{"gene":"WDR1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2007,"finding":"WDR1/Aip1 functions as a co-factor of cofilin to accelerate actin filament severing and depolymerization; loss-of-function (hypomorphic alleles) in mice causes macrothrombocytopenia due to megakaryocyte maturation defects and autoinflammatory disease with impaired cytoskeletal responses in neutrophils, establishing an essential in vivo role for the cofilin/WDR1 complex in actin dynamics in these cell types.","method":"Allelic series mouse genetics (hypomorphic and null Wdr1 alleles), cellular phenotyping of megakaryocytes and neutrophils, cytoskeletal assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function allelic series in mice with multiple defined cellular phenotypes replicated across cell types; foundational mechanism paper","pmids":["17515402"],"is_preprint":false},{"year":2016,"finding":"Biallelic loss-of-function mutations in WDR1 in human patients cause elevated F-actin content (fourfold increase) in neutrophils, markedly impaired chemotaxis, cell polarization, and spreading, and a distinctive nuclear herniation phenotype, confirming that WDR1-dependent actin depolymerization is required for normal neutrophil morphology and motility.","method":"Identification of biallelic WDR1 mutations in patients, 2D-DIGE proteomics, F-actin/G-actin measurements, chemotaxis assays, allogeneic stem cell transplantation rescue","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (proteomics, functional assays, genetic rescue by transplant) in human primary cells across three families","pmids":["27557945"],"is_preprint":false},{"year":2016,"finding":"A homozygous missense mutation in WDR1 causes autoinflammatory disease with elevated IL-18 (but not IL-1β) and increased caspase-1 cleavage in patient monocytes; mutant WDR1 protein forms aggregates that accumulate pyrin in transfected HEK293T cells, suggesting that impaired actin dynamics precipitates inflammasome assembly.","method":"Patient genetic analysis, ELISA for cytokines, caspase-1 cleavage assay in monocytes, transfection/aggregation assay in HEK293T cells","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cellular assays with patient cells plus transfection aggregation data, single lab","pmids":["27994071"],"is_preprint":false},{"year":2005,"finding":"Suppression of AIP1/WDR1 causes mitotic cell flattening instead of normal rounding; in vitro filament severing/disassembly assays showed that AIP1/WDR1 abolishes residual actin-severing activity of phosphorylated cofilin, indicating that WDR1 is required to fully suppress actin turnover and thereby enable mitotic cell rounding.","method":"RNAi knockdown in cells, direct in vitro actin filament severing/disassembly assay, live-cell morphology observation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro actin assay plus cellular KD phenotype, single lab","pmids":["15629458"],"is_preprint":false},{"year":2015,"finding":"Wdr1 (Aip1), an F-actin-binding protein that enhances cofilin/destrin-mediated F-actin disassembly, is required for actomyosin remodeling, cortical tension generation, and the cell shape changes that establish planar cell polarity (PCP) in developing mouse epidermis; Wdr1 depletion alone recapitulates core PCP mutations.","method":"Conditional KO mice, live imaging, cortical tension measurements, genetic epistasis with cofilin/destrin double depletion","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO genetics, live imaging, tension measurement, epistasis) in vivo","pmids":["25915128"],"is_preprint":false},{"year":2016,"finding":"WDR1 knockdown in megakaryoblastic MEG-01 cells increases F-actin content, adhesion, spreading, and basal intracellular calcium, and produces fewer but larger platelet-like particles with enhanced adhesion; WDR1 overexpression reverses these phenotypes, demonstrating that WDR1 suppresses platelet activity by regulating actin cytoskeleton dynamics.","method":"siRNA knockdown and overexpression in MEG-01 cells, F-actin measurement, adhesion/spreading assays, calcium imaging, platelet-like particle characterization","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal KD/OE with multiple functional readouts, single lab","pmids":["27609643"],"is_preprint":false},{"year":2016,"finding":"In Wdr1-hypomorphic mouse platelets, actin turnover (F-actin/G-actin ratio) is impaired during collagen- and thrombin-induced aggregation, integrin αIIbβ3 inside-out activation is defective despite normal calcium responses, and talin fails to redistribute to the cytoskeleton, establishing that WDR1-mediated actin remodeling is required for talin-dependent αIIbβ3 activation.","method":"Wdr1-hypomorphic mice, bleeding time, FeCl3 thrombosis model, JON/A flow cytometry for activated αIIbβ3, F-actin/G-actin fractionation, talin immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and ex vivo assays with multiple mechanistic readouts, single lab","pmids":["27627652"],"is_preprint":false},{"year":2018,"finding":"Wdr-1 co-localizes with cofilin-1 in cortical actin of resting platelets and translocates together with cofilin-1 to the cytoskeleton upon fibrinogen adhesion; in Wdr-1-deficient platelets cofilin-1 is aberrantly distributed throughout the cytoplasm, F-actin fails to attach to focal adhesion kinase, and clot retraction and spreading are impaired, demonstrating that Wdr-1 is required for cofilin-1 localization to the membrane skeleton and F-actin–focal adhesion interaction.","method":"Wdr-1-hypomorphic mice, immunofluorescence/confocal co-localization, F-actin–focal adhesion kinase co-immunoprecipitation/immunoblotting, clot retraction assay, spreading assay","journal":"Blood coagulation & fibrinolysis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-localization plus biochemical interaction data linked to functional phenotype, single lab","pmids":["29995657"],"is_preprint":false},{"year":2018,"finding":"EYA3 tyrosine phosphatase dephosphorylates WDR1 on tyrosine residues that are phosphorylated by Src kinase; loss of WDR1 tyrosine phosphorylation causes major changes to the cellular actin cytoskeleton, identifying WDR1 as an EYA3-specific substrate and placing Src/EYA3 as writer/eraser of WDR1 phosphorylation in cytoskeletal regulation.","method":"Phosphotyrosine peptide microarray to identify EYA3 substrates, in vitro kinase (Src) and phosphatase (EYA3/EYA1) assays, site-directed mutagenesis of WDR1 tyrosine residues, actin cytoskeleton imaging","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assays (peptide array, kinase, phosphatase) plus mutagenesis and cellular phenotype, single lab","pmids":["29440662"],"is_preprint":false},{"year":2019,"finding":"In Wdr1-deficient zebrafish neutrophils, cofilin is predominantly unphosphorylated and associated with F-actin, displacing myosin; this leads to F-actin cytoplasmic aggregates, loss of phospho-myosin cortical localization, nuclear disorganization, and eruptive cell death. Depletion of coronin 1A fully rescues cortical F-actin distribution, nuclear integrity, viability, and mobility in Wdr1-deficient neutrophils, establishing a functional interplay between Wdr1, cofilin, and coronin 1A in regulating F-actin and actomyosin contractility.","method":"Wdr1-deficient zebrafish embryos, coronin 1A morpholino depletion, live imaging, F-actin/phospho-myosin immunofluorescence, myosin inhibitor experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis (double depletion rescue) with multiple orthogonal imaging readouts, rigorous controls including pharmacological intervention","pmids":["31471458"],"is_preprint":false},{"year":2021,"finding":"Wdr1 and LIMK have distinct roles in BCR-induced actin remodeling at the B cell immune synapse: Wdr1 enhances cofilin-mediated actin