{"gene":"WT1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1993,"finding":"WT-1 is required for early kidney and gonad development; homozygous null mice show metanephric blastema apoptosis, failure of ureteric bud outgrowth, and absence of kidney and gonad formation, establishing WT1 as essential for the inductive events of metanephric kidney development.","method":"Gene targeting in embryonic stem cells (knockout mouse); histological and developmental analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with specific developmental phenotype, widely replicated as foundational result","pmids":["8395349"],"is_preprint":false},{"year":1993,"finding":"WT1 protein physically associates with p53 in transfected cells; this interaction modulates transcriptional activity: in the absence of p53, WT1 acts as a transcriptional activator of EGR1 sites rather than a repressor, and WT1 cooperatively enhances p53-mediated transactivation of the muscle creatine kinase promoter.","method":"Co-immunoprecipitation in transfected cells; transient transfection transcriptional reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional reporter assays, single lab","pmids":["8389468"],"is_preprint":false},{"year":1995,"finding":"WT1 can self-associate in vitro and in vivo through its amino-terminal domain; mutant WT1 alleles that impair DNA recognition can oligomerize with wild-type WT1 and antagonize WT1-mediated transcriptional repression, providing a molecular mechanism for dominant-negative action of Denys-Drash syndrome mutations.","method":"In vitro binding assay; co-immunoprecipitation in cells; transcriptional repression reporter assay with mutant alleles","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro assay plus Co-IP plus functional reporter, single lab","pmids":["7479946"],"is_preprint":false},{"year":1995,"finding":"Denys-Drash syndrome missense and truncating mutations in the WT1 zinc finger domain abolish DNA binding to all tested WT1 targets (EGR1 consensus, IGF2P2, PDGFA-chain promoter, and +P5 genomic fragment) for both -KTS and +KTS isoforms, indicating these mutations act as dominant-negative antimorphs or through disturbed isoform dosage.","method":"GST fusion protein DNA-binding assay with recombinant wild-type and mutant WT1 zinc finger domains","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted DNA-binding assay with mutagenesis, multiple targets tested, single lab","pmids":["7795587"],"is_preprint":false},{"year":1996,"finding":"Structural modelling identified an evolutionarily conserved N-terminal RNA recognition motif (RRM) in all known WT1 isoforms, similar to the constitutive splicing factor U1A; WT1 co-immunoprecipitates with spliceosomal proteins and its subnuclear speckled localization is abolished by RNA degradation, indicating WT1 binds RNA and associates with the splicing machinery.","method":"Structural modelling; co-immunoprecipitation with spliceosomal proteins; RNA degradation experiment affecting subnuclear localization","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — structural modelling plus Co-IP plus localization experiment, single lab, multiple orthogonal methods","pmids":["8589729"],"is_preprint":false},{"year":2000,"finding":"E-cadherin is a direct transcriptional target of WT1; WT1 activates E-cadherin promoter activity through a conserved GC-rich EGR1-like binding site and a CAAT box, and WT1 protein produced in vitro or from nuclear extracts directly binds the WT1-response element in the E-cadherin promoter.","method":"Transient transfection reporter assays; retroviral overexpression in NIH 3T3 cells; in vitro transcription/translation and nuclear extract DNA-binding assay (EMSA)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro DNA binding reconstitution plus promoter reporter assays plus gain-of-function cellular assay, single lab, multiple orthogonal methods","pmids":["10753894"],"is_preprint":false},{"year":2006,"finding":"WT1 directly interacts with heterogeneous nuclear ribonucleoprotein U (hnRNP-U); this interaction is direct (does not require other proteins or nucleic acids), involves the zinc fingers of WT1 and the middle domain of hnRNP-U, and hnRNP-U modulates WT1 transcriptional activation of a bona fide WT1 target gene.","method":"Genetic and biochemical approaches including co-immunoprecipitation of endogenous proteins; domain-mapping pulldown; transcriptional reporter assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP of endogenous proteins plus domain mapping plus functional reporter, single lab","pmids":["16924231"],"is_preprint":false},{"year":2008,"finding":"WT1 