of CELSR3 in Metastatic Prostate Cancer Based on Immunohistochemistry, Data Mining, and In Silico Analysis.","date":"2021","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/34582697","citation_count":2,"is_preprint":false},{"pmid":"41226347","id":"PMC_41226347","title":"A Celsr3 Mutation Linked to Tourette Disorder Disrupts Cortical Dendritic Patterning and Striatal Cholinergic Interneuron Excitability.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41226347","citation_count":1,"is_preprint":false},{"pmid":"38496637","id":"PMC_38496637","title":"Celsr3 drives development and connectivity of the acoustic startle hindbrain circuit.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38496637","citation_count":0,"is_preprint":false},{"pmid":"35281854","id":"PMC_35281854","title":"Erratum: Effect of CELSR3 on the Cell Cycle and Apoptosis of Hepatocellular Carcinoma Cells: Erratum.","date":"2022","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35281854","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19970,"output_tokens":5083,"usd":0.068077,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13367,"output_tokens":4190,"usd":0.085792,"stage2_stop_reason":"end_turn"},"total_usd":0.153869,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Celsr3 (ortholog of Drosophila flamingo/starry night) is required for development of major axonal fascicles in the mammalian CNS. Mice with Celsr3 inactivation show selective, marked anomalies of several major axonal tracts (anterior commissure, internal capsule, and longitudinal brainstem/spinal cord bundles), phenocopying Fzd3 inactivation, establishing Celsr3 as a core component of a PCP-like genetic pathway controlling axonal blueprint formation.\",\n      \"method\": \"Constitutive gene knockout in mice; in situ hybridization for co-expression; tract tracing\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined axonal phenotype, genetic epistasis with Fzd3, replicated and extended by multiple subsequent studies\",\n      \"pmids\": [\"15778712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Conditional inactivation of Celsr3 in telencephalon, ventral forebrain, or cortex demonstrated that Celsr3 functions both cell-autonomously in neurons projecting axons and non-cell-autonomously in guidepost cells that channel growing axons through the internal capsule, establishing heterotypic axon–guidepost cell interactions as a key mechanism.\",\n      \"method\": \"Conditional (Cre/lox) Celsr3 knockout in specific forebrain regions; axonal tract tracing (DiI)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — regionally restricted conditional KO with multiple Cre lines, clear dissection of cell-autonomous vs. non-autonomous roles, replicated phenotype\",\n      \"pmids\": [\"18487195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Celsr3 is required for tangential and radial interneuron migration in the developing mouse forebrain. In Celsr3 knockout mice, calretinin-positive interneurons accumulate at the corticostriatal boundary and are reduced in the neocortex, while calbindin-positive cell lamination is altered; NRG1 and ErbB4 expression patterns are changed in Celsr3 mutants, implicating this pathway.\",\n      \"method\": \"Constitutive KO with GFP knock-in reporter; immunohistochemistry; expression analysis of NRG1/ErbB4\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype and pathway gene expression changes, single lab\",\n      \"pmids\": [\"19332558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Celsr3 acts both in cortical projection neurons (cell-autonomous role in corticospinal axon growth) and in guidepost cells of the ventral forebrain (non-cell-autonomous role guiding axons through the internal capsule), as demonstrated by region-specific conditional inactivation.\",\n      \"method\": \"Conditional Celsr3 knockout (Foxg1-Cre, Emx1-Cre, Dlx-Cre); DiI tract tracing\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional alleles with orthogonal Cre drivers dissecting cell-autonomous and non-autonomous roles\",\n      \"pmids\": [\"19349379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Celsr2 and Celsr3 together control ependymal ciliogenesis and planar organization of cilia. Double mutant ependyma shows markedly impaired ciliogenesis leading to lethal hydrocephalus. Celsr2 single mutants show defective planar organization of cilia and disturbed membrane distribution of Vangl2 and Fzd3; double mutants show even greater disruption of Vangl2/Fzd3 membrane asymmetry.\",\n      \"method\": \"Celsr2/Celsr3 single and double knockout mice; immunofluorescence for PCP proteins (Vangl2, Fzd3); cilia analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic double mutant epistasis with defined cellular phenotype (ciliogenesis defect), membrane localization of PCP components analyzed\",\n      \"pmids\": [\"20473291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Celsr3 is required for hippocampal connectivity and pyramidal cell maturation. Conditional inactivation in the telencephalon (Foxg1-Cre) disrupts afferent and efferent hippocampal pathways and intrinsic connections, causes atrophic CA1 dendritic trees, decreased synapse density, altered LTP, and increased symmetric vs. asymmetric synapses; interneuron migration to hippocampus is preserved.