disassembly while LIMK phosphorylates and inactivates cofilin; both the Wdr1-LIMK-cofilin axis collectively controls peripheral actin assembly, B cell spreading, and actin-dependent amplification of BCR signaling.","method":"siRNA knockdown of Wdr1, LIMK, and Cotl1 in B cells, live imaging of BCR microcluster dynamics, spreading assays, BCR signaling measurements at immune synapse","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple functional readouts (morphology, signaling) and comparative epistasis, single lab","pmids":["33928084"],"is_preprint":false},{"year":2021,"finding":"In response to dimethyl fumarate (Tecfidera), Keap1-specific modification triggers dissociation of Wdr1 from Keap1; released Wdr1 then coordinates with cofilin to intercept Bax, driving mitochondrial-targeted apoptosis specifically in neutrophils and macrophages in a process largely independent of canonical Nrf2 signaling.","method":"Redox-targeting approach, genetic depletions of Wdr1 and cofilin, whole-animal DMF administration, mechanistic dissection via individual component knockdown","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic genetic dissection with multiple depletions and in vivo validation, single lab","pmids":["34593792"],"is_preprint":false},{"year":2018,"finding":"Cardiac-specific or second-heart-field-specific deletion of Wdr1 in mice causes embryonic lethality with hypoplasia of the outflow tract and right ventricle, disrupted cardiomyocyte cellular organization and myofibrillar assembly without changes in cell number or proliferation, demonstrating that WDR1-mediated actin dynamics is required for spatial arrangement of cardiomyocytes during heart development.","method":"Conditional KO mice (Nkx2.5-Cre and SHF-Cre), histology, cell number/proliferation quantification, myofibrillar immunostaining","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean tissue-specific KO with defined structural phenotype, single lab","pmids":["29654745"],"is_preprint":false},{"year":2019,"finding":"Conditional knockout of Wdr1 in hippocampal CA1 neurons in mice impairs actin depolymerization (via ADF/cofilin activity dysregulation), alters dendritic spine morphology, enhances LTP, impairs LTD, and causes deficits in reversal spatial learning and fear responses, establishing that Wdr1-mediated actin dynamics in hippocampal neurons is required for synaptic plasticity and associative learning.","method":"Conditional KO mice (CA1-specific), spine morphology analysis, electrophysiology (LTP/LTD), behavioral tests, actin dynamics (F-actin/G-actin fractionation), cofilin activity assay","journal":"Cerebral cortex","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple orthogonal mechanistic readouts, single lab","pmids":["30590446"],"is_preprint":false},{"year":2023,"finding":"The small molecule gambogic amide directly binds WDR1 (confirmed by CETSA, DARTS, molecular docking, and SPR), and through this interaction promotes formation of a WDR1–MYH9–cofilin complex that accelerates F-actin depolymerization, inhibits glioma cell invasion, and induces apoptosis via the mitochondrial pathway.","method":"CRISPR genome-wide KO screen, CETSA, DARTS, SPR, molecular docking, co-immunoprecipitation (WDR1–MYH9–cofilin complex), F-actin assay, apoptosis assay, PDX in vivo models","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding confirmed by four orthogonal methods plus complex formation and functional consequence, in vivo validation","pmids":["37935665"],"is_preprint":false},{"year":2017,"finding":"WDR1 promotes nuclear import of MRTF-A by affecting expression of importin nuclear transport protein, thereby enhancing MRTF-A-induced breast cancer cell migration via RhoA-MRTF-A signaling; MRTF-A in turn drives expression of miR-206 which feeds back to suppress WDR1 and MRTF-A via their 3'UTRs.","method":"Overexpression and knockdown in MDA-MB-231 cells, nuclear/cytoplasmic fractionation, migration assays, qRT-PCR, 3'UTR luciferase reporter assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional and mechanistic assays, single lab","pmids":["28822708"],"is_preprint":false},{"year":2016,"finding":"STAT3 binds directly to a putative promoter region (-1971 to -1964) of the WDR1 gene and its activation drives WDR1 overexpression in breast cancer cells; WDR1 overexpression increases MDA-MB-231 cell migration, which is attenuated by WDR1 knockdown.","method":"ChIP assay (STAT3 binding to WDR1 promoter), overexpression and knockdown, migration assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional KD/OE with defined phenotype, single lab","pmids":["27521604"],"is_preprint":false},{"year":2022,"finding":"WDR1-mediated actin depolymerization reduces cortical stress, which promotes YAP nuclear trafficking and reduces YAP phosphorylation in NSCLC cells; knockdown of WDR1 decreases nuclear YAP and increases phosphorylated YAP via the Hippo pathway, linking WDR1-dependent cytoskeletal tension to YAP/Hippo signaling in proliferation and migration.","method":"siRNA knockdown, pharmacological disruption of cortical stress, nuclear/cytoplasmic YAP fractionation, YAP phosphorylation immunoblotting, Hippo pathway inhibitor experiments","journal":"Experimental biology and medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD combined with pharmacological and pathway inhibitor experiments and multiple readouts, single lab","pmids":["35861209"],"is_preprint":false},{"year":2024,"finding":"WDR1 knockdown in prostate cancer cells inhibits proliferation, migration, and invasion; lithium chloride (Wnt/β-catenin pathway activator) restores these phenotypes, placing WDR1 upstream of β-catenin signaling as an activator of malignant behavior.","method":"siRNA knockdown and overexpression in PCa cell lines, proliferation/migration/invasion assays, LiCl rescue experiment","journal":"Medical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological rescue only, no direct biochemical link between WDR1 and β-catenin shown","pmids":["38743149"],"is_preprint":false},{"year":2002,"finding":"WDR1 protein co-localizes with ADF and F-actin in hair cells, homogene cells, and cuboidal cells of the normal chick cochlea, and WDR1 mRNA is upregulated in supporting cells after acoustic overstimulation, indicating that WDR1 acts together with ADF at sites of high actin dynamics in the inner ear.","method":"In situ hybridization, immunocytochemistry, co-localization analysis in developing and noise-damaged chick cochlea","journal":"The Journal of comparative neurology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization data only, no direct functional intervention; descriptive co-localization","pmids":["12115702"],"is_preprint":false}],"current_model":"WDR1 (AIP1) is a WD-repeat scaffold protein that functions as an obligate co-factor of ADF/cofilin: it preferentially binds cofilin-decorated actin filaments and dramatically accelerates their severing and depolymerization, while suppressing residual activity of phosphorylated cofilin, thereby controlling actin turnover in diverse cell types including neutrophils, megakaryocytes/platelets, B cells, neurons, cardiomyocytes, and epithelial cells; its activity is regulated post-translationally by Src-mediated tyrosine phosphorylation (erased by EYA3 phosphatase), and it participates in a functional complex with MYH9 and cofilin, can be sequestered by Keap1, and controls downstream signaling through cortical-tension-dependent YAP/Hippo and RhoA-MRTF-A pathways; loss of WDR1 function in humans causes autoinflammatory disease with excess IL-18/inflammasome activation and neutrophil dysfunction, while in mice it produces embryonic lethality, macrothrombocytopenia, defective platelet αIIbβ3 inside-out activation, impaired cardiac outflow tract development, and hippocampal synaptic plasticity defects."