and its transcriptional cosuppressor BASP1 co-occupy promoters of Bak, c-myc, and podocalyxin genes in podocyte precursor cells; during differentiation, BASP1 occupancy is selectively reduced at the podocalyxin promoter allowing activation, while the repressive WT1/BASP1 complex is maintained at c-myc and Bak promoters; regulation of BASP1 promoter occupancy involves sumoylation of BASP1.","method":"Chromatin immunoprecipitation (ChIP) in podocyte precursor cell line during differentiation; sumoylation analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP in differentiating cells with multiple promoters examined, single lab","pmids":["19050011"],"is_preprint":false},{"year":2008,"finding":"Histone deacetylase inhibitor Trichostatin A (TSA) downregulates Wt1 expression primarily by cessation of transcription mediated by sequences in intron 3, and also enhances Wt1 protein degradation by the proteasome, at least partly through induction of the ubiquitin-conjugating enzyme UBCH8.","method":"Cell line treatment with TSA; transcriptional run-on/reporter assays; proteasome inhibitor experiments; UBCH8 induction analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays (transcriptional, proteasomal, ubiquitin pathway), single lab","pmids":["18535006"],"is_preprint":false},{"year":2009,"finding":"WT1(+KTS) isoform cell-autonomously regulates Sry expression in XY gonads; Wt1(+KTS)-null mice show reduced SRY protein per cell and fewer SRY-expressing cells, reduced cell proliferation at the coelomic epithelium, and blocked Sertoli cell differentiation (loss of SOX9/Fgf9); addition of recombinant FGF9 to ex vivo gonad cultures rescued the mutant phenotype, indicating WT1(+KTS) acts upstream of Sry, which in turn drives cell proliferation and Sertoli differentiation via FGF9.","method":"Immunofluorescence analysis; targeted Wt1(+KTS)-null mouse model; ex vivo gonad culture with recombinant FGF9 rescue experiment","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific genetic model with defined rescue experiment and multiple cellular readouts","pmids":["19549635"],"is_preprint":false},{"year":2010,"finding":"WT1 is a critical regulator of senescence and proliferation downstream of oncogenic KRAS signaling; deletion or suppression of Wt1 leads to senescence of mouse primary cells expressing physiological levels of oncogenic Kras, decreases tumor burden in a Kras-driven lung cancer mouse model, and in human lung cancer lines dependent on KRAS, WT1 loss decreases proliferation and induces senescence.","method":"Functional genomics screen; mouse genetics (Wt1 conditional deletion in Kras-driven lung cancer model); shRNA knockdown in human cell lines; senescence assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — combination of functional genomics, in vivo mouse model, and human cell line validation with specific phenotypic readouts","pmids":["20972333"],"is_preprint":false},{"year":2010,"finding":"WT1 activates transcription of CXXC5/WID, a gene that negatively regulates WNT/β-catenin signaling through Dishevelled; WT1 acts through an upstream enhancer region of WID; WID protein interacts with Dishevelled via its C-terminal CXXC zinc finger and Dishevelled-binding domains, inhibiting WNT/β-catenin signaling in vitro and in vivo.","method":"Transcriptional reporter assay; promoter/enhancer deletion analysis; co-immunoprecipitation; antisense morpholino knockdown in zebrafish; in vivo WNT signaling assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays plus Co-IP plus in vivo rescue, single lab, multiple methods","pmids":["20220130"],"is_preprint":false},{"year":2013,"finding":"Prohibitin is part of the WT1-BASP1 transcriptional repression complex; prohibitin interacts with BASP1, co-localizes with BASP1 in the nucleus, and is recruited to WT1 target gene promoters to elicit BASP1-dependent transcriptional repression; BASP1 and prohibitin cooperate to recruit chromatin remodeling factor BRG1 and to cause dissociation of CBP from WT1-responsive promoters, and are also required for recruitment of PIP2 and HDAC1 to these promoters.","method":"Co-immunoprecipitation; ChIP; immunofluorescence co-localization; transcriptional reporter assays; knockdown experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ChIP plus functional reporter assays, single lab, multiple orthogonal methods","pmids":["24166496"],"is_preprint":false},{"year":2013,"finding":"WT1 regulates expression of inhibitory chemokines CCL5 and CXCL10 in epicardial cells by direct and indirect (via IRF7) transcriptional repression; CXCL10 inhibits epicardial cell migration and CCL5 