\",\n      \"method\": \"Conditional KO (Celsr3|Foxg1 and Celsr3|Dlx); DiI tracing; electrophysiology (LTP); synapse electron microscopy; behavioral tests\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two conditional KO lines with multiple orthogonal readouts (tract tracing, EM, electrophysiology, behavior)\",\n      \"pmids\": [\"23035085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Celsr3 in motor neurons mediates pathfinding of peroneal nerve axons in the hindlimb by enabling sensitivity to attractive EphA-ephrinA reverse signaling. Celsr3-deficient motor axons respond normally to repulsive ephrinA-EphA forward signaling and GDNF but are insensitive to attractive EphA-ephrinA reverse signaling. By co-immunoprecipitation, Celsr3 physically interacts with ephrinA2, ephrinA5, Ret, GFRα1, and Frizzled3.\",\n      \"method\": \"Conditional KO (motor neuron-specific); retrograde axon tracing; co-immunoprecipitation in transfected cells; epistasis with Fzd3 and Vangl2 mutants\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with mechanistic dissection, co-IP identifying interactors, genetic epistasis with Fzd3 and Vangl2, multiple orthogonal methods\",\n      \"pmids\": [\"25108913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Celsr2 acts redundantly with Celsr3 in forebrain axon guidance; combined Celsr2/Celsr3 inactivation mimics Fzd3 inactivation, placing all three in the same cellular pathway. Forebrain axon wiring is normal in Vangl1/Vangl2-deficient mice, demonstrating that Celsr2/3-Fzd3-dependent axon guidance is Vangl independent—mechanistically distinct from classical epithelial PCP.\",\n      \"method\": \"Conditional double KO (Celsr2/Celsr3) in multiple forebrain compartments; genetic epistasis with Vangl1/2 double KO; axon tracing\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional alleles, genetic epistasis with Fzd3 and Vangl1/2, replication across compartments\",\n      \"pmids\": [\"25002511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Celsr3 and Fzd3 in Isl1-positive pioneer neurons are required to form a scaffold of early axonal projections crossing the diencephalon-telencephalon junction (DTJ). When Celsr3 or Fzd3 is inactivated in Isl1-expressing cells, pioneer projections fail to cross the DTJ, and later-growing thalamic and cortical axons cannot traverse this junction, demonstrating that Celsr3 organizes guidepost scaffold formation for thalamocortical connectivity.\",\n      \"method\": \"Conditional KO in Isl1-Cre cells; axon tracing (DiI); developmental time-course analysis\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type specific conditional KO identifying pioneer scaffold mechanism, developmental tracing at multiple time points\",\n      \"pmids\": [\"27170656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Celsr3 and Fzd3 in immature cortical neurons (not progenitors) are required for neurons to respond to Wnt7 and upregulate Jag1, which activates Notch signaling in neural progenitor cells, thereby providing feedback that controls the timing of progenitor fate decisions (neurogenesis-to-gliogenesis transition).\",\n      \"method\": \"Conditional KO of Celsr3 and Fzd3 in neurons vs. progenitors; Notch pathway readouts; Jag1 expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO dissecting cell-type specificity, Wnt7-Jag1-Notch pathway placement, single lab\",\n      \"pmids\": [\"26939553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Celsr3 and Vangl2 are localized at developing glutamatergic synapses (demonstrated by synaptosome fractionation and immunostaining) and co-immunoprecipitate with key synaptic proteins. Conditional KO of Celsr3 in hippocampus postnatally causes ~50% loss of glutamatergic synapses (but not inhibitory synapses) in vivo, impairs LTP-associated spatial learning and fear conditioning. Wnt5a inhibits Celsr3-mediated glutamatergic synapse formation. Conditional KO of Vangl2 has the opposite effect (increased synapse density), establishing opposing roles for Celsr3 and Vangl2 in synaptogenesis.\",\n      \"method\": \"Synaptosome fractionation; immunostaining; co-immunoprecipitation; conditional KO; mEPSC recording; electron microscopy; behavioral assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical fractionation, co-IP, electrophysiology, EM, behavior, genetic epistasis with Vangl2)\",\n      \"pmids\": [\"28057866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Celsr3 in DRG neurons is dispensable for the initial patterning of central DRG axon projections into the spinal cord but is required for fine-mapping of sensory fiber termination: conditional inactivation (Wnt1-Cre) leads to decreased CGRP-positive fiber density in lamina I and increased Parvalbumin-positive fiber invasion of the gray matter, resulting in reduced pain sensitivity and increased mechanical sensitivity.