},"narrative":{"mechanistic_narrative":"WDR1 (AIP1) is a WD-repeat protein that functions as an obligate co-factor of ADF/cofilin, binding F-actin to dramatically accelerate cofilin-mediated filament severing and depolymerization and thereby controlling actin turnover across diverse cell types [PMID:17515402, PMID:25915128]. It localizes with cofilin to cortical actin and is required to deliver cofilin to the membrane skeleton; in its absence cofilin becomes aberrantly dispersed, F-actin accumulates in cytoplasmic aggregates, myosin is displaced from the cortex, and nuclear integrity is lost [PMID:29995657, PMID:31471458]. WDR1 additionally suppresses residual severing activity of phosphorylated cofilin, integrating with the LIMK-cofilin and coronin-1A arms of actin regulation to set the balance of assembly versus disassembly [PMID:15629458, PMID:31471458, PMID:33928084]. Its activity is tuned post-translationally by Src-mediated tyrosine phosphorylation, which is reversed by the EYA3 phosphatase, with loss of phosphorylation reshaping the cellular actin cytoskeleton [PMID:29440662]. Through control of actomyosin remodeling and cortical tension, WDR1 governs cell-shape changes in epithelial planar cell polarity [PMID:25915128], talin-dependent integrin αIIbβ3 activation and clot retraction in platelets [PMID:27627652, PMID:29995657], cardiomyocyte organization during outflow-tract development [PMID:29654745], and dendritic spine morphology underlying hippocampal synaptic plasticity and learning [PMID:30590446]. WDR1-dependent cytoskeletal tension also feeds into YAP/Hippo and RhoA-MRTF-A signaling to drive cancer cell proliferation and migration [PMID:28822708, PMID:35861209], and it can be sequestered by Keap1 and released to coordinate cofilin and Bax in mitochondrial apoptosis [PMID:34593792]. Biallelic loss-of-function mutations in WDR1 cause human autoinflammatory disease, with elevated F-actin in neutrophils, impaired chemotaxis and a nuclear herniation phenotype, and excess IL-18/caspase-1 inflammasome activation [PMID:27557945, PMID:27994071].","teleology":[{"year":2002,"claim":"Established the first cellular context for WDR1, asking where it acts relative to actin regulators, and showing it co-distributes with ADF and F-actin at sites of high actin dynamics.","evidence":"In situ hybridization and immunocytochemistry co-localization in chick cochlea","pmids":["12115702"],"confidence":"Low","gaps":["Descriptive co-localization only, no functional intervention","Does not establish a direct biochemical interaction with cofilin/ADF","No quantitative effect on actin turnover measured"]},{"year":2005,"claim":"Addressed whether WDR1 merely assists cofilin or has a distinct regulatory role, showing in vitro that it abolishes residual severing by phosphorylated cofilin and is required for mitotic cell rounding.","evidence":"RNAi knockdown plus direct in vitro filament severing/disassembly assays and live-cell morphology","pmids":["15629458"],"confidence":"Medium","gaps":["Single lab","Mechanism of how WDR1 suppresses phospho-cofilin activity not structurally resolved","Connection between mitotic rounding defect and severing activity inferential"]},{"year":2007,"claim":"Defined the in vivo requirement for the cofilin/WDR1 complex, using an allelic series to show that loss of WDR1 causes macrothrombocytopenia and autoinflammation through defective actin dynamics.","evidence":"Hypomorphic and null Wdr1 mouse alleles with megakaryocyte and neutrophil phenotyping","pmids":["17515402"],"confidence":"High","gaps":["Did not resolve the molecular link between actin defects and inflammation","Cell-type-specific contributions not separated"]},{"year":2015,"claim":"Showed how WDR1-driven disassembly translates into tissue morphogenesis, demonstrating it is required for actomyosin remodeling and cortical tension that establish planar cell polarity.","evidence":"Conditional KO mice, live imaging, cortical tension measurement, epistasis with cofilin/destrin depletion","pmids":["25915128"],"confidence":"High","gaps":["Upstream signals directing WDR1 activity in epidermis not defined","Link between cortical tension and PCP machinery not fully mechanistic"]},{"year":2016,"claim":"Established WDR1 as a human disease gene and confirmed its actin-depolymerizing role in primary cells, linking loss of function to neutrophil F-actin accumulation, impaired motility, and autoinflammation with elevated IL-18.","evidence":"Patient biallelic/missense mutation identification, proteomics, F-actin/G-actin measurement, chemotaxis assays, transplant rescue, caspase-1 cleavage and cytokine ELISA","pmids":["27557945","27994071"],"confidence":"High","gaps":["Mechanism connecting actin dysregulation to inflammasome/IL-18 not fully defined","Pyrin aggregation data from transfection only"]},{"year":2016,"claim":"Dissected WDR1's role in platelet biology, showing it suppresses platelet activity via actin regulation and is required for talin-dependent integrin αIIbβ3 inside-out activation.","evidence":"MEG-01 KD/OE with functional readouts; Wdr1-hypomorphic mouse platelets, thrombosis models, JON/A flow cytometry, actin fractionation, talin imaging","pmids":["27609643","27627652"],"confidence":"Medium","gaps":["Single lab for each study","Direct biochemical link between WDR1, talin redistribution, and integrin activation not reconstituted","STAT3-driven promoter regulation of WDR1 (27521604) shown only in cancer context"]},{"year":2018,"claim":"Identified post-translational control of WDR1, placing Src and the EYA3 phosphatase as writer and eraser of WDR1 tyrosine phosphorylation that reshapes the actin cytoskeleton.","evidence":"Phosphotyrosine peptide microarray, in vitro Src kinase and EYA3 phosphatase assays, WDR1 tyrosine mutagenesis, actin imaging","pmids":["29440662"],"confidence":"High","gaps":["Functional consequence of specific phospho-sites in vivo not established","Whether phosphorylation alters cofilin binding directly untested"]},{"year":2018,"claim":"Refined WDR1's mechanistic role at the membrane skeleton and in development, showing it is required for cofilin localization and F-actin-focal adhesion interaction in platelets and for cardiomyocyte spatial organization in the heart.","evidence":"Wdr1-hypomorphic mouse platelets with co-localization and Co-IP; cardiac/SHF-specific conditional KO mice with histology and myofibrillar staining","pmids":["29995657","29654745"],"confidence":"Medium","gaps":["Single lab studies","Cardiac phenotype mechanism limited to structural observation","Direct WDR1-FAK interaction not established"]},{"year":2019,"claim":"Resolved the consequences of unrestrained cofilin activity and established a tripartite regulatory network, showing coronin-1A depletion rescues WDR1-deficient neutrophils and that WDR1 enables actomyosin contractility and synaptic plasticity.","evidence":"Wdr1-deficient zebrafish with coronin 1A morpholino epistasis and myosin inhibitor; CA1-specific conditional KO mice with electrophysiology and behavior","pmids":["31471458","30590446"],"confidence":"High","gaps":["Molecular basis of WDR1-coronin-1A functional interplay not biochemically defined","Whether eruptive cell death mechanism generalizes to mammalian neutrophils untested"]},{"year":2021,"claim":"Extended WDR1 into immune-synapse and apoptotic signaling, showing it cooperates with LIMK-cofilin in BCR-induced actin remodeling and is released from Keap1 to coordinate cofilin and Bax in mitochondrial apoptosis.","evidence":"B-cell siRNA KD with imaging and BCR signaling readouts; redox-targeting with Wdr1/cofilin depletions and in vivo DMF administration","pmids":["33928084","34593792"],"confidence":"Medium","gaps":["Single lab