{"gene":"WDPCP","run_date":"2026-04-28T23:00:23","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 failure of these proteins to localize to the transition zone, impairing ciliogenesis.","method":"Wdpcp knockout mouse model; immunofluorescence localization; loss-of-function phenotypic analysis","journal":"PLoS Biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined cellular phenotype and direct localization experiments, multiple orthogonal methods","pmids":["24302887"],"is_preprint":false},{"year":2013,"finding":"WDPCP localizes to the actin cytoskeleton and focal adhesions in the cytoplasm, where it interacts with Sept2 and is required for Sept2 recruitment to actin filaments; Wdpcp deficiency disrupts actin filament organization, focal contacts, membrane ruffling, cell polarity, and directional cell migration.","method":"Co-immunoprecipitation/co-localization; Wdpcp knockout mouse fibroblasts; actin staining; focal adhesion assays; migration assays","journal":"PLoS Biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-localization and Co-IP with functional KO phenotype, multiple orthogonal methods in single rigorous study","pmids":["24302887"],"is_preprint":false},{"year":2013,"finding":"PCP defects in Wdpcp mutant cochlea occur despite normal kinocilia, indicating Wdpcp regulates planar cell polarity via direct modulation of the actin cytoskeleton rather than through cilia.","method":"Wdpcp knockout mouse; cochlear hair cell analysis; kinocilia and PCP marker examination","journal":"PLoS Biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with defined cellular phenotype and structural control, replicated in vivo","pmids":["24302887"],"is_preprint":false},{"year":2005,"finding":"Drosophila Fritz (ortholog of WDPCP), a coiled-coil WD40 protein, functions cell-autonomously downstream of core PCP proteins (Frizzled) to regulate the location and number of wing cell prehair initiation sites by organizing actin cytoskeletal polarity.","method":"Drosophila genetics; clonal analysis; epistasis experiments; loss-of-function mutants","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila ortholog with defined cellular phenotype","pmids":["15654087"],"is_preprint":false},{"year":2014,"finding":"WDPCP (Fritz) is required for basolateral plasma membrane stability and cortical rigidity in epithelial cells by controlling cortical septin localization and acting via actomyosin to maintain balanced cortical tension.","method":"In vivo 3D time-lapse imaging; Xenopus mucociliary epithelium; septin localization assays; actomyosin inhibition experiments","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging and multiple functional assays in a single lab study","pmids":["25436430"],"is_preprint":false},{"year":2014,"finding":"Drosophila Fritz (WDPCP ortholog) physically interacts with Inturned and Fuzzy (other PPE proteins), and when overexpressed can repatterning the accumulation of upstream PCP proteins (e.g., Frizzled), indicating context-dependent feedback in the PCP hierarchy.","method":"Co-immunoprecipitation; genetic overexpression; immunofluorescence in Drosophila wing","journal":"Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and genetic overexpression in Drosophila ortholog","pmids":["25072625"],"is_preprint":false},{"year":2017,"finding":"Drosophila Fritz (WDPCP ortholog) directly interacts with Dishevelled, providing a potential mechanistic link by which upstream PCP core proteins instruct PPE protein accumulation; Fritz also shows In-independent PCP activity.","method":"Co-immunoprecipitation; genetic rescue of inturned deletion; CRISPR/Cas9-tagged Fritz live imaging in Drosophila wing","journal":"G3 (Bethesda)","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct Co-IP interaction plus genetic rescue, single lab","pmids":["28258110"],"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 coverage; epicardium-specific deletion of Wdpcp recapitulates the coronary artery defect, and Wdpcp mutant hearts show enhanced chemotactic responses to Shh.","method":"Tissue-specific Cre-lox deletion (Wdpcp epicardium-specific KO); immunofluorescence; EMT/mesenchymal marker expression; cell migration assays","journal":"Science Signaling","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO with defined cellular and molecular phenotype, multiple markers","pmids":["29487191"],"is_preprint":false},{"year":2021,"finding":"Loss of Wdpcp in limb bud mesenchyme (via