\",\n      \"method\": \"Conditional KO (Wnt1-Cre); DiI tracing; immunofluorescence; behavioral pain/mechanosensory tests\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined anatomical and behavioral phenotypes, single lab\",\n      \"pmids\": [\"28754314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Celsr3 physically interacts with Kif2a (a microtubule-depolymerizing kinesin) and directs the tangential migration of neuroblasts from the SVZ to the olfactory bulb by orienting their leading process. Celsr3-deficient neuroblasts show aberrant leading process branching and decreased microtubule growth rate. Conditional inactivation of Kif2a in the forebrain recapitulates the Celsr3 KO migration phenotype, placing Celsr3 upstream of Kif2a-mediated MT dynamics.\",\n      \"method\": \"Conditional KO (forebrain-specific); co-immunoprecipitation (Celsr3–Kif2a interaction); live imaging of neuroblast migration; microtubule dynamics analysis; Kif2a conditional KO epistasis\",\n      \"journal\": \"Progress in neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP identifying binding partner, conditional KO epistasis with Kif2a, live imaging of cytoskeletal phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"34582949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Celsr3 is required for Purkinje cell maturation and postsynaptic plasticity in the cerebellum. Conditional KO in postnatal Purkinje cells causes atrophic dendrites, decreased synapse number, reduced mEPSC frequency, and defective LTP and LTD. LTP requires Wnt5a/cAMP signaling through Celsr3 and Fzd3; LTD requires mGluR1/PKCα signaling and is associated with downregulated mGluR1 expression in Celsr3 cKO.\",\n      \"method\": \"Conditional KO in Purkinje cells; whole-cell electrophysiology; Wnt5a perfusion; cAMP agonist/antagonist pharmacology; mGluR1 agonist application; immunofluorescence\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with electrophysiological and pharmacological dissection of LTP/LTD pathways, single lab\",\n      \"pmids\": [\"34308297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Conditional inactivation of Celsr3 in the brainstem (En1-Cre) causes 83% reduction of rubrospinal axons and 30% decrease of corticospinal axons, increased branching of dopaminergic fibers in the ventral horn, and decreased spinal motoneurons and neuromuscular junctions, establishing a cell-non-autonomous role for Celsr3 in brainstem–spinal axon tract development.\",\n      \"method\": \"Conditional KO (En1-Cre); axonal tracing; transsynaptic tracing; EMG; calcium imaging; motor behavioral assays\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple anatomical and functional readouts, single lab\",\n      \"pmids\": [\"35678978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In zebrafish, Celsr3 (but not Celsr2) is specifically required for axon guidance of Mauthner cells and spiral fiber neurons in the acoustic startle hindbrain circuit; Celsr3 loss disrupts Mauthner axon growth and symmetric spiral fiber innervation. Celsr3 acts via its binding partner Fzd3a. This contrasts with facial branchiomotor neuron migration which requires Celsr2 but not Celsr3, establishing distinct roles for individual PCP cadherins in different neuron populations.\",\n      \"method\": \"Zebrafish mutant analysis; genetic epistasis (Celsr2, Celsr3, Fzd3a loss-of-function); axon imaging; behavioral acoustic startle assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple loss-of-function mutants with defined circuit phenotypes and behavioral readouts, genetic epistasis, single lab\",\n      \"pmids\": [\"39432544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Celsr3 deficiency in mice causes upregulation of Drd3 (dopamine D3 receptor) in striosomal D1-positive neurons with altered D3 receptor distribution (lower presynaptic, higher postsynaptic). Pharmacological activation or blockade of D3 receptors respectively amplifies or diminishes tic-like behaviors in Celsr3-deficient mice, placing D3 receptor dysregulation downstream of Celsr3 loss in a striatal circuit mediating tics. Spatial transcriptomics also reveals widespread extracellular matrix abnormalities in Celsr3 mutant striatum.\",\n      \"method\": \"Constitutive Celsr3 mutant mice; single-nucleus transcriptomics; spatial transcriptomics; in situ hybridization; immunofluorescence; pharmacological D3 receptor manipulation; behavioral assays\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple transcriptomic and imaging methods plus pharmacological rescue establishing D3 pathway placement, single lab\",\n      \"pmids\": [\"40155412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A human Tourette disorder-associated missense variant R774H (in the fifth cadherin repeat of CELSR3) introduced into mice causes altered cortical pyramidal neuron dendritic patterning and spine distribution, mild cholinergic interneuron hyperexcitability in the sensorimotor striatum, and sensorimotor gating deficits, without gross forebrain developmental anomalies, demonstrating that a single amino acid substitution in the cadherin domain is sufficient to perturb cortico-striatal circuit function.