{"gene":"WDPCP","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2013,"finding":"WDPCP localizes to the ciliary transition zone, where it is required for recruitment of Sept2, Nphp1, and Mks1; loss of WDPCP causes these proteins to disappear from the transition zone, impairing ciliogenesis.","method":"Immunofluorescence localization in Wdpcp-deficient mouse cells; genetic loss-of-function mouse model","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments in a defined KO mouse model with multiple marker readouts, replicated across cell types","pmids":["24302887"],"is_preprint":false},{"year":2013,"finding":"WDPCP localizes to the cytoplasmic actin cytoskeleton and focal adhesions, where it interacts with Sept2 and is co-localized with Sept2 in actin filaments; in WDPCP-deficient cells, Sept2 is lost from actin filaments, actin filament organization is disrupted, and focal contacts are markedly changed.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, loss-of-function mouse model with actin/focal adhesion phenotypic readouts","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-localization and Co-IP for Sept2 interaction, multiple orthogonal cellular phenotypes in a defined KO model","pmids":["24302887"],"is_preprint":false},{"year":2013,"finding":"WDPCP deficiency causes failure to establish cell polarity, loss of membrane ruffling, and loss of directional cell migration, demonstrating that WDPCP regulates PCP by direct modulation of the actin cytoskeleton independently of cilia (Wdpcp mutant cochlea has normal kinocilia yet shows PCP defects).","method":"Loss-of-function mouse model; cell migration assays; live-cell membrane dynamics; cochlear kinocilia analysis","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotypes and cilium-independent epistasis established by cochlear analysis","pmids":["24302887"],"is_preprint":false},{"year":2014,"finding":"The PCP effector WDPCP (Fritz) is required for basolateral plasma membrane stability in epithelial tissues and controls cortical septin localization to maintain cortical rigidity in mucociliary epithelial cells; it acts via actomyosin to maintain balanced cortical tension.","method":"In vivo 3D time-lapse imaging; loss-of-function in Xenopus epithelium; septin localization assays; actomyosin inhibition experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus pharmacological actomyosin manipulation, single lab","pmids":["25436430"],"is_preprint":false},{"year":2018,"finding":"Wdpcp promotes epicardial epithelial-mesenchymal transition (EMT) and epicardium-derived cell (EPDC) migration required for coronary artery smooth muscle cell coverage; epicardium-specific deletion of Wdpcp recapitulates the coronary artery defect, placing Wdpcp in the epicardial EMT pathway upstream of EPDC migration.","method":"Conditional (epicardium-specific Cre) Wdpcp knockout mice; EMT/mesenchymal marker expression analysis; cell migration assays; histological quantification of smooth muscle cell coverage","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional KO with rescue of pleiotropic phenotype, multiple orthogonal readouts","pmids":["29487191"],"is_preprint":false},{"year":2021,"finding":"Loss of Wdpcp in skeletal progenitors abolishes hedgehog signaling responsiveness and the associated proliferative response; Wdpcp null mesenchymal progenitors show decreased osteogenic and chondrogenic differentiation in response to hedgehog stimulation, placing Wdpcp as a positive regulator of the hedgehog signaling pathway in limb development.","method":"Prx1-Cre conditional Wdpcp knockout mice; in vitro chondrogenesis and osteogenesis assays with Hh stimulation; growth plate marker analysis","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with in vitro functional assays, single lab","pmids":["34225660"],"is_preprint":false},{"year":2021,"finding":"WDPCP knockdown in human sinonasal epithelial cells impairs mitochondrial biogenesis and mitochondrial function via the MAPK/ERK pathway, contributing to cilia beating dysfunction; dexamethasone or pharmacological MAPK activation partially rescues this defect.","method":"siRNA knockdown in air-liquid interface cultures; MAPK inhibitor (U0126) treatment; mitochondrial function assays; cilia beat frequency measurement","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD plus pharmacological rescue with defined pathway readout, single