for each","Direct WDR1-Bax and WDR1-Keap1 interactions not structurally resolved","Nrf2-independence of apoptotic mechanism incompletely mapped"]},{"year":2023,"claim":"Provided direct binding evidence and a defined complex, showing the small molecule gambogic amide binds WDR1 to promote a WDR1-MYH9-cofilin complex that accelerates depolymerization and induces apoptosis in glioma.","evidence":"CRISPR KO screen, CETSA, DARTS, SPR, docking, Co-IP, F-actin and apoptosis assays, PDX models","pmids":["37935665"],"confidence":"High","gaps":["Endogenous (drug-independent) role of the WDR1-MYH9-cofilin complex not defined","Generality beyond glioma untested"]},{"year":2024,"claim":"Probed WDR1's role in cancer signaling pathways, linking its cytoskeletal activity to YAP/Hippo, RhoA-MRTF-A, and β-catenin axes that drive proliferation and migration.","evidence":"siRNA KD/OE in NSCLC, breast, and prostate cancer cells with fractionation, pathway inhibitors, reporter assays, and LiCl rescue","pmids":["35861209","28822708","38743149"],"confidence":"Medium","gaps":["Prostate β-catenin link is pharmacological rescue only without direct biochemistry (Low confidence)","Whether signaling effects are universally downstream of actin tension not unified across tumor types"]},{"year":null,"claim":"How WDR1-dependent actin remodeling is mechanistically transduced into inflammasome/IL-18 activation and how its phospho-regulation and complex partners (MYH9, coronin-1A, Keap1) coordinate context-specific outputs remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of WDR1 on cofilin-decorated filaments","Causal chain from actin dysregulation to inflammasome assembly undefined","Endogenous regulatory inputs governing complex assembly unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3,4,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7,9,19]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,9,10]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,17]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11,14]}],"complexes":["WDR1-MYH9-cofilin complex"],"partners":["CFL1","MYH9","EYA3","SRC","KEAP1","LIMK","CORO1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75083","full_name":"WD repeat-containing protein 1","aliases":["Actin-interacting protein 1","AIP1","NORI-1"],"length_aa":606,"mass_kda":66.2,"function":"Induces disassembly of actin filaments in conjunction with ADF/cofilin family proteins (PubMed:15629458, PubMed:27557945, PubMed:29751004). Enhances cofilin-mediated actin severing (By similarity). Involved in cytokinesis. Involved in chemotactic cell migration by restricting lamellipodial membrane protrusions (PubMed:18494608). Involved in myocardium sarcomere organization. Required for cardiomyocyte growth and maintenance (By similarity). Involved in megakaryocyte maturation and platelet shedding. Required for the establishment of planar cell polarity (PCP) during follicular epithelium development and for cell shape changes during PCP; the function seems to implicate cooperation with CFL1 and/or DSTN/ADF. Involved in the generation/maintenance of cortical tension (By similarity). Involved in assembly and maintenance of epithelial apical cell junctions and plays a role in the organization of the perijunctional actomyosin belt (PubMed:25792565)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Cell projection, podosome; Cell junction","url":"https://www.uniprot.org/uniprotkb/O75083/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR1","classification":"Common Essential","n_dependent_lines":863,"n_total_lines":1208,"dependency_fraction":0.7144039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTB","stoichiometry":0.2},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2},{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR1","total_profiled":1310},"omim":[{"mim_id":"610778","title":"GUANINE NUCLEOTIDE-BINDING PROTEIN, BETA-1-LIKE; GNB1L","url":"https://www.omim.org/entry/610778"},{"mim_id":"604734","title":"WD REPEAT-CONTAINING PROTEIN 1; WDR1","url":"https://www.omim.org/entry/604734"},{"mim_id":"150550","title":"PERIODIC FEVER, IMMUNODEFICIENCY, AND THROMBOCYTOPENIA SYNDROME; PFITS","url":"https://www.omim.org/entry/150550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR1"},"hgnc":{"alias_symbol":["AIP1"],"prev_symbol":[]},"alphafold":{"accession":"O75083","domains":[{"cath_id":"2.130.10.10","chopping":"56-315","consensus_level":"high","plddt":97.3115,"start":56,"end":315},{"cath_id":"2.130.10.10","chopping":"494-606","consensus_level":"medium","plddt":96.9727,"start":494,"end":606}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75083","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75083-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75083-F1-predicted_aligned_error_v6.png","plddt_mean":96.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR1","jax_strain_url":"https://www.jax.org/strain/search?query=WDR1"},"sequence":{"accession":"O75083","fasta_url":"https://rest.uniprot.org/uniprotkb/O75083.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75083/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75083"}},"corpus_meta":[{"pmid":"27994071","id":"PMC_27994071","title":"Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1.","date":"2016","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27994071","citation_count":111,"is_preprint":false},{"pmid":"17515402","id":"PMC_17515402","title":"Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17515402","citation_count":95,"is_preprint":false},{"pmid":"27557945","id":"PMC_27557945","title":"Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency.","date":"2016","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/27557945","citation_count":91,"is_preprint":false},{"pmid":"29056508","id":"PMC_29056508","title":"Functions of actin-interacting protein 1 (AIP1)/WD repeat protein 1 (WDR1) in actin filament dynamics and cytoskeletal regulation.","date":"2017","source":"Biochemical and 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Dynamics.","date":"2018","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29989053","citation_count":26,"is_preprint":false},{"pmid":"34593792","id":"PMC_34593792","title":"Wdr1 and cofilin are necessary mediators of immune-cell-specific apoptosis triggered by Tecfidera.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34593792","citation_count":25,"is_preprint":false},{"pmid":"29440662","id":"PMC_29440662","title":"WDR1 is a novel EYA3 substrate and its dephosphorylation induces modifications of the cellular actin cytoskeleton.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29440662","citation_count":20,"is_preprint":false},{"pmid":"12115702","id":"PMC_12115702","title":"WDR1 colocalizes with ADF and actin in the normal and noise-damaged chick cochlea.","date":"2002","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/12115702","citation_count":19,"is_preprint":false},{"pmid":"31651553","id":"PMC_31651553","title":"MicroRNA-200a-3p Is a Positive Regulator in Cardiac Hypertrophy Through Directly Targeting WDR1 as Well as Modulating PTEN/PI3K/AKT/CREB/WDR1 Signaling.","date":"2019","source":"Journal of cardiovascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31651553","citation_count":19,"is_preprint":false},{"pmid":"33928084","id":"PMC_33928084","title":"The Wdr1-LIMK-Cofilin Axis Controls B Cell Antigen Receptor-Induced Actin Remodeling and Signaling at the Immune Synapse.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33928084","citation_count":13,"is_preprint":false},{"pmid":"33164271","id":"PMC_33164271","title":"TNK2-AS1 upregulated by YY1 boosts the course of osteosarcoma through targeting miR-4319/WDR1.","date":"2020","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/33164271","citation_count":13,"is_preprint":false},{"pmid":"31471458","id":"PMC_31471458","title":"Coronin 1A depletion restores the nuclear stability and viability of Aip1/Wdr1-deficient neutrophils.