Prx1-Cre) abolishes hedgehog signaling responsiveness, impairs chondrogenic and osteogenic differentiation, and disrupts growth plate organization, placing Wdpcp as a positive regulator of Hh pathway activity in skeletal progenitors.","method":"Conditional KO (Prx1-Cre); in vitro chondrogenesis and osteogenesis assays; Hh signaling marker expression; growth plate histology","journal":"BMC Developmental Biology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with multiple in vitro and in vivo functional assays","pmids":["34225660"],"is_preprint":false},{"year":2021,"finding":"WDPCP regulates cilia beating in sinonasal epithelial cells via the MAPK/ERK pathway; WDPCP knockdown impairs mitochondrial biogenesis and function, which can be partially restored by dexamethasone.","method":"Air-liquid interface culture; siRNA knockdown; MAPK/ERK pathway inhibition (U0126); mitochondrial function assays","journal":"Frontiers in Cell and Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, in vitro knockdown with pathway inhibitor, partial mechanistic follow-up","pmids":["33598458"],"is_preprint":false},{"year":2017,"finding":"WDPCP is required for ciliogenesis in human sinonasal epithelial cells; knockdown of WDPCP reduces cilia quantity and length and decreases Septin7 expression in an air-liquid interface model.","method":"siRNA knockdown in primary human sinonasal epithelial cells; air-liquid interface culture; immunofluorescence for cilia and Septin7","journal":"Cytoskeleton (Hoboken)","confidence":"Medium","confidence_rationale":"Tier 3 — single lab knockdown with ciliary phenotype and septin marker, moderate follow-up","pmids":["28001338"],"is_preprint":false},{"year":2025,"finding":"Residues D481 and W482 (human N512/W513) in WDPCP are essential for its docking to the apical cell surface and for ciliogenesis and Hh signaling; structure predictions place these residues at the junction of two alpha helices in WDPCP, and their deletion impairs protein conformational stability without abolishing expression.","method":"Genetically engineered mouse model (Wdpcp-Z11); rescue experiments with reintroduction of D481/W482; structure prediction; immunofluorescence for cilia and Hh signaling markers","journal":"Disease Models & Mechanisms","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis with phenotypic rescue, structural prediction with functional validation, in vivo model","pmids":["41268724"],"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, and the WDPCP/MAPK axis regulates endomucin (EMCN) upregulation induced by high leucine.","method":"High-leucine mouse model; WDPCP overexpression and MAPK activation in HCMECs; EMT marker expression; migration assays; EMCN expression analysis","journal":"Pulmonary Circulation","confidence":"Medium","confidence_rationale":"Tier 2–3 — rescue experiments with overexpression plus pathway activation, multiple functional assays, single lab","pmids":["39582775"],"is_preprint":false}],"current_model":"WDPCP is a planar cell polarity (PCP) effector protein that localizes to the ciliary transition zone (where it recruits Sept2, Nphp1, and Mks1 for ciliogenesis) and to the actin cytoskeleton and focal adhesions (where it interacts with Sept2 to organize actin filaments), thereby regulating cell polarity and directional migration independently of cilia; it also acts as a positive regulator of Hedgehog signaling, promotes epithelial EMT via the MAPK/ERK axis, and requires key residues D481/W482 for apical docking and ciliogenic function."},"narrative":{"teleology":[{"year":2005,"claim":"Identification of Fritz (Drosophila WDPCP ortholog) as a cell-autonomous PCP effector established that a WD40/coiled-coil protein functions downstream of Frizzled to organize cytoskeletal polarity at hair initiation sites.","evidence":"Drosophila loss-of-function mutants with clonal and epistasis analyses in wing cells","pmids":["15654087"],"confidence":"High","gaps":["Mammalian function not yet tested","Direct binding partners unidentified","Mechanism of actin reorganization unknown"]},{"year":2013,"claim":"Demonstration that WDPCP localizes to both the ciliary transition zone and the actin cytoskeleton/focal adhesions, and recruits Sept2, Nphp1, and Mks1 to the transition zone, unified its dual roles in ciliogenesis and actin-based polarity.","evidence":"Wdpcp knockout mouse; co-immunoprecipitation of WDPCP–Sept2; immunofluorescence for transition zone