lab","pmids":["33598458"],"is_preprint":false},{"year":2017,"finding":"WDPCP knockdown in primary human sinonasal epithelial cells reduces cilia quantity and length and decreases Septin7 expression, demonstrating WDPCP is required for ciliogenesis in human nasal epithelium.","method":"siRNA knockdown in air-liquid interface human sinonasal epithelial cultures; immunofluorescence for cilia and Septin7","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with morphological and molecular readouts, single lab","pmids":["28001338"],"is_preprint":false},{"year":2024,"finding":"High leucine levels suppress WDPCP expression and attenuate MAPK/ERK signaling in cardiac microvascular endothelial cells, impairing EMT and cell migration; overexpression of WDPCP or MAPK activation rescues these defects; WDPCP/MAPK signaling regulates endomucin (EMCN) overexpression induced by high leucine, which mediates the impaired EMT and migration.","method":"WDPCP overexpression and siRNA knockdown in HCMECs; MAPK activator rescue; EMCN expression analysis; high-leucine mouse model; EMT and migration assays","journal":"Pulmonary circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with pathway rescue, single lab","pmids":["39582775"],"is_preprint":false},{"year":2025,"finding":"Residues D481 and W482 (human N512/W513) in WDPCP are essential for its apical surface docking in cells; a mouse model expressing a deletion of these two residues shows loss of WDPCP apical localization, severe impairment of cilia formation and Hh signaling, and developmental defects; structure prediction places these residues at the junction of two alpha helices required for conformational stability.","method":"Genetically engineered Wdpcp-Z11 mouse (two-codon deletion); rescue experiments restoring D481/W482; subcellular localization assays; cilia formation and Hh signaling readouts; structure prediction","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structure-guided mutagenesis in a knock-in mouse model with rescue experiments and multiple functional readouts","pmids":["41268724"],"is_preprint":false}],"current_model":"WDPCP is a PCP effector protein that localizes to the ciliary transition zone (where it recruits Sept2, Nphp1, and Mks1 for ciliogenesis) and to cytoplasmic actin filaments and focal adhesions (where it recruits Sept2 to maintain actin organization, cortical tension via actomyosin, cell polarity, and directional migration); specific conserved residues (D481/W482) are required for apical docking and for sustaining Hedgehog signaling, and WDPCP additionally signals through the MAPK/ERK axis to promote EMT, mitochondrial function, and cilia beating in epithelial cells."},"narrative":{"mechanistic_narrative":"WDPCP is a planar cell polarity (PCP) effector that coordinates ciliogenesis and actin-based cell behavior by acting as a recruitment scaffold for septins [PMID:24302887]. At the ciliary transition zone it is required to assemble Sept2, Nphp1, and Mks1, and its loss removes these components and impairs cilium formation [PMID:24302887]; in human airway epithelium WDPCP similarly supports cilia number and length and Septin7 expression [PMID:28001338]. In parallel, WDPCP localizes to the cytoplasmic actin cytoskeleton and focal adhesions where it binds and co-localizes with Sept2, so that its loss disrupts actin filament organization and focal contacts, abolishes membrane ruffling, and prevents establishment of cell polarity and directional migration — a function it executes independently of cilia [PMID:24302887]. Through control of cortical septin localization it maintains basolateral membrane stability and balanced cortical tension via actomyosin [PMID:25436430]. Beyond these structural roles, WDPCP is a positive regulator of Hedgehog signaling required for the proliferative and differentiation responses of skeletal progenitors [PMID:34225660], and it drives epithelial-mesenchymal transition and migration of epicardium-derived cells needed for coronary artery smooth muscle coverage [PMID:29487191]. In epithelial and endothelial cells WDPCP signals through the MAPK/ERK axis to support mitochondrial biogenesis and cilia beating and to promote EMT and migration [PMID:33598458, PMID:39582775]. The conserved residues D481/W482 are required for apical docking and for sustaining ciliogenesis and Hedgehog signaling, defining a structural determinant of WDPCP localization and function [PMID:41268724].","teleology":[{"year":2013,"claim":"Established