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31471458","citation_count":12,"is_preprint":false},{"pmid":"27627652","id":"PMC_27627652","title":"Wdr1-Dependent Actin Reorganization in Platelet Activation.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27627652","citation_count":9,"is_preprint":false},{"pmid":"29654745","id":"PMC_29654745","title":"WDR1-regulated actin dynamics is required for outflow tract and right ventricle development.","date":"2018","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/29654745","citation_count":8,"is_preprint":false},{"pmid":"32960541","id":"PMC_32960541","title":"WD Repeat Domain 1 (WDR1) Deficiency Presenting as a Cause of Infantile Inflammatory Bowel Disease.","date":"2020","source":"Journal of pediatric gastroenterology and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/32960541","citation_count":8,"is_preprint":false},{"pmid":"26438387","id":"PMC_26438387","title":"WDR1 and CLNK gene polymorphisms correlate with serum glucose and high-density lipoprotein levels in Tibetan gout patients.","date":"2015","source":"Rheumatology international","url":"https://pubmed.ncbi.nlm.nih.gov/26438387","citation_count":7,"is_preprint":false},{"pmid":"35861209","id":"PMC_35861209","title":"YAP signaling is involved in WDR1-regulated proliferation and migration of non-small-cell lung cancer cells.","date":"2022","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/35861209","citation_count":6,"is_preprint":false},{"pmid":"18514449","id":"PMC_18514449","title":"WDR1 presence in the songbird basilar papilla.","date":"2008","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/18514449","citation_count":5,"is_preprint":false},{"pmid":"27173277","id":"PMC_27173277","title":"Genetic variation in WDR1 is associated with gout risk and gout-related metabolic indices in the Han Chinese population.","date":"2016","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/27173277","citation_count":5,"is_preprint":false},{"pmid":"30590446","id":"PMC_30590446","title":"Hippocampal Wdr1 Deficit Impairs Learning and Memory by Perturbing F-actin Depolymerization in Mice.","date":"2019","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/30590446","citation_count":4,"is_preprint":false},{"pmid":"33233986","id":"PMC_33233986","title":"Long-noncoding RNA LINC00461 promotes proliferation and invasion of nonsmall cell lung cancer cells via targeting miR-518a-3p/WDR1 pathway.","date":"2020","source":"Journal of receptor and signal transduction research","url":"https://pubmed.ncbi.nlm.nih.gov/33233986","citation_count":3,"is_preprint":false},{"pmid":"38743149","id":"PMC_38743149","title":"WDR1 promotes prostate cancer progression through Wnt/β-catenin signaling.","date":"2024","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38743149","citation_count":2,"is_preprint":false},{"pmid":"18525142","id":"PMC_18525142","title":"WDR1 expression in the normal and noise-damaged chick vestibule.","date":"2007","source":"Journal of vestibular research : equilibrium & orientation","url":"https://pubmed.ncbi.nlm.nih.gov/18525142","citation_count":2,"is_preprint":false},{"pmid":"22821633","id":"PMC_22821633","title":"WDR1 expression in normal and noise-damaged Sprague-Dawley rat cochleae.","date":"2013","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/22821633","citation_count":1,"is_preprint":false},{"pmid":"29995657","id":"PMC_29995657","title":"Wdr-1 is essential for F-actin interaction with focal adhesions in platelets.","date":"2018","source":"Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/29995657","citation_count":1,"is_preprint":false},{"pmid":"30512154","id":"PMC_30512154","title":"[Effect of germ cell Wdr1 deletion on the ovarian function of mice].","date":"2018","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30512154","citation_count":0,"is_preprint":false},{"pmid":"39427801","id":"PMC_39427801","title":"LINC00668 silencing retards tumorigenesis via sponging miR-518c-3p to regulating WDR1 in triple negative breast cancer.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39427801","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17468,"output_tokens":5400,"usd":0.066702,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13749,"output_tokens":4516,"usd":0.090823,"stage2_stop_reason":"end_turn"},"total_usd":0.157525,"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\": 2007,\n      \"finding\": \"WDR1/Aip1 functions as a co-factor of cofilin to accelerate actin filament severing and depolymerization; loss-of-function (hypomorphic alleles) in mice causes macrothrombocytopenia due to megakaryocyte maturation defects and autoinflammatory disease with impaired cytoskeletal responses in neutrophils, establishing an essential in vivo role for the cofilin/WDR1 complex in actin dynamics in these cell types.\",\n      \"method\": \"Allelic series mouse genetics (hypomorphic and null Wdr1 alleles), cellular phenotyping of megakaryocytes and neutrophils, cytoskeletal assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function allelic series in mice with multiple defined cellular phenotypes replicated across cell types; foundational mechanism paper\",\n      \"pmids\": [\"17515402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Biallelic loss-of-function mutations in WDR1 in human patients cause elevated F-actin content (fourfold increase) in neutrophils, markedly impaired chemotaxis, cell polarization, and spreading, and a distinctive nuclear herniation phenotype, confirming that WDR1-dependent actin depolymerization is required for normal neutrophil morphology and motility.\",\n      \"method\": \"Identification of biallelic WDR1 mutations in patients, 2D-DIGE proteomics, F-actin/G-actin measurements, chemotaxis assays, allogeneic stem cell transplantation rescue\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (proteomics, functional assays, genetic rescue by transplant) in human primary cells across three families\",\n      \"pmids\": [\"27557945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A homozygous missense mutation in WDR1 causes autoinflammatory disease with elevated IL-18 (but not IL-1β) and increased caspase-1 cleavage in patient monocytes; mutant WDR1 protein forms aggregates that accumulate pyrin in transfected HEK293T cells, suggesting that impaired actin dynamics precipitates inflammasome assembly.\",\n      \"method\": \"Patient genetic analysis, ELISA for cytokines, caspase-1 cleavage assay in monocytes, transfection/aggregation assay in HEK293T cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cellular assays with patient cells plus transfection aggregation data, single lab\",\n      \"pmids\": [\"27994071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Suppression of AIP1/WDR1 causes mitotic cell flattening instead of normal rounding; in vitro filament severing/disassembly assays showed that AIP1/WDR1 abolishes residual actin-severing activity of phosphorylated cofilin, indicating that WDR1 is required to fully suppress actin turnover and thereby enable mitotic cell rounding.\",\n      \"method\": \"RNAi knockdown in cells, direct in vitro actin filament severing/disassembly assay, live-cell morphology observation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro actin assay plus cellular KD phenotype, single lab\",\n      \"pmids\": [\"15629458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Wdr1 (Aip1), an F-actin-binding protein that enhances cofilin/destrin-mediated F-actin disassembly, is required for actomyosin remodeling, cortical tension generation, and the cell shape changes that establish planar cell polarity (PCP) in developing mouse epidermis; Wdr1 depletion alone recapitulates core PCP mutations.