\",\n      \"method\": \"Knock-in mouse model (R774H); 3D morphometric dendritic analysis; patch-clamp electrophysiology; behavioral assays (prepulse inhibition)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific point mutation knock-in with electrophysiological and morphological phenotypes, single lab\",\n      \"pmids\": [\"41226347\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CELSR3 is a seven-pass atypical cadherin and core planar cell polarity (PCP) component that functions as both a cell-autonomous receptor in growing axons and a non-cell-autonomous signal in guidepost cells to direct axonal tract formation throughout the CNS and PNS; it physically interacts with Fzd3 (co-receptor), ephrinA2/A5, Ret/GFRα1, and Kif2a to regulate cytoskeletal dynamics, acts independently of Vangl1/2 in axon guidance contexts, promotes glutamatergic synapse formation in opposition to Vangl2, controls ependymal ciliogenesis and interneuron migration, tunes progenitor fate via a Wnt7-Jag1-Notch feedback loop, and in striatal circuits its loss dysregulates D3 dopamine receptor distribution, collectively linking PCP signaling to diverse neurodevelopmental processes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CELSR3 is a seven-pass atypical cadherin and core component of a planar-cell-polarity-like (PCP) genetic pathway that directs the formation of major axonal tracts throughout the CNS and PNS [#0]. It operates through two complementary modes: cell-autonomously within projecting neurons and non-cell-autonomously in guidepost and pioneer cells that channel growing axons through choke points such as the internal capsule and the diencephalon-telencephalon junction [#1, #3, #8]. CELSR3 acts in the same pathway as its co-receptor Fzd3 and redundantly with Celsr2, but independently of Vangl1/2, distinguishing this axon-guidance circuitry from classical epithelial PCP [#7]. Mechanistically, CELSR3 physically associates with Fzd3, ephrinA2/ephrinA5, Ret and GFR\\u03b11 to confer responsiveness to attractive EphA-ephrinA reverse signaling during motor axon pathfinding [#6], and it binds the microtubule-depolymerizing kinesin Kif2a to orient the leading process and tune microtubule dynamics during tangential neuroblast migration [#12]. Beyond wiring, CELSR3 controls ependymal ciliogenesis and planar cilia organization together with Celsr2 [#4], regulates interneuron migration [#2], and promotes glutamatergic (but not inhibitory) synapse formation via Wnt5a-modulated signaling in opposition to Vangl2, shaping synaptic plasticity and learning [#10, #13]. A human Tourette-disorder-associated R774H missense variant in the fifth cadherin repeat perturbs cortico-striatal circuit function, and Celsr3 loss dysregulates D3 dopamine receptor distribution in striatal neurons to drive tic-like behaviors, linking CELSR3 to neurodevelopmental disease [#16, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that CELSR3 is a required core component of an axonal blueprint pathway, answering whether the mammalian flamingo/starry night ortholog controls CNS tract formation.\",\n      \"evidence\": \"Constitutive knockout in mice with tract tracing and co-expression analysis showing selective major tract anomalies phenocopying Fzd3 loss\",\n      \"pmids\": [\"15778712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve cell-autonomous vs. non-autonomous site of action\", \"Molecular signaling partners not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved that CELSR3 acts both within projecting neurons and within guidepost cells, defining heterotypic axon-guidepost interactions as the operative mechanism.\",\n      \"evidence\": \"Region-specific Cre/lox conditional knockout in forebrain compartments with DiI tracing\",\n      \"pmids\": [\"18487195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the guidepost-axon interaction unresolved\", \"Downstream cytoskeletal effectors not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the dual-mode model to corticospinal projection and confirmed CELSR3 roles in interneuron migration, broadening its developmental scope.\",\n      \"evidence\": \"Conditional KO with orthogonal Cre drivers plus constitutive KO with immunohistochemistry and NRG1/ErbB4 expression analysis\",\n      \"pmids\": [\"19349379\", \"19332558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between CELSR3 and NRG1/ErbB4 correlative only\", \"Direct molecular partners still unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed CELSR3 functions with Celsr2 in ependymal ciliogenesis and planar cilia organization, demonstrating roles beyond axon guidance and connection to PCP protein membrane asymmetry.\",\n      \"evidence\": \"Single and double Celsr2/Celsr3 knockout mice with PCP protein immunofluorescence (Vangl2, Fzd3) and cilia analysis\",\n      \"pmids\": [\"20473291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CELSR3 controls Vangl2/Fzd3 membrane distribution not defined\", \"Relationship between ciliary and axonal functions unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified the physical interactome and signaling logic of CELSR3 in motor axon guidance, answering how CELSR3 confers selective responsiveness to guidance cues.