WDPCP's dual molecular role by showing it is a septin-recruiting scaffold both at the ciliary transition zone and on the cytoplasmic actin cytoskeleton, defining how a single PCP effector links ciliogenesis to actin organization.","evidence":"Immunofluorescence localization, Co-IP, and loss-of-function phenotyping in a Wdpcp-deficient mouse model with cochlear epistasis","pmids":["24302887"],"confidence":"High","gaps":["Mechanism by which WDPCP selects between transition-zone and actin/focal-adhesion pools not defined","Whether Sept2 binding is direct or bridged by other factors not resolved","Stoichiometry and structure of the WDPCP-septin assembly unknown"]},{"year":2014,"claim":"Extended the actin role to tissue mechanics, showing WDPCP controls cortical septin localization to maintain basolateral membrane stability and cortical tension through actomyosin.","evidence":"In vivo 3D time-lapse imaging and pharmacological actomyosin manipulation in Xenopus epithelium","pmids":["25436430"],"confidence":"Medium","gaps":["Single-lab, single-organism evidence","Direct molecular link between WDPCP and actomyosin regulators not established","Quantitative relationship between septin localization and tension not defined"]},{"year":2017,"claim":"Confirmed WDPCP's ciliogenic requirement in human cells and linked it to a specific septin, showing knockdown reduces cilia and Septin7 expression in human sinonasal epithelium.","evidence":"siRNA knockdown in air-liquid interface human sinonasal epithelial cultures with cilia and Septin7 immunofluorescence","pmids":["28001338"],"confidence":"Medium","gaps":["Whether Septin7 reduction is cause or consequence of cilia loss unresolved","Single-lab knockdown without rescue","Relationship to the Sept2 axis from mouse work not reconciled"]},{"year":2018,"claim":"Placed WDPCP in a developmental signaling pathway by showing epicardium-specific deletion blocks EMT and EPDC migration required for coronary artery smooth muscle coverage.","evidence":"Epicardium-specific conditional Wdpcp knockout mice with EMT marker, migration, and histological readouts","pmids":["29487191"],"confidence":"High","gaps":["Molecular effectors connecting WDPCP to EMT not identified in this study","Whether the EMT role depends on cilia or actin functions not separated"]},{"year":2021,"claim":"Defined WDPCP as a positive regulator of Hedgehog signaling, showing its loss in skeletal progenitors abolishes Hh responsiveness and impairs chondro-/osteogenic differentiation.","evidence":"Prx1-Cre conditional Wdpcp knockout mice with in vitro Hh-stimulated differentiation assays","pmids":["34225660"],"confidence":"Medium","gaps":["Whether the Hh defect is secondary to ciliary dysfunction not disentangled","Step in the Hh cascade affected by WDPCP unknown","Single-lab evidence"]},{"year":2021,"claim":"Identified a signaling output for WDPCP in cilia function, showing knockdown impairs mitochondrial biogenesis and cilia beating via MAPK/ERK, with pharmacological rescue.","evidence":"siRNA knockdown in air-liquid interface cultures with U0126 inhibition and MAPK activation, mitochondrial and cilia beat frequency assays","pmids":["33598458"],"confidence":"Medium","gaps":["Mechanism linking WDPCP to MAPK activation not defined","Whether mitochondrial effect is direct or downstream of ciliary defect unclear","Single-lab knockdown study"]},{"year":2024,"claim":"Connected WDPCP/MAPK signaling to a downstream effector and a metabolic input, showing high leucine suppresses WDPCP to attenuate ERK signaling and impair endothelial EMT and migration via EMCN.","evidence":"WDPCP overexpression and knockdown in HCMECs with MAPK activator rescue, EMCN analysis, and high-leucine mouse model","pmids":["39582775"],"confidence":"Medium","gaps":["Mechanism by which leucine suppresses WDPCP expression unknown","Whether EMCN is a direct WDPCP/MAPK target not established","Single-lab evidence"]},{"year":2025,"claim":"Mapped a structural determinant of WDPCP function, showing conserved residues D481/W482 are required for apical docking and that their deletion abolishes localization, ciliogenesis, and Hh signaling.","evidence":"Structure-guided two-codon-deletion knock-in mouse with rescue experiments, localization, cilia, and Hh readouts, plus structure prediction","pmids":["41268724"],"confidence":"High","gaps":["Experimental structure of WDPCP not determined","Identity of the apical