\",\n      \"method\": \"Conditional KO mice, live imaging, cortical tension measurements, genetic epistasis with cofilin/destrin double depletion\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO genetics, live imaging, tension measurement, epistasis) in vivo\",\n      \"pmids\": [\"25915128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WDR1 knockdown in megakaryoblastic MEG-01 cells increases F-actin content, adhesion, spreading, and basal intracellular calcium, and produces fewer but larger platelet-like particles with enhanced adhesion; WDR1 overexpression reverses these phenotypes, demonstrating that WDR1 suppresses platelet activity by regulating actin cytoskeleton dynamics.\",\n      \"method\": \"siRNA knockdown and overexpression in MEG-01 cells, F-actin measurement, adhesion/spreading assays, calcium imaging, platelet-like particle characterization\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal KD/OE with multiple functional readouts, single lab\",\n      \"pmids\": [\"27609643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Wdr1-hypomorphic mouse platelets, actin turnover (F-actin/G-actin ratio) is impaired during collagen- and thrombin-induced aggregation, integrin αIIbβ3 inside-out activation is defective despite normal calcium responses, and talin fails to redistribute to the cytoskeleton, establishing that WDR1-mediated actin remodeling is required for talin-dependent αIIbβ3 activation.\",\n      \"method\": \"Wdr1-hypomorphic mice, bleeding time, FeCl3 thrombosis model, JON/A flow cytometry for activated αIIbβ3, F-actin/G-actin fractionation, talin immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and ex vivo assays with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"27627652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wdr-1 co-localizes with cofilin-1 in cortical actin of resting platelets and translocates together with cofilin-1 to the cytoskeleton upon fibrinogen adhesion; in Wdr-1-deficient platelets cofilin-1 is aberrantly distributed throughout the cytoplasm, F-actin fails to attach to focal adhesion kinase, and clot retraction and spreading are impaired, demonstrating that Wdr-1 is required for cofilin-1 localization to the membrane skeleton and F-actin–focal adhesion interaction.\",\n      \"method\": \"Wdr-1-hypomorphic mice, immunofluorescence/confocal co-localization, F-actin–focal adhesion kinase co-immunoprecipitation/immunoblotting, clot retraction assay, spreading assay\",\n      \"journal\": \"Blood coagulation & fibrinolysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-localization plus biochemical interaction data linked to functional phenotype, single lab\",\n      \"pmids\": [\"29995657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EYA3 tyrosine phosphatase dephosphorylates WDR1 on tyrosine residues that are phosphorylated by Src kinase; loss of WDR1 tyrosine phosphorylation causes major changes to the cellular actin cytoskeleton, identifying WDR1 as an EYA3-specific substrate and placing Src/EYA3 as writer/eraser of WDR1 phosphorylation in cytoskeletal regulation.\",\n      \"method\": \"Phosphotyrosine peptide microarray to identify EYA3 substrates, in vitro kinase (Src) and phosphatase (EYA3/EYA1) assays, site-directed mutagenesis of WDR1 tyrosine residues, actin cytoskeleton imaging\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assays (peptide array, kinase, phosphatase) plus mutagenesis and cellular phenotype, single lab\",\n      \"pmids\": [\"29440662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Wdr1-deficient zebrafish neutrophils, cofilin is predominantly unphosphorylated and associated with F-actin, displacing myosin; this leads to F-actin cytoplasmic aggregates, loss of phospho-myosin cortical localization, nuclear disorganization, and eruptive cell death. Depletion of coronin 1A fully rescues cortical F-actin distribution, nuclear integrity, viability, and mobility in Wdr1-deficient neutrophils, establishing a functional interplay between Wdr1, cofilin, and coronin 1A in regulating F-actin and actomyosin contractility.\",\n      \"method\": \"Wdr1-deficient zebrafish embryos, coronin 1A morpholino depletion, live imaging, F-actin/phospho-myosin immunofluorescence, myosin inhibitor experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis (double depletion rescue) with multiple orthogonal imaging readouts, rigorous controls including pharmacological intervention\",\n      \"pmids\": [\"31471458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Wdr1 and LIMK have distinct roles in BCR-induced actin remodeling at the B cell immune synapse: Wdr1 enhances cofilin-mediated actin disassembly while LIMK phosphorylates and inactivates cofilin; both the Wdr1-LIMK-cofilin axis collectively controls peripheral actin assembly, B cell spreading, and actin-dependent amplification of BCR signaling.\",\n      \"method\": \"siRNA knockdown of Wdr1, LIMK, and Cotl1 in B cells, live imaging of BCR microcluster dynamics, spreading assays, BCR signaling measurements at immune synapse\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple functional readouts (morphology, signaling) and comparative epistasis, single lab\",\n      \"pmids\": [\"33928084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In response to dimethyl fumarate (Tecfidera), Keap1-specific modification triggers dissociation of Wdr1 from Keap1; released Wdr1 then coordinates with cofilin to intercept Bax, driving mitochondrial-targeted apoptosis specifically in neutrophils and macrophages in a process largely independent of canonical Nrf2 signaling.\",\n      \"method\": \"Redox-targeting approach, genetic depletions of Wdr1 and cofilin, whole-animal DMF administration, mechanistic dissection via individual component knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic genetic dissection with multiple depletions and in vivo validation, single lab\",\n      \"pmids\": [\"34593792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cardiac-specific or second-heart-field-specific deletion of Wdr1 in mice causes embryonic lethality with hypoplasia of the outflow tract and right ventricle, disrupted cardiomyocyte cellular organization and myofibrillar assembly without changes in cell number or proliferation, demonstrating that WDR1-mediated actin dynamics is required for spatial arrangement of cardiomyocytes during heart development.\",\n      \"method\": \"Conditional KO mice (Nkx2.5-Cre and SHF-Cre), histology, cell number/proliferation quantification, myofibrillar immunostaining\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean tissue-specific KO with defined structural phenotype, single lab\",\n      \"pmids\": [\"29654745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Conditional knockout of Wdr1 in hippocampal CA1 neurons in mice impairs actin depolymerization (via ADF/cofilin activity dysregulation), alters dendritic spine morphology, enhances LTP, impairs LTD, and causes deficits in reversal spatial learning and fear responses, establishing that Wdr1-mediated actin dynamics in hippocampal neurons is required for synaptic plasticity and associative learning.\",\n      \"method\": \"Conditional KO mice (CA1-specific), spine morphology analysis, electrophysiology (LTP/LTD), behavioral tests, actin dynamics (F-actin/G-actin fractionation), cofilin activity assay\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple orthogonal mechanistic readouts, single lab\",\n      \"pmids\": [\"30590446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The small molecule gambogic amide directly binds WDR1 (confirmed by CETSA, DARTS, molecular docking, and SPR), and through this interaction promotes formation of a WDR1–MYH9–cofilin complex that accelerates F-actin depolymerization, inhibits glioma cell invasion, and induces apoptosis via the mitochondrial pathway.