inhibits cardiomyocyte proliferation, revealing a role for WT1 in heart morphogenesis through chemokine repression.","method":"Transcriptome analysis of Wt1KO epicardial cells; functional migration and proliferation assays with recombinant chemokines; ChIP; IRF7 expression analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomics plus functional assays plus ChIP, single lab","pmids":["23900076"],"is_preprint":false},{"year":2015,"finding":"WT1 regulates the fidelity of chromosome segregation through interaction with the spindle assembly checkpoint protein MAD2; WT1 delays anaphase entry by inhibiting the ubiquitination activity of the Anaphase Promoting Complex/Cyclosome (APC/C).","method":"Co-immunoprecipitation; functional cell division assays; APC/C ubiquitination assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional APC/C assay, single lab","pmids":["25789599"],"is_preprint":false},{"year":2018,"finding":"Loss of WT1 in mature podocytes activates Notch signaling (upregulation of Notch1 and transcriptional targets including Nrarp, HES1), with repression of FoxC2 and upregulation of Hey2, implicating a WT1/FoxC2/Notch transcriptional network in podocyte injury; HES1 induction was associated with upregulation of epithelial-mesenchymal transition genes; pharmacological Notch inhibition ameliorated glomerular scarring and albuminuria.","method":"Tamoxifen-inducible CRE-LoxP Wt1 deletion in adult mice; immunofluorescence; gene expression analysis; pharmacological Notch inhibition","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined molecular pathway, pharmacological rescue, single lab","pmids":["29398135"],"is_preprint":false},{"year":2021,"finding":"PRMT5 regulates WT1 protein levels in granulosa cells by facilitating IRES-dependent translation of Wt1 mRNA through methylation of HnRNPA1; loss of PRMT5 dramatically reduces WT1 protein without affecting mRNA levels, and Wt1 overexpression rescues the premature differentiation phenotype caused by Prmt5 deletion.","method":"Conditional Prmt5 knockout mice; western blot and qRT-PCR; IRES-dependent translation assay; WT1 overexpression rescue experiment; HnRNPA1 methylation analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined rescue, IRES translation assay, methylation of identified substrate, single lab","pmids":["34448450"],"is_preprint":false},{"year":2022,"finding":"Autophagy degrades WT1 protein in ovarian granulosa cells; inhibition of autophagy (by siRNA knockdown of ATG5/BECN1 or chloroquine treatment) causes WT1 accumulation and inhibits granulosa cell differentiation (reduced CYP19A1/FSHR expression and estradiol synthesis), establishing autophagy-mediated degradation of WT1 as a mechanism regulating granulosa cell differentiation.","method":"siRNA knockdown of ATG5 and BECN1; pharmacological autophagy inhibition with chloroquine; co-immunoprecipitation; cycloheximide chase assay; western blot for autophagy markers","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological inhibition of autophagy with defined protein accumulation and functional differentiation readout, single lab","pmids":["35025698"],"is_preprint":false}],"current_model":"WT1 is a multi-isoform zinc finger protein that functions as both a transcriptional activator/repressor (binding EGR1-like DNA sequences to regulate target genes including E-cadherin, CXXC5/WID, and chemokines CCL5/CXCL10) and an RNA-binding/processing factor (via an N-terminal RRM, association with spliceosomal proteins, and IRES-dependent translation regulation); its transcriptional repression is executed through a complex with BASP1 and prohibitin that recruits BRG1, HDAC1, and PIP2 to promoters; WT1 physically interacts with p53 and hnRNP-U to modulate their activities, self-associates through its N-terminal domain enabling dominant-negative inhibition by Denys-Drash mutations, interacts with MAD2 to inhibit APC/C and regulate chromosome segregation, and is regulated post-translationally by autophagy-mediated degradation and proteasomal degradation facilitated by UBCH8; the +KTS isoform cell-autonomously regulates Sry expression upstream of FGF9-driven Sertoli cell differentiation, while WT1 is essential for kidney morphogenesis (metanephric blastema survival and ureteric bud outgrowth) and acts as a downstream effector of oncogenic KRAS signaling to suppress cellular senescence."