docking partner recognized via D481/W482 unknown","Whether the same residues mediate the actin/septin functions not tested"]},{"year":null,"claim":"How WDPCP is partitioned between its transition-zone, cytoplasmic actin, and MAPK-signaling roles, and which direct partners couple it to Hedgehog and EMT outputs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism links the septin-scaffolding and MAPK-signaling functions","Direct molecular partner mediating apical docking unidentified","Whether Hh and EMT roles are cilium-dependent or cilium-independent not fully separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,8]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,9]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,7]}],"complexes":[],"partners":["SEPT2","NPHP1","MKS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95876","full_name":"WD repeat-containing and planar cell polarity effector protein fritz homolog","aliases":["Bardet-Biedl syndrome 15 protein","WD repeat-containing and planar cell polarity effector protein"],"length_aa":746,"mass_kda":85.1,"function":"Probable effector of the planar cell polarity signaling pathway which regulates the septin cytoskeleton in both ciliogenesis and collective cell movements. Together with FUZ and WDPCP proposed to function as core component of the CPLANE (ciliogenesis and planar polarity effectors) complex involved in the recruitment of peripheral IFT-A proteins to basal bodies (By similarity). Binds phosphatidylinositol 3-phosphate with highest affinity, followed by phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate (PubMed:35427153)","subcellular_location":"Cell membrane; Cytoplasm, cytoskeleton, cilium axoneme; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/O95876/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDPCP","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WDPCP","total_profiled":1310},"omim":[{"mim_id":"619431","title":"MEGACYSTIS-MICROCOLON-INTESTINAL HYPOPERISTALSIS SYNDROME 5; MMIHS5","url":"https://www.omim.org/entry/619431"},{"mim_id":"615992","title":"BARDET-BIEDL SYNDROME 15; BBS15","url":"https://www.omim.org/entry/615992"},{"mim_id":"613580","title":"WD REPEAT-CONTAINING PLANAR CELL POLARITY EFFECTOR; WDPCP","url":"https://www.omim.org/entry/613580"},{"mim_id":"610622","title":"FUZZY PLANAR CELL POLARITY PROTEIN; FUZ","url":"https://www.omim.org/entry/610622"},{"mim_id":"610621","title":"INTURNED PLANAR CELL POLARITY PROTEIN; INTU","url":"https://www.omim.org/entry/610621"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Flagellar centriole","reliability":"Approved"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDPCP"},"hgnc":{"alias_symbol":["hFrtz","fritz","BBS15","CPLANE5"],"prev_symbol":["C2orf86"]},"alphafold":{"accession":"O95876","domains":[{"cath_id":"2.130.10.10","chopping":"34-43_344-449_458-487","consensus_level":"medium","plddt":91.0299,"start":34,"end":487},{"cath_id":"1.25.40","chopping":"489-634","consensus_level":"medium","plddt":92.2101,"start":489,"end":634}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95876","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95876-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95876-F1-predicted_aligned_error_v6.png","plddt_mean":76.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDPCP","jax_strain_url":"https://www.jax.org/strain/search?query=WDPCP"},"sequence":{"accession":"O95876","fasta_url":"https://rest.uniprot.org/uniprotkb/O95876.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95876/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95876"}},"corpus_meta":[{"pmid":"24302887","id":"PMC_24302887","title":"Wdpcp, a PCP protein required for ciliogenesis, regulates directional cell migration and cell polarity by direct modulation of the actin cytoskeleton.","date":"2013","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/24302887","citation_count":92,"is_preprint":false},{"pmid":"25427950","id":"PMC_25427950","title":"Compound heterozygosity for a frame shift mutation and a likely pathogenic sequence variant in the planar cell polarity—ciliogenesis gene WDPCP in a girl with polysyndactyly, coarctation of the aorta, and tongue hamartomas.","date":"2014","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/25427950","citation_count":24,"is_preprint":false},{"pmid":"29487191","id":"PMC_29487191","title":"Wdpcp promotes epicardial EMT and epicardium-derived cell migration to facilitate coronary artery remodeling.","date":"2018","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/29487191","citation_count":16,"is_preprint":false},{"pmid":"25436430","id":"PMC_25436430","title":"The planar cell polarity effector protein Wdpcp (Fritz) controls epithelial cell cortex dynamics via septins and actomyosin.