and actin markers; migration assays","pmids":["24302887"],"confidence":"High","gaps":["Structural basis for WDPCP–Sept2 interaction unknown","How WDPCP is itself recruited to the transition zone not defined"]},{"year":2013,"claim":"Showing that PCP defects in Wdpcp-mutant cochlea occur despite normal kinocilia separated the actin-organizing function of WDPCP from its ciliogenic role, establishing cilia-independent polarity regulation.","evidence":"Wdpcp knockout mouse cochlear hair cell analysis with kinocilia and PCP marker examination","pmids":["24302887"],"confidence":"High","gaps":["Signaling intermediate linking WDPCP to PCP effectors in the inner ear not identified","Whether cilia-independent polarity function is conserved in other tissues unclear"]},{"year":2014,"claim":"Fritz/WDPCP was shown to physically interact with other PPE proteins (Inturned, Fuzzy) and Dishevelled, and to maintain cortical rigidity via actomyosin/septin control, revealing its position as a node linking upstream PCP signals to cortical mechanics.","evidence":"Co-immunoprecipitation in Drosophila; Xenopus mucociliary epithelium live imaging; septin localization and actomyosin inhibition experiments","pmids":["25072625","25436430"],"confidence":"Medium","gaps":["Whether Inturned/Fuzzy interactions are conserved in mammals not tested","Direct versus bridged nature of these interactions not resolved"]},{"year":2017,"claim":"Extension to human airway epithelium confirmed WDPCP is required for ciliogenesis and Septin7 expression in primary sinonasal cells, and a direct Fritz–Dishevelled interaction was demonstrated, solidifying WDPCP as a PCP-to-cilia signal relay.","evidence":"siRNA knockdown in air-liquid interface cultured human sinonasal epithelial cells; Co-IP and CRISPR-tagged Fritz in Drosophila wing","pmids":["28001338","28258110"],"confidence":"Medium","gaps":["Mechanism by which WDPCP regulates septin expression versus localization not distinguished","Dishevelled interaction not confirmed in mammalian cells"]},{"year":2018,"claim":"Tissue-specific deletion revealed WDPCP promotes epicardial EMT and migration required for coronary artery smooth muscle coverage, establishing a developmental role beyond canonical ciliogenesis.","evidence":"Epicardium-specific Cre-lox deletion in mouse; EMT and mesenchymal marker expression; cell migration assays","pmids":["29487191"],"confidence":"High","gaps":["Whether EMT function depends on cilia or is cilia-independent not formally tested","Downstream transcriptional targets of WDPCP in EMT not catalogued"]},{"year":2021,"claim":"Conditional limb mesenchyme knockout showed WDPCP is a positive regulator of Hedgehog signaling required for chondrogenic and osteogenic differentiation, while airway studies linked WDPCP to MAPK/ERK-dependent cilia beating and mitochondrial biogenesis.","evidence":"Prx1-Cre conditional KO with Hh marker analysis and growth plate histology; siRNA knockdown in sinonasal ALI cultures with U0126 MAPK inhibition and mitochondrial assays","pmids":["34225660","33598458"],"confidence":"High","gaps":["Whether WDPCP acts on Hh signaling purely via cilia or also intracellularly not resolved","Link between MAPK/ERK and mitochondrial function through WDPCP is correlative"]},{"year":2024,"claim":"The WDPCP–MAPK/ERK axis was shown to mediate EMT and migration in cardiac microvascular endothelial cells, with leucine-induced WDPCP suppression causing vascular dysfunction rescuable by WDPCP overexpression.","evidence":"High-leucine mouse model; WDPCP overexpression and MAPK activation rescue in HCMECs; EMT marker and endomucin expression analysis","pmids":["39582775"],"confidence":"Medium","gaps":["Mechanism by which leucine suppresses WDPCP expression unknown","In vivo cardiovascular phenotype from endothelial-specific WDPCP loss not shown"]},{"year":2025,"claim":"Identification of D481/W482 as essential residues for apical docking and ciliogenesis provided the first structure–function insight into WDPCP, showing that conformational integrity at an alpha-helix junction is required for its ciliogenic and Hh signaling functions.","evidence":"Wdpcp-Z11 knock-in mouse; rescue by reintroduction of D481/W482; AlphaFold structure prediction; immunofluorescence for cilia and Hh markers","pmids":["41268724"],"confidence":"High","gaps":["No experimental high-resolution structure available","Binding partner that recognizes the D481/W482 surface not identified","Whether these residues affect actin/PCP functions not tested"]},{"year":null,"claim":"Key unresolved questions include the molecular basis of WDPCP apical targeting and transition zone anchoring, whether its EMT and MAPK/ERK functions are cilia-dependent or -independent, and the identity of the direct binding surface recognized by D481/W482.