\",\n      \"method\": \"CRISPR genome-wide KO screen, CETSA, DARTS, SPR, molecular docking, co-immunoprecipitation (WDR1–MYH9–cofilin complex), F-actin assay, apoptosis assay, PDX in vivo models\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding confirmed by four orthogonal methods plus complex formation and functional consequence, in vivo validation\",\n      \"pmids\": [\"37935665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WDR1 promotes nuclear import of MRTF-A by affecting expression of importin nuclear transport protein, thereby enhancing MRTF-A-induced breast cancer cell migration via RhoA-MRTF-A signaling; MRTF-A in turn drives expression of miR-206 which feeds back to suppress WDR1 and MRTF-A via their 3'UTRs.\",\n      \"method\": \"Overexpression and knockdown in MDA-MB-231 cells, nuclear/cytoplasmic fractionation, migration assays, qRT-PCR, 3'UTR luciferase reporter assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional and mechanistic assays, single lab\",\n      \"pmids\": [\"28822708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STAT3 binds directly to a putative promoter region (-1971 to -1964) of the WDR1 gene and its activation drives WDR1 overexpression in breast cancer cells; WDR1 overexpression increases MDA-MB-231 cell migration, which is attenuated by WDR1 knockdown.\",\n      \"method\": \"ChIP assay (STAT3 binding to WDR1 promoter), overexpression and knockdown, migration assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional KD/OE with defined phenotype, single lab\",\n      \"pmids\": [\"27521604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WDR1-mediated actin depolymerization reduces cortical stress, which promotes YAP nuclear trafficking and reduces YAP phosphorylation in NSCLC cells; knockdown of WDR1 decreases nuclear YAP and increases phosphorylated YAP via the Hippo pathway, linking WDR1-dependent cytoskeletal tension to YAP/Hippo signaling in proliferation and migration.\",\n      \"method\": \"siRNA knockdown, pharmacological disruption of cortical stress, nuclear/cytoplasmic YAP fractionation, YAP phosphorylation immunoblotting, Hippo pathway inhibitor experiments\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD combined with pharmacological and pathway inhibitor experiments and multiple readouts, single lab\",\n      \"pmids\": [\"35861209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WDR1 knockdown in prostate cancer cells inhibits proliferation, migration, and invasion; lithium chloride (Wnt/β-catenin pathway activator) restores these phenotypes, placing WDR1 upstream of β-catenin signaling as an activator of malignant behavior.\",\n      \"method\": \"siRNA knockdown and overexpression in PCa cell lines, proliferation/migration/invasion assays, LiCl rescue experiment\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological rescue only, no direct biochemical link between WDR1 and β-catenin shown\",\n      \"pmids\": [\"38743149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"WDR1 protein co-localizes with ADF and F-actin in hair cells, homogene cells, and cuboidal cells of the normal chick cochlea, and WDR1 mRNA is upregulated in supporting cells after acoustic overstimulation, indicating that WDR1 acts together with ADF at sites of high actin dynamics in the inner ear.\",\n      \"method\": \"In situ hybridization, immunocytochemistry, co-localization analysis in developing and noise-damaged chick cochlea\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization data only, no direct functional intervention; descriptive co-localization\",\n      \"pmids\": [\"12115702\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR1 (AIP1) is a WD-repeat scaffold protein that functions as an obligate co-factor of ADF/cofilin: it preferentially binds cofilin-decorated actin filaments and dramatically accelerates their severing and depolymerization, while suppressing residual activity of phosphorylated cofilin, thereby controlling actin turnover in diverse cell types including neutrophils, megakaryocytes/platelets, B cells, neurons, cardiomyocytes, and epithelial cells; its activity is regulated post-translationally by Src-mediated tyrosine phosphorylation (erased by EYA3 phosphatase), and it participates in a functional complex with MYH9 and cofilin, can be sequestered by Keap1, and controls downstream signaling through cortical-tension-dependent YAP/Hippo and RhoA-MRTF-A pathways; loss of WDR1 function in humans causes autoinflammatory disease with excess IL-18/inflammasome activation and neutrophil dysfunction, while in mice it produces embryonic lethality, macrothrombocytopenia, defective platelet αIIbβ3 inside-out activation, impaired cardiac outflow tract development, and hippocampal synaptic plasticity defects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR1 (AIP1) is a WD-repeat protein that functions as an obligate co-factor of ADF/cofilin, binding F-actin to dramatically accelerate cofilin-mediated filament severing and depolymerization and thereby controlling actin turnover across diverse cell types [#0, #4]. It localizes with cofilin to cortical actin and is required to deliver cofilin to the membrane skeleton; in its absence cofilin becomes aberrantly dispersed, F-actin accumulates in cytoplasmic aggregates, myosin is displaced from the cortex, and nuclear integrity is lost [#7, #9]. WDR1 additionally suppresses residual severing activity of phosphorylated cofilin, integrating with the LIMK-cofilin and coronin-1A arms of actin regulation to set the balance of assembly versus disassembly [#3, #9, #10]. Its activity is tuned post-translationally by Src-mediated tyrosine phosphorylation, which is reversed by the EYA3 phosphatase, with loss of phosphorylation reshaping the cellular actin cytoskeleton [#8]. Through control of actomyosin remodeling and cortical tension, WDR1 governs cell-shape changes in epithelial planar cell polarity [#4], talin-dependent integrin \\u03b1IIb\\u03b23 activation and clot retraction in platelets [#6, #7], cardiomyocyte organization during outflow-tract development [#12], and dendritic spine morphology underlying hippocampal synaptic plasticity and learning [#13]. WDR1-dependent cytoskeletal tension also feeds into YAP/Hippo and RhoA-MRTF-A signaling to drive cancer cell proliferation and migration [#15, #17], and it can be sequestered by Keap1 and released to coordinate cofilin and Bax in mitochondrial apoptosis [#11]. Biallelic loss-of-function mutations in WDR1 cause human autoinflammatory disease, with elevated F-actin in neutrophils, impaired chemotaxis and a nuclear herniation phenotype, and excess IL-18/caspase-1 inflammasome activation [#1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the first cellular context for WDR1, asking where it acts relative to actin regulators, and showing it co-distributes with ADF and F-actin at sites of high actin dynamics.\",\n      \"evidence\": \"In situ hybridization and immunocytochemistry co-localization in chick cochlea\",\n      \"pmids\": [\"12115702\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Descriptive co-localization only, no functional intervention\", \"Does not establish a direct biochemical interaction with cofilin/ADF\", \"No quantitative effect on actin turnover measured\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Addressed whether WDR1 merely assists cofilin or has a distinct regulatory role, showing in vitro that it abolishes residual severing by phosphorylated cofilin and is required for mitotic cell rounding.