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25436430","citation_count":16,"is_preprint":false},{"pmid":"33598458","id":"PMC_33598458","title":"WDPCP Modulates Cilia Beating Through the MAPK/ERK Pathway in Chronic Rhinosinusitis With Nasal Polyps.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33598458","citation_count":11,"is_preprint":false},{"pmid":"28001338","id":"PMC_28001338","title":"WDPCP regulates the ciliogenesis of human sinonasal epithelial cells in chronic rhinosinusitis.","date":"2017","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/28001338","citation_count":9,"is_preprint":false},{"pmid":"37996473","id":"PMC_37996473","title":"Evidence for involvement of the alcohol consumption WDPCP gene in lipid metabolism, and liver cirrhosis.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37996473","citation_count":7,"is_preprint":false},{"pmid":"34225660","id":"PMC_34225660","title":"Wdpcp regulates cellular proliferation and differentiation in the developing limb via hedgehog signaling.","date":"2021","source":"BMC developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34225660","citation_count":7,"is_preprint":false},{"pmid":"39582775","id":"PMC_39582775","title":"High gestational leucine level dampens WDPCP/MAPK signaling to impair the EMT and migration of cardiac microvascular endothelial cells in congenital heart defects.","date":"2024","source":"Pulmonary circulation","url":"https://pubmed.ncbi.nlm.nih.gov/39582775","citation_count":2,"is_preprint":false},{"pmid":"39669798","id":"PMC_39669798","title":"A cross-tissue transcriptome-wide association study identifies WDPCP as a potential susceptibility gene for coronary atherosclerosis.","date":"2024","source":"Atherosclerosis plus","url":"https://pubmed.ncbi.nlm.nih.gov/39669798","citation_count":1,"is_preprint":false},{"pmid":"41268724","id":"PMC_41268724","title":"Identification of conserved residues essential for the ciliogenic functions of WDPCP.","date":"2025","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/41268724","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.17.24312688","title":"Causal associations between plasma proteins and prostate cancer: a Proteome-Wide Mendelian Randomization","date":"2024-09-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.17.24312688","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8276,"output_tokens":2439,"usd":0.030707,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9558,"output_tokens":3279,"usd":0.064882,"stage2_stop_reason":"end_turn"},"total_usd":0.095589,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"WDPCP localizes to the ciliary transition zone, where it is required for recruitment of Sept2, Nphp1, and Mks1; loss of WDPCP causes these proteins to disappear from the transition zone, impairing ciliogenesis.\",\n      \"method\": \"Immunofluorescence localization in Wdpcp-deficient mouse cells; genetic loss-of-function mouse model\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments in a defined KO mouse model with multiple marker readouts, replicated across cell types\",\n      \"pmids\": [\"24302887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WDPCP localizes to the cytoplasmic actin cytoskeleton and focal adhesions, where it interacts with Sept2 and is co-localized with Sept2 in actin filaments; in WDPCP-deficient cells, Sept2 is lost from actin filaments, actin filament organization is disrupted, and focal contacts are markedly changed.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, loss-of-function mouse model with actin/focal adhesion phenotypic readouts\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-localization and Co-IP for Sept2 interaction, multiple orthogonal cellular phenotypes in a defined KO model\",\n      \"pmids\": [\"24302887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WDPCP deficiency causes failure to establish cell polarity, loss of membrane ruffling, and loss of directional cell migration, demonstrating that WDPCP regulates PCP by direct modulation of the actin cytoskeleton independently of cilia (Wdpcp mutant cochlea has normal kinocilia yet shows PCP defects).