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental 3D structure of WDPCP","Cilia-dependent versus -independent EMT regulation not formally separated","Upstream signals controlling WDPCP expression and localization largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,5,6]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,10,11]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,3,4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,6,8,9,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,10,11]}],"complexes":[],"partners":["SEPT2","NPHP1","MKS1","SEPT7","DVL","INTU","FUZ"],"other_free_text":[]},"mechanistic_narrative":"WDPCP is a WD40-repeat-containing planar cell polarity (PCP) effector protein that functions downstream of core PCP components to organize the actin cytoskeleton, regulate ciliogenesis, and promote Hedgehog signaling. At the ciliary transition zone, WDPCP recruits Sept2, Nphp1, and Mks1 to enable ciliogenesis and Hedgehog pathway activation, with residues D481/W482 essential for apical docking and ciliogenic function [PMID:24302887, PMID:41268724, PMID:34225660]. In the cytoplasm, WDPCP interacts with Sept2 at actin filaments and focal adhesions to control actin organization, cortical tension, cell polarity, and directional migration—functions that operate independently of cilia, as demonstrated by intact kinocilia in Wdpcp-mutant cochlea [PMID:24302887, PMID:25436430]. WDPCP also promotes epithelial-mesenchymal transition via the MAPK/ERK signaling axis, a function required for coronary artery smooth muscle development and cardiac microvascular endothelial cell migration [PMID:29487191, PMID:39582775]."},"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":"9178261","id":"PMC_9178261","title":"Fritz: a secreted frizzled-related protein that inhibits Wnt activity.","date":"1997","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/9178261","citation_count":61,"is_preprint":false},{"pmid":"15654087","id":"PMC_15654087","title":"The WD40 repeat protein fritz links cytoskeletal planar polarity to frizzled subcellular localization in the Drosophila epidermis.","date":"2005","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15654087","citation_count":48,"is_preprint":false},{"pmid":"8267876","id":"PMC_8267876","title":"17th Fritz Lipmann Lecture. Wanderings (wonderings) in metabolism.","date":"1993","source":"Biological chemistry Hoppe-Seyler","url":"https://pubmed.ncbi.nlm.nih.gov/8267876","citation_count":37,"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":"16764955","id":"PMC_16764955","title":"Fritz Verzár was born 120 years ago: his contribution to experimental gerontology through the collagen research as assessed after half a century.","date":"2006","source":"Archives of gerontology and geriatrics","url":"https://pubmed.ncbi.nlm.nih.gov/16764955","citation_count":19,"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":"25072625","id":"PMC_25072625","title":"The proteins encoded by the Drosophila Planar Polarity Effector genes inturned, fuzzy and fritz interact physically and can re-pattern the accumulation of \"upstream\" Planar Cell Polarity proteins.","date":"2014","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/25072625","citation_count":12,"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":9,"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":"28258110","id":"PMC_28258110","title":"Planar Cell Polarity Effector Fritz Interacts with Dishevelled and Has Multiple Functions in Regulating PCP.","date":"2017","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/28258110","citation_count":7,"is_preprint":false},{"pmid":"36462112","id":"PMC_36462112","title":"Ancylobacter moscoviensis sp. nov., novel facultatively methylotrophic bacteria from activated sludge and the reclassification of Starkeya novella (Starkey 1934) Kelly et al. 2000 as Ancylobacter novellus comb. nov., Starkeya koreensis Im et al. 2006 as Ancylobacter koreensis comb.nov., Angulomicrobium tetraedrale Vasil'eva et al. 1986 as Ancylobacter tetraedralis comb. nov., Angulomicrobium