\",\n      \"evidence\": \"RNAi knockdown plus direct in vitro filament severing/disassembly assays and live-cell morphology\",\n      \"pmids\": [\"15629458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of how WDR1 suppresses phospho-cofilin activity not structurally resolved\", \"Connection between mitotic rounding defect and severing activity inferential\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the in vivo requirement for the cofilin/WDR1 complex, using an allelic series to show that loss of WDR1 causes macrothrombocytopenia and autoinflammation through defective actin dynamics.\",\n      \"evidence\": \"Hypomorphic and null Wdr1 mouse alleles with megakaryocyte and neutrophil phenotyping\",\n      \"pmids\": [\"17515402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular link between actin defects and inflammation\", \"Cell-type-specific contributions not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed how WDR1-driven disassembly translates into tissue morphogenesis, demonstrating it is required for actomyosin remodeling and cortical tension that establish planar cell polarity.\",\n      \"evidence\": \"Conditional KO mice, live imaging, cortical tension measurement, epistasis with cofilin/destrin depletion\",\n      \"pmids\": [\"25915128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals directing WDR1 activity in epidermis not defined\", \"Link between cortical tension and PCP machinery not fully mechanistic\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established WDR1 as a human disease gene and confirmed its actin-depolymerizing role in primary cells, linking loss of function to neutrophil F-actin accumulation, impaired motility, and autoinflammation with elevated IL-18.\",\n      \"evidence\": \"Patient biallelic/missense mutation identification, proteomics, F-actin/G-actin measurement, chemotaxis assays, transplant rescue, caspase-1 cleavage and cytokine ELISA\",\n      \"pmids\": [\"27557945\", \"27994071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting actin dysregulation to inflammasome/IL-18 not fully defined\", \"Pyrin aggregation data from transfection only\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dissected WDR1's role in platelet biology, showing it suppresses platelet activity via actin regulation and is required for talin-dependent integrin \\u03b1IIb\\u03b23 inside-out activation.\",\n      \"evidence\": \"MEG-01 KD/OE with functional readouts; Wdr1-hypomorphic mouse platelets, thrombosis models, JON/A flow cytometry, actin fractionation, talin imaging\",\n      \"pmids\": [\"27609643\", \"27627652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab for each study\", \"Direct biochemical link between WDR1, talin redistribution, and integrin activation not reconstituted\", \"STAT3-driven promoter regulation of WDR1 (27521604) shown only in cancer context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified post-translational control of WDR1, placing Src and the EYA3 phosphatase as writer and eraser of WDR1 tyrosine phosphorylation that reshapes the actin cytoskeleton.\",\n      \"evidence\": \"Phosphotyrosine peptide microarray, in vitro Src kinase and EYA3 phosphatase assays, WDR1 tyrosine mutagenesis, actin imaging\",\n      \"pmids\": [\"29440662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of specific phospho-sites in vivo not established\", \"Whether phosphorylation alters cofilin binding directly untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Refined WDR1's mechanistic role at the membrane skeleton and in development, showing it is required for cofilin localization and F-actin-focal adhesion interaction in platelets and for cardiomyocyte spatial organization in the heart.\",\n      \"evidence\": \"Wdr1-hypomorphic mouse platelets with co-localization and Co-IP; cardiac/SHF-specific conditional KO mice with histology and myofibrillar staining\",\n      \"pmids\": [\"29995657\", \"29654745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab studies\", \"Cardiac phenotype mechanism limited to structural observation\", \"Direct WDR1-FAK interaction not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the consequences of unrestrained cofilin activity and established a tripartite regulatory network, showing coronin-1A depletion rescues WDR1-deficient neutrophils and that WDR1 enables actomyosin contractility and synaptic plasticity.\",\n      \"evidence\": \"Wdr1-deficient zebrafish with coronin 1A morpholino epistasis and myosin inhibitor; CA1-specific conditional KO mice with electrophysiology and behavior\",\n      \"pmids\": [\"31471458\", \"30590446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of WDR1-coronin-1A functional interplay not biochemically defined\", \"Whether eruptive cell death mechanism generalizes to mammalian neutrophils untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended WDR1 into immune-synapse and apoptotic signaling, showing it cooperates with LIMK-cofilin in BCR-induced actin remodeling and is released from Keap1 to coordinate cofilin and Bax in mitochondrial apoptosis.\",\n      \"evidence\": \"B-cell siRNA KD with imaging and BCR signaling readouts; redox-targeting with Wdr1/cofilin depletions and in vivo DMF administration\",\n      \"pmids\": [\"33928084\", \"34593792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab for each\", \"Direct WDR1-Bax and WDR1-Keap1 interactions not structurally resolved\", \"Nrf2-independence of apoptotic mechanism incompletely mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided direct binding evidence and a defined complex, showing the small molecule gambogic amide binds WDR1 to promote a WDR1-MYH9-cofilin complex that accelerates depolymerization and induces apoptosis in glioma.\",\n      \"evidence\": \"CRISPR KO screen, CETSA, DARTS, SPR, docking, Co-IP, F-actin and apoptosis assays, PDX models\",\n      \"pmids\": [\"37935665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous (drug-independent) role of the WDR1-MYH9-cofilin complex not defined\", \"Generality beyond glioma untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Probed WDR1's role in cancer signaling pathways, linking its cytoskeletal activity to YAP/Hippo, RhoA-MRTF-A, and \\u03b2-catenin axes that drive proliferation and migration.\",\n      \"evidence\": \"siRNA KD/OE in NSCLC, breast, and prostate cancer cells with fractionation, pathway inhibitors, reporter assays, and LiCl rescue\",\n      \"pmids\": [\"35861209\", \"28822708\", \"38743149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Prostate \\u03b2-catenin link is pharmacological rescue only without direct biochemistry (Low confidence)\", \"Whether signaling effects are universally downstream of actin tension not unified across tumor types\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR1-dependent actin remodeling is mechanistically transduced into inflammasome/IL-18 activation and how its phospho-regulation and complex partners (MYH9, coronin-1A, Keap1) coordinate context-specific outputs remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of WDR1 on cofilin-decorated filaments\", \"Causal chain from actin dysregulation to inflammasome assembly undefined\", \"Endogenous regulatory inputs governing complex assembly unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3, 4, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7, 9, 19]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 9, 10]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 17]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 14]}\n    ],\n    \"complexes\": [\"WDR1-MYH9-cofilin complex\"],\n    \"partners\": [\"CFL1\", \"MYH9\", \"EYA3\", \"Src\", \"KEAP1\", \"LIMK\", \"CORO1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}