\",\n      \"method\": \"Loss-of-function mouse model; cell migration assays; live-cell membrane dynamics; cochlear kinocilia analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotypes and cilium-independent epistasis established by cochlear analysis\",\n      \"pmids\": [\"24302887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The PCP effector WDPCP (Fritz) is required for basolateral plasma membrane stability in epithelial tissues and controls cortical septin localization to maintain cortical rigidity in mucociliary epithelial cells; it acts via actomyosin to maintain balanced cortical tension.\",\n      \"method\": \"In vivo 3D time-lapse imaging; loss-of-function in Xenopus epithelium; septin localization assays; actomyosin inhibition experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus pharmacological actomyosin manipulation, single lab\",\n      \"pmids\": [\"25436430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wdpcp promotes epicardial epithelial-mesenchymal transition (EMT) and epicardium-derived cell (EPDC) migration required for coronary artery smooth muscle cell coverage; epicardium-specific deletion of Wdpcp recapitulates the coronary artery defect, placing Wdpcp in the epicardial EMT pathway upstream of EPDC migration.\",\n      \"method\": \"Conditional (epicardium-specific Cre) Wdpcp knockout mice; EMT/mesenchymal marker expression analysis; cell migration assays; histological quantification of smooth muscle cell coverage\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional KO with rescue of pleiotropic phenotype, multiple orthogonal readouts\",\n      \"pmids\": [\"29487191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of Wdpcp in skeletal progenitors abolishes hedgehog signaling responsiveness and the associated proliferative response; Wdpcp null mesenchymal progenitors show decreased osteogenic and chondrogenic differentiation in response to hedgehog stimulation, placing Wdpcp as a positive regulator of the hedgehog signaling pathway in limb development.\",\n      \"method\": \"Prx1-Cre conditional Wdpcp knockout mice; in vitro chondrogenesis and osteogenesis assays with Hh stimulation; growth plate marker analysis\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with in vitro functional assays, single lab\",\n      \"pmids\": [\"34225660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDPCP knockdown in human sinonasal epithelial cells impairs mitochondrial biogenesis and mitochondrial function via the MAPK/ERK pathway, contributing to cilia beating dysfunction; dexamethasone or pharmacological MAPK activation partially rescues this defect.\",\n      \"method\": \"siRNA knockdown in air-liquid interface cultures; MAPK inhibitor (U0126) treatment; mitochondrial function assays; cilia beat frequency measurement\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD plus pharmacological rescue with defined pathway readout, single lab\",\n      \"pmids\": [\"33598458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WDPCP knockdown in primary human sinonasal epithelial cells reduces cilia quantity and length and decreases Septin7 expression, demonstrating WDPCP is required for ciliogenesis in human nasal epithelium.\",\n      \"method\": \"siRNA knockdown in air-liquid interface human sinonasal epithelial cultures; immunofluorescence for cilia and Septin7\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with morphological and molecular readouts, single lab\",\n      \"pmids\": [\"28001338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"High leucine levels suppress WDPCP expression and attenuate MAPK/ERK signaling in cardiac microvascular endothelial cells, impairing EMT and cell migration; overexpression of WDPCP or MAPK activation rescues these defects; WDPCP/MAPK signaling regulates endomucin (EMCN) overexpression induced by high leucine, which mediates the impaired EMT and migration.\",\n      \"method\": \"WDPCP overexpression and siRNA knockdown in HCMECs; MAPK activator rescue; EMCN expression analysis; high-leucine mouse model; EMT and migration assays\",\n      \"journal\": \"Pulmonary circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with pathway rescue, single lab\",\n      \"pmids\": [\"39582775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Residues D481 and W482 (human N512/W513) in WDPCP are essential for its apical surface docking in cells; a mouse model expressing a deletion of these two residues shows loss of WDPCP apical localization, severe impairment of cilia formation and Hh signaling, and developmental defects; structure prediction places these residues at the junction of two alpha helices required for conformational stability.