amanitiforme Fritz et al. 2004 as Ancylobacter amanitiformis comb. nov., and Methylorhabdus multivorans Doronina et al. 1996 as Ancylobacter multivorans comb. nov., and emended description of the genus Ancylobacter.","date":"2022","source":"Antonie van Leeuwenhoek","url":"https://pubmed.ncbi.nlm.nih.gov/36462112","citation_count":5,"is_preprint":false},{"pmid":"16974097","id":"PMC_16974097","title":"An original approach to aging: an appreciation of Fritz Verzár's contribution in the light of the last 50 years of gerontological facts and thinking.","date":"2006","source":"Gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/16974097","citation_count":3,"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":"35930095","id":"PMC_35930095","title":"Development and Heredity in the Interwar Period: Hans Spemann and Fritz Baltzer on Organizers and Merogones.","date":"2022","source":"Journal of the history of biology","url":"https://pubmed.ncbi.nlm.nih.gov/35930095","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":"40326535","id":"PMC_40326535","title":"The magic bullet: a tribute to Fritz Eckstein.","date":"2025","source":"Nucleosides, nucleotides & nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/40326535","citation_count":0,"is_preprint":false},{"pmid":"30914418","id":"PMC_30914418","title":"Lillian Fritz-Laylin: Keeping up to speed with evolutionary cell biology.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30914418","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":11697,"output_tokens":2870,"usd":0.039071},"stage2":{"model":"claude-opus-4-6","input_tokens":6240,"output_tokens":2563,"usd":0.142912},"total_usd":0.181983,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","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 failure of these proteins to localize to the transition zone, impairing ciliogenesis.\",\n      \"method\": \"Wdpcp knockout mouse model; immunofluorescence localization; loss-of-function phenotypic analysis\",\n      \"journal\": \"PLoS Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined cellular phenotype and direct localization experiments, multiple orthogonal methods\",\n      \"pmids\": [\"24302887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WDPCP localizes to the actin cytoskeleton and focal adhesions in the cytoplasm, where it interacts with Sept2 and is required for Sept2 recruitment to actin filaments; Wdpcp deficiency disrupts actin filament organization, focal contacts, membrane ruffling, cell polarity, and directional cell migration.\",\n      \"method\": \"Co-immunoprecipitation/co-localization; Wdpcp knockout mouse fibroblasts; actin staining; focal adhesion assays; migration assays\",\n      \"journal\": \"PLoS Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-localization and Co-IP with functional KO phenotype, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"24302887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PCP defects in Wdpcp mutant cochlea occur despite normal kinocilia, indicating Wdpcp regulates planar cell polarity via direct modulation of the actin cytoskeleton rather than through cilia.\",\n      \"method\": \"Wdpcp knockout mouse; cochlear hair cell analysis; kinocilia and PCP marker examination\",\n      \"journal\": \"PLoS Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined cellular phenotype and structural control, replicated in vivo\",\n      \"pmids\": [\"24302887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila Fritz (ortholog of WDPCP), a coiled-coil WD40 protein, functions cell-autonomously downstream of core PCP proteins (Frizzled) to regulate the location and number of wing cell prehair initiation sites by organizing actin cytoskeletal polarity.\",\n      \"method\": \"Drosophila genetics; clonal analysis; epistasis experiments; loss-of-function mutants\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila ortholog with defined cellular phenotype\",\n      \"pmids\": [\"15654087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"WDPCP (Fritz) is required for basolateral plasma membrane stability and cortical rigidity in epithelial cells by controlling cortical septin localization and acting via actomyosin to maintain balanced cortical tension.