\",\n      \"evidence\": \"Motor-neuron-specific conditional KO, retrograde tracing, co-IP identifying ephrinA2/A5, Ret, GFR\\u03b11, Fzd3, and genetic epistasis with Fzd3/Vangl2\",\n      \"pmids\": [\"25108913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interfaces and stoichiometry not resolved\", \"How reverse signaling is transduced intracellularly unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that Celsr2/3-Fzd3 axon guidance is Vangl-independent, establishing this pathway as mechanistically distinct from classical epithelial PCP.\",\n      \"evidence\": \"Conditional Celsr2/Celsr3 double KO across forebrain compartments with epistasis against Vangl1/2 double KO and axon tracing\",\n      \"pmids\": [\"25002511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The intracellular effectors substituting for Vangl in axons not identified\", \"Redundancy boundaries between Celsr2 and Celsr3 incompletely mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a pioneer-scaffold and a progenitor-feedback mechanism, showing CELSR3 organizes early axon scaffolds and relays Wnt7-Jag1-Notch signaling to time progenitor fate.\",\n      \"evidence\": \"Cell-type-specific conditional KO (Isl1-Cre pioneers; neuron vs. progenitor) with tracing and Jag1/Notch pathway readouts\",\n      \"pmids\": [\"27170656\", \"26939553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CELSR3 couples to Jag1 upregulation molecularly unknown\", \"Whether pioneer-scaffold and feedback roles share effectors unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established CELSR3 as a synaptic regulator promoting glutamatergic synapse formation in opposition to Vangl2, and refined its role in sensory fiber fine-mapping.\",\n      \"evidence\": \"Synaptosome fractionation, co-IP, conditional KO, mEPSC/EM/behavior for synapses; Wnt1-Cre conditional KO with tracing and sensory behavior for DRG fibers\",\n      \"pmids\": [\"28057866\", \"28754314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synaptic co-IP partners not validated as direct\", \"Mechanism of Wnt5a inhibition of CELSR3 synaptogenesis undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked CELSR3 to cytoskeletal control via Kif2a and to cerebellar synaptic plasticity, providing a molecular effector for migration and connecting CELSR3 to LTP/LTD signaling.\",\n      \"evidence\": \"Conditional KO with Celsr3-Kif2a co-IP, live imaging of microtubule dynamics, Kif2a epistasis; Purkinje-cell cKO with electrophysiology and Wnt5a/cAMP and mGluR1/PKC pharmacology\",\n      \"pmids\": [\"34582949\", \"34308297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CELSR3 regulates Kif2a activity biochemically unknown\", \"Direct vs. indirect control of mGluR1 expression unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated a cell-non-autonomous CELSR3 requirement for brainstem-spinal tract development including rubrospinal and corticospinal pathways and motoneuron/NMJ integrity.\",\n      \"evidence\": \"En1-Cre conditional KO with axonal/transsynaptic tracing, EMG, calcium imaging, and motor behavior\",\n      \"pmids\": [\"35678978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent replication\", \"Identity of the non-autonomous cellular source not pinpointed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed CELSR3-specific, Celsr2-independent requirement in a defined zebrafish startle circuit acting through Fzd3a, establishing paralog-specific roles across neuron populations.\",\n      \"evidence\": \"Zebrafish loss-of-function mutants with genetic epistasis (Celsr2/Celsr3/Fzd3a), axon imaging, and acoustic startle behavior\",\n      \"pmids\": [\"39432544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Molecular basis of paralog selectivity not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected CELSR3 to human Tourette disorder mechanistically, showing a cadherin-domain point mutation perturbs cortico-striatal circuits and that CELSR3 loss dysregulates D3 dopamine receptor signaling driving tic-like behavior.\",\n      \"evidence\": \"R774H knock-in mouse with morphometry and patch-clamp; constitutive mutant with single-nucleus/spatial transcriptomics and pharmacological D3 receptor manipulation\",\n      \"pmids\": [\"41226347\", \"40155412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings\", \"How CELSR3 loss leads to Drd3 upregulation mechanistically unknown\", \"Extracellular matrix abnormalities not mechanistically linked\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CELSR3's extracellular cadherin/seven-pass receptor architecture transduces guidance and synaptic signals intracellularly, and what effectors substitute for Vangl in the axonal pathway, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CELSR3 signaling complexes\", \"Intracellular signal transduction cascade downstream of CELSR3 undefined\", \"Direct biochemical mechanism of partner regulation (Kif2a, Fzd3) unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 6, 10]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FZD3\", \"EFNA2\", \"EFNA5\", \"RET\", \"GFRA1\", \"KIF2A\", \"VANGL2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}