\",\n      \"method\": \"Genetically engineered Wdpcp-Z11 mouse (two-codon deletion); rescue experiments restoring D481/W482; subcellular localization assays; cilia formation and Hh signaling readouts; structure prediction\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structure-guided mutagenesis in a knock-in mouse model with rescue experiments and multiple functional readouts\",\n      \"pmids\": [\"41268724\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDPCP is a PCP effector protein that localizes to the ciliary transition zone (where it recruits Sept2, Nphp1, and Mks1 for ciliogenesis) and to cytoplasmic actin filaments and focal adhesions (where it recruits Sept2 to maintain actin organization, cortical tension via actomyosin, cell polarity, and directional migration); specific conserved residues (D481/W482) are required for apical docking and for sustaining Hedgehog signaling, and WDPCP additionally signals through the MAPK/ERK axis to promote EMT, mitochondrial function, and cilia beating in epithelial cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDPCP is a planar cell polarity (PCP) effector that coordinates ciliogenesis and actin-based cell behavior by acting as a recruitment scaffold for septins [#0, #1]. At the ciliary transition zone it is required to assemble Sept2, Nphp1, and Mks1, and its loss removes these components and impairs cilium formation [#0]; in human airway epithelium WDPCP similarly supports cilia number and length and Septin7 expression [#7]. In parallel, WDPCP localizes to the cytoplasmic actin cytoskeleton and focal adhesions where it binds and co-localizes with Sept2, so that its loss disrupts actin filament organization and focal contacts, abolishes membrane ruffling, and prevents establishment of cell polarity and directional migration — a function it executes independently of cilia [#1, #2]. Through control of cortical septin localization it maintains basolateral membrane stability and balanced cortical tension via actomyosin [#3]. Beyond these structural roles, WDPCP is a positive regulator of Hedgehog signaling required for the proliferative and differentiation responses of skeletal progenitors [#5], and it drives epithelial-mesenchymal transition and migration of epicardium-derived cells needed for coronary artery smooth muscle coverage [#4]. In epithelial and endothelial cells WDPCP signals through the MAPK/ERK axis to support mitochondrial biogenesis and cilia beating and to promote EMT and migration [#6, #8]. The conserved residues D481/W482 are required for apical docking and for sustaining ciliogenesis and Hedgehog signaling, defining a structural determinant of WDPCP localization and function [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established WDPCP's dual molecular role by showing it is a septin-recruiting scaffold both at the ciliary transition zone and on the cytoplasmic actin cytoskeleton, defining how a single PCP effector links ciliogenesis to actin organization.\",\n      \"evidence\": \"Immunofluorescence localization, Co-IP, and loss-of-function phenotyping in a Wdpcp-deficient mouse model with cochlear epistasis\",\n      \"pmids\": [\"24302887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which WDPCP selects between transition-zone and actin/focal-adhesion pools not defined\",\n        \"Whether Sept2 binding is direct or bridged by other factors not resolved\",\n        \"Stoichiometry and structure of the WDPCP-septin assembly unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the actin role to tissue mechanics, showing WDPCP controls cortical septin localization to maintain basolateral membrane stability and cortical tension through actomyosin.\",\n      \"evidence\": \"In vivo 3D time-lapse imaging and pharmacological actomyosin manipulation in Xenopus epithelium\",\n      \"pmids\": [\"25436430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab, single-organism evidence\",\n        \"Direct molecular link between WDPCP and actomyosin regulators not established\",\n        \"Quantitative relationship between septin localization and tension not defined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed WDPCP's ciliogenic requirement in human cells and linked it to a specific septin, showing knockdown reduces cilia and Septin7 expression in human sinonasal epithelium.