\",\n      \"method\": \"In vivo 3D time-lapse imaging; Xenopus mucociliary epithelium; septin localization assays; actomyosin inhibition experiments\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging and multiple functional assays in a single lab study\",\n      \"pmids\": [\"25436430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila Fritz (WDPCP ortholog) physically interacts with Inturned and Fuzzy (other PPE proteins), and when overexpressed can repatterning the accumulation of upstream PCP proteins (e.g., Frizzled), indicating context-dependent feedback in the PCP hierarchy.\",\n      \"method\": \"Co-immunoprecipitation; genetic overexpression; immunofluorescence in Drosophila wing\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and genetic overexpression in Drosophila ortholog\",\n      \"pmids\": [\"25072625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Drosophila Fritz (WDPCP ortholog) directly interacts with Dishevelled, providing a potential mechanistic link by which upstream PCP core proteins instruct PPE protein accumulation; Fritz also shows In-independent PCP activity.\",\n      \"method\": \"Co-immunoprecipitation; genetic rescue of inturned deletion; CRISPR/Cas9-tagged Fritz live imaging in Drosophila wing\",\n      \"journal\": \"G3 (Bethesda)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct Co-IP interaction plus genetic rescue, single lab\",\n      \"pmids\": [\"28258110\"],\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 coverage; epicardium-specific deletion of Wdpcp recapitulates the coronary artery defect, and Wdpcp mutant hearts show enhanced chemotactic responses to Shh.\",\n      \"method\": \"Tissue-specific Cre-lox deletion (Wdpcp epicardium-specific KO); immunofluorescence; EMT/mesenchymal marker expression; cell migration assays\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with defined cellular and molecular phenotype, multiple markers\",\n      \"pmids\": [\"29487191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of Wdpcp in limb bud mesenchyme (via Prx1-Cre) abolishes hedgehog signaling responsiveness, impairs chondrogenic and osteogenic differentiation, and disrupts growth plate organization, placing Wdpcp as a positive regulator of Hh pathway activity in skeletal progenitors.\",\n      \"method\": \"Conditional KO (Prx1-Cre); in vitro chondrogenesis and osteogenesis assays; Hh signaling marker expression; growth plate histology\",\n      \"journal\": \"BMC Developmental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple in vitro and in vivo functional assays\",\n      \"pmids\": [\"34225660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDPCP regulates cilia beating in sinonasal epithelial cells via the MAPK/ERK pathway; WDPCP knockdown impairs mitochondrial biogenesis and function, which can be partially restored by dexamethasone.\",\n      \"method\": \"Air-liquid interface culture; siRNA knockdown; MAPK/ERK pathway inhibition (U0126); mitochondrial function assays\",\n      \"journal\": \"Frontiers in Cell and Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, in vitro knockdown with pathway inhibitor, partial mechanistic follow-up\",\n      \"pmids\": [\"33598458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WDPCP is required for ciliogenesis in human sinonasal epithelial cells; knockdown of WDPCP reduces cilia quantity and length and decreases Septin7 expression in an air-liquid interface model.\",\n      \"method\": \"siRNA knockdown in primary human sinonasal epithelial cells; air-liquid interface culture; immunofluorescence for cilia and Septin7\",\n      \"journal\": \"Cytoskeleton (Hoboken)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab knockdown with ciliary phenotype and septin marker, moderate follow-up\",\n      \"pmids\": [\"28001338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Residues D481 and W482 (human N512/W513) in WDPCP are essential for its docking to the apical cell surface and for ciliogenesis and Hh signaling; structure predictions place these residues at the junction of two alpha helices in WDPCP, and their deletion impairs protein conformational stability without abolishing expression.\",\n      \"method\": \"Genetically engineered mouse model (Wdpcp-Z11); rescue experiments with reintroduction of D481/W482; structure prediction; immunofluorescence for cilia and Hh signaling markers\",\n      \"journal\": \"Disease Models & Mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis with phenotypic rescue, structural prediction with functional validation, in vivo model\",\n      \"pmids\": [\"41268724\"],\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, and the WDPCP/MAPK axis regulates endomucin (EMCN) upregulation induced by high leucine.