},"narrative":{"mechanistic_narrative":"WT1 is a zinc finger transcription factor that orchestrates organogenesis of the kidney and gonad and modulates cellular proliferation, with loss-of-function causing metanephric blastema apoptosis, failure of ureteric bud outgrowth, and absence of kidney and gonad [PMID:8395349]. Through its zinc fingers it binds EGR1-like GC-rich elements to control specific target genes, directly activating E-cadherin via a conserved WT1-response element [PMID:10753894] and CXXC5/WID to restrain WNT/β-catenin signaling [PMID:20220130], while repressing other targets; its repressive output is executed by a BASP1–prohibitin corepressor module that recruits BRG1, HDAC1, and PIP2 and displaces CBP from WT1-responsive promoters [PMID:19050011, PMID:24166496]. WT1 activity is further shaped by direct protein partners: it associates with p53 to switch between activation and repression [PMID:8389468], binds hnRNP-U through its zinc fingers to modulate transactivation [PMID:16924231], and self-associates via its N-terminal domain, the basis for dominant-negative action of Denys-Drash zinc finger mutations that abolish DNA binding [PMID:7479946, PMID:7795587]. Beyond transcription, WT1 contains a conserved N-terminal RNA recognition motif and associates with spliceosomal proteins in an RNA-dependent subnuclear distribution, linking it to RNA processing [PMID:8589729], and it safeguards chromosome segregation by binding the spindle checkpoint protein MAD2 to inhibit APC/C ubiquitination activity [PMID:25789599]. The +KTS isoform cell-autonomously drives Sry expression upstream of FGF9-dependent Sertoli cell differentiation [PMID:19549635], and WT1 acts as a downstream effector of oncogenic KRAS that suppresses senescence to sustain tumor growth [PMID:20972333]. WT1 protein abundance is controlled post-translationally by proteasomal degradation involving UBCH8 [PMID:18535006], by autophagy [PMID:35025698], and by PRMT5-dependent IRES-mediated translation [PMID:34448450].","teleology":[{"year":1993,"claim":"Established WT1 as essential for the inductive events of kidney and gonad development, defining its physiological importance before its molecular targets were known.","evidence":"Knockout mouse with histological and developmental analysis","pmids":["8395349"],"confidence":"High","gaps":["Does not identify the transcriptional targets mediating blastema survival","Does not distinguish isoform-specific contributions"]},{"year":1993,"claim":"Showed WT1 activity is context-dependent on p53, explaining how the same protein can act as activator or repressor.","evidence":"Co-IP in transfected cells plus reporter assays","pmids":["8389468"],"confidence":"Medium","gaps":["Interaction shown in overexpression context","Endogenous relevance and interface not mapped"]},{"year":1995,"claim":"Defined the molecular basis of dominant-negative Denys-Drash mutations through N-terminal self-association and zinc-finger DNA-binding loss.","evidence":"In vitro binding, Co-IP, GST DNA-binding assays with mutant alleles across multiple targets","pmids":["7479946","7795587"],"confidence":"High","gaps":["Does not establish in vivo dosage consequences across tissues","Self-association interface not structurally resolved"]},{"year":1996,"claim":"Revealed an RNA-binding facet of WT1 via a conserved RRM and spliceosomal association, broadening its function beyond transcription.","evidence":"Structural modelling, Co-IP with spliceosomal proteins, RNA-dependent localization","pmids":["8589729"],"confidence":"Medium","gaps":["No defined RNA substrate identified","Functional consequence for splicing not demonstrated"]},{"year":2000,"claim":"Identified E-cadherin as a direct WT1 target, linking WT1 to epithelial adhesion programs.","evidence":"Reporter assays, overexpression, in vitro/nuclear-extract DNA binding (EMSA)","pmids":["10753894"],"confidence":"High","gaps":["Endogenous regulation in developing tissue not shown","Isoform dependence not addressed"]},{"year":2006,"claim":"Demonstrated a direct WT1–hnRNP-U interaction that modulates WT1 transactivation, connecting WT1 to an RNA/chromatin-associated partner.","evidence":"Endogenous Co-IP, domain mapping, reporter assay","pmids":["16924231"],"confidence":"Medium","gaps":["Target gene scope of modulation limited","Single lab"]},{"year":2008,"claim":"Defined the BASP1-based repressive mechanism and its promoter-selective regulation during differentiation.","evidence":"ChIP across multiple promoters in differentiating podocyte precursors plus sumoylation analysis","pmids":["19050011"],"confidence":"Medium","gaps":["Sumoylation enzymes not identified","Generality beyond examined promoters unknown"]},{"year":2008,"claim":"Established post-transcriptional control of WT1 abundance via proteasomal degradation and UBCH8 induction.","evidence":"TSA treatment, transcriptional and proteasome inhibitor assays, UBCH8 induction analysis","pmids":["18535006"],"confidence":"Medium","gaps":["Direct ubiquitination of WT1 by UBCH8 not reconstituted","Physiological trigger unclear"]},{"year":2009,"claim":"Showed the +KTS isoform cell-autonomously drives Sry upstream of FGF9, placing WT1 at the top of the male sex-determination cascade.","evidence":"Isoform-specific null mouse, immunofluorescence, ex vivo FGF9 rescue","pmids":["19549635"],"confidence":"High","gaps":["Direct binding to Sry regulatory elements not mapped here","Mechanism of +KTS isoform specificity unknown"]},{"year":2010,"claim":"Placed WT1 downstream of oncogenic KRAS as a suppressor of senescence required for tumor maintenance.","evidence":"Functional genomics screen, conditional Wt1 deletion in Kras lung model, human cell line knockdown, senescence assays","pmids":["20972333"],"confidence":"High","gaps":["Direct WT1 targets enforcing senescence not defined","Connection to KRAS signaling intermediates unresolved"]},{"year":2010,"claim":"Linked WT1 to WNT pathway restraint by transactivating CXXC5/WID, which inhibits Dishevelled.","evidence":"Reporter/enhancer-deletion assays, Co-IP, zebrafish morpholino, in vivo WNT assays","pmids":["20220130"],"confidence":"Medium","gaps":["Direct WT1 occupancy of WID enhancer in vivo limited","Tissue contexts of this axis not broadly tested"]},{"year":2013,"claim":"Completed the WT1 corepressor architecture, showing prohibitin and BASP1 recruit BRG1, HDAC1 and PIP2 while evicting CBP.","evidence":"Co-IP, ChIP, co-localization, reporter assays, knockdowns","pmids":["24166496"],"confidence":"Medium","gaps":["Stoichiometry and assembly order not resolved","Promoter selectivity determinants unclear"]},{"year":2013,"claim":"Extended WT1's developmental repression program to cardiac chemokines, controlling epicardial migration and cardiomyocyte proliferation.","evidence":"Transcriptomics of Wt1KO epicardial cells, functional assays, ChIP, IRF7 analysis","pmids":["23900076"],"confidence":"Medium","gaps":["Direct vs IRF7-indirect contributions not fully separated","In vivo heart phenotype linkage partial"]},{"year":2015,"claim":"Uncovered a mitotic role for WT1 in chromosome segregation through MAD2 binding and APC/C inhibition.","evidence":"Co-IP, cell division assays, APC/C ubiquitination assay","pmids":["25789599"],"confidence":"Medium","gaps":["Structural basis of MAD2 interaction unknown","Single lab, not independently confirmed"]},{"year":2018,"claim":"Defined a WT1/FoxC2/Notch network whose disruption drives podocyte injury, mechanistically connecting WT1 loss to glomerular disease.","evidence":"Inducible adult Wt1 deletion, expression analysis, pharmacological Notch inhibition","pmids":["29398135"],"confidence":"Medium","gaps":["Direct WT1 binding to FoxC2/Notch loci not shown here","EMT linkage correlative"]},{"year":2021,"claim":"Showed WT1 protein output is set by IRES-dependent translation under PRMT5 control via hnRNPA1 methylation.","evidence":"Conditional Prmt5 KO, IRES translation assay, hnRNPA1 methylation analysis, WT1 rescue","pmids":["34448450"],"confidence":"Medium","gaps":["Direct PRMT5 action on the Wt1 IRES not fully isolated","Generality beyond granulosa cells unknown"]},{"year":2022,"claim":"Identified autophagy as a degradation route controlling WT1 levels during granulosa cell differentiation.","evidence":"ATG5/BECN1 siRNA, chloroquine, Co-IP, cycloheximide chase, autophagy marker blots","pmids":["35025698"],"confidence":"Medium","gaps":["Autophagy receptor recognizing WT1 not identified","Tissue specificity unresolved"]},{"year":null,"claim":"How WT1 integrates its transcriptional, RNA-processing, and mitotic activities, and what determines isoform- and context-specific choice among activator, repressor, and non-transcriptional roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking RRM-mediated RNA functions to DNA-binding roles","Determinants of activator-vs-repressor switching incompletely defined","Structural basis of partner-selective interactions lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,7,11,12,13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,5]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,7,12]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,7,12,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,9,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,11,15]}],"complexes":["WT1-BASP1-prohibitin transcriptional repression complex"],"partners":["BASP1","PHB","TP53","HNRNPU","MAD2","BRG1","HDAC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19544","full_name":"