\",\n      \"evidence\": \"siRNA knockdown in air-liquid interface human sinonasal epithelial cultures with cilia and Septin7 immunofluorescence\",\n      \"pmids\": [\"28001338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Septin7 reduction is cause or consequence of cilia loss unresolved\",\n        \"Single-lab knockdown without rescue\",\n        \"Relationship to the Sept2 axis from mouse work not reconciled\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed WDPCP in a developmental signaling pathway by showing epicardium-specific deletion blocks EMT and EPDC migration required for coronary artery smooth muscle coverage.\",\n      \"evidence\": \"Epicardium-specific conditional Wdpcp knockout mice with EMT marker, migration, and histological readouts\",\n      \"pmids\": [\"29487191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular effectors connecting WDPCP to EMT not identified in this study\",\n        \"Whether the EMT role depends on cilia or actin functions not separated\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined WDPCP as a positive regulator of Hedgehog signaling, showing its loss in skeletal progenitors abolishes Hh responsiveness and impairs chondro-/osteogenic differentiation.\",\n      \"evidence\": \"Prx1-Cre conditional Wdpcp knockout mice with in vitro Hh-stimulated differentiation assays\",\n      \"pmids\": [\"34225660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the Hh defect is secondary to ciliary dysfunction not disentangled\",\n        \"Step in the Hh cascade affected by WDPCP unknown\",\n        \"Single-lab evidence\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a signaling output for WDPCP in cilia function, showing knockdown impairs mitochondrial biogenesis and cilia beating via MAPK/ERK, with pharmacological rescue.\",\n      \"evidence\": \"siRNA knockdown in air-liquid interface cultures with U0126 inhibition and MAPK activation, mitochondrial and cilia beat frequency assays\",\n      \"pmids\": [\"33598458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking WDPCP to MAPK activation not defined\",\n        \"Whether mitochondrial effect is direct or downstream of ciliary defect unclear\",\n        \"Single-lab knockdown study\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected WDPCP/MAPK signaling to a downstream effector and a metabolic input, showing high leucine suppresses WDPCP to attenuate ERK signaling and impair endothelial EMT and migration via EMCN.\",\n      \"evidence\": \"WDPCP overexpression and knockdown in HCMECs with MAPK activator rescue, EMCN analysis, and high-leucine mouse model\",\n      \"pmids\": [\"39582775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which leucine suppresses WDPCP expression unknown\",\n        \"Whether EMCN is a direct WDPCP/MAPK target not established\",\n        \"Single-lab evidence\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped a structural determinant of WDPCP function, showing conserved residues D481/W482 are required for apical docking and that their deletion abolishes localization, ciliogenesis, and Hh signaling.\",\n      \"evidence\": \"Structure-guided two-codon-deletion knock-in mouse with rescue experiments, localization, cilia, and Hh readouts, plus structure prediction\",\n      \"pmids\": [\"41268724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Experimental structure of WDPCP not determined\",\n        \"Identity of the apical docking partner recognized via D481/W482 unknown\",\n        \"Whether the same residues mediate the actin/septin functions not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDPCP is partitioned between its transition-zone, cytoplasmic actin, and MAPK-signaling roles, and which direct partners couple it to Hedgehog and EMT outputs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying mechanism links the septin-scaffolding and MAPK-signaling functions\",\n        \"Direct molecular partner mediating apical docking unidentified\",\n        \"Whether Hh and EMT roles are cilium-dependent or cilium-independent not fully separated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SEPT2\", \"NPHP1\", \"MKS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}