\",\n      \"method\": \"High-leucine mouse model; WDPCP overexpression and MAPK activation in HCMECs; EMT marker expression; migration assays; EMCN expression analysis\",\n      \"journal\": \"Pulmonary Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — rescue experiments with overexpression plus pathway activation, multiple functional assays, single lab\",\n      \"pmids\": [\"39582775\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDPCP is a planar cell polarity (PCP) effector protein that localizes to the ciliary transition zone (where it recruits Sept2, Nphp1, and Mks1 for ciliogenesis) and to the actin cytoskeleton and focal adhesions (where it interacts with Sept2 to organize actin filaments), thereby regulating cell polarity and directional migration independently of cilia; it also acts as a positive regulator of Hedgehog signaling, promotes epithelial EMT via the MAPK/ERK axis, and requires key residues D481/W482 for apical docking and ciliogenic function.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"WDPCP is a WD40-repeat-containing planar cell polarity (PCP) effector protein that functions downstream of core PCP components to organize the actin cytoskeleton, regulate ciliogenesis, and promote Hedgehog signaling. At the ciliary transition zone, WDPCP recruits Sept2, Nphp1, and Mks1 to enable ciliogenesis and Hedgehog pathway activation, with residues D481/W482 essential for apical docking and ciliogenic function [PMID:24302887, PMID:41268724, PMID:34225660]. In the cytoplasm, WDPCP interacts with Sept2 at actin filaments and focal adhesions to control actin organization, cortical tension, cell polarity, and directional migration—functions that operate independently of cilia, as demonstrated by intact kinocilia in Wdpcp-mutant cochlea [PMID:24302887, PMID:25436430]. WDPCP also promotes epithelial-mesenchymal transition via the MAPK/ERK signaling axis, a function required for coronary artery smooth muscle development and cardiac microvascular endothelial cell migration [PMID:29487191, PMID:39582775].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of Fritz (Drosophila WDPCP ortholog) as a cell-autonomous PCP effector established that a WD40/coiled-coil protein functions downstream of Frizzled to organize cytoskeletal polarity at hair initiation sites.\",\n      \"evidence\": \"Drosophila loss-of-function mutants with clonal and epistasis analyses in wing cells\",\n      \"pmids\": [\"15654087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian function not yet tested\", \"Direct binding partners unidentified\", \"Mechanism of actin reorganization unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that WDPCP localizes to both the ciliary transition zone and the actin cytoskeleton/focal adhesions, and recruits Sept2, Nphp1, and Mks1 to the transition zone, unified its dual roles in ciliogenesis and actin-based polarity.\",\n      \"evidence\": \"Wdpcp knockout mouse; co-immunoprecipitation of WDPCP–Sept2; immunofluorescence for transition zone and actin markers; migration assays\",\n      \"pmids\": [\"24302887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for WDPCP–Sept2 interaction unknown\", \"How WDPCP is itself recruited to the transition zone not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that PCP defects in Wdpcp-mutant cochlea occur despite normal kinocilia separated the actin-organizing function of WDPCP from its ciliogenic role, establishing cilia-independent polarity regulation.\",\n      \"evidence\": \"Wdpcp knockout mouse cochlear hair cell analysis with kinocilia and PCP marker examination\",\n      \"pmids\": [\"24302887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediate linking WDPCP to PCP effectors in the inner ear not identified\", \"Whether cilia-independent polarity function is conserved in other tissues unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Fritz/WDPCP was shown to physically interact with other PPE proteins (Inturned, Fuzzy) and Dishevelled, and to maintain cortical rigidity via actomyosin/septin control, revealing its position as a node linking upstream PCP signals to cortical mechanics.\",\n      \"evidence\": \"Co-immunoprecipitation in Drosophila; Xenopus mucociliary epithelium live imaging; septin localization and actomyosin inhibition experiments\",\n      \"pmids\": [\"25072625\", \"25436430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Inturned/Fuzzy interactions are conserved in mammals not tested\", \"Direct versus bridged nature of these interactions not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extension to human airway epithelium confirmed WDPCP is required for ciliogenesis and Septin7 expression in primary sinonasal cells, and a direct Fritz–Dishevelled interaction was demonstrated, solidifying WDPCP as a PCP-to-cilia signal relay.\",\n      \"evidence\": \"siRNA knockdown in air-liquid interface cultured human sinonasal epithelial cells; Co-IP and CRISPR-tagged Fritz in Drosophila wing\",\n      \"pmids\": [\"28001338\", \"28258110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which WDPCP regulates septin expression versus localization not distinguished\", \"Dishevelled interaction not confirmed in mammalian cells\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tissue-specific deletion revealed WDPCP promotes epicardial EMT and migration required for coronary artery smooth muscle coverage, establishing a developmental role beyond canonical ciliogenesis.\",\n      \"evidence\": \"Epicardium-specific Cre-lox deletion in mouse; EMT and mesenchymal marker expression; cell migration assays\",\n      \"pmids\": [\"29487191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EMT function depends on cilia or is cilia-independent not formally tested\", \"Downstream transcriptional targets of WDPCP in EMT not catalogued\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Conditional limb mesenchyme knockout showed WDPCP is a positive regulator of Hedgehog signaling required for chondrogenic and osteogenic differentiation, while airway studies linked WDPCP to MAPK/ERK-dependent cilia beating and mitochondrial biogenesis.\",\n      \"evidence\": \"Prx1-Cre conditional KO with Hh marker analysis and growth plate histology; siRNA knockdown in sinonasal ALI cultures with U0126 MAPK inhibition and mitochondrial assays\",\n      \"pmids\": [\"34225660\", \"33598458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WDPCP acts on Hh signaling purely via cilia or also intracellularly not resolved\", \"Link between MAPK/ERK and mitochondrial function through WDPCP is correlative\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The WDPCP–MAPK/ERK axis was shown to mediate EMT and migration in cardiac microvascular endothelial cells, with leucine-induced WDPCP suppression causing vascular dysfunction rescuable by WDPCP overexpression.\",\n      \"evidence\": \"High-leucine mouse model; WDPCP overexpression and MAPK activation rescue in HCMECs; EMT marker and endomucin expression analysis\",\n      \"pmids\": [\"39582775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which leucine suppresses WDPCP expression unknown\", \"In vivo cardiovascular phenotype from endothelial-specific WDPCP loss not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of D481/W482 as essential residues for apical docking and ciliogenesis provided the first structure–function insight into WDPCP, showing that conformational integrity at an alpha-helix junction is required for its ciliogenic and Hh signaling functions.\",\n      \"evidence\": \"Wdpcp-Z11 knock-in mouse; rescue by reintroduction of D481/W482; AlphaFold structure prediction; immunofluorescence for cilia and Hh markers\",\n      \"pmids\": [\"41268724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental high-resolution structure available\", \"Binding partner that recognizes the D481/W482 surface not identified\", \"Whether these residues affect actin/PCP functions not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the molecular basis of WDPCP apical targeting and transition zone anchoring, whether its EMT and MAPK/ERK functions are cilia-dependent or -independent, and the identity of the direct binding surface recognized by D481/W482.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental 3D structure of WDPCP\", \"Cilia-dependent versus -independent EMT regulation not formally separated\", \"Upstream signals controlling WDPCP expression and localization largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 10, 11]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 6, 8, 9, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SEPT2\", \"NPHP1\", \"MKS1\", \"SEPT7\", \"DVL\", \"INTU\", \"FUZ\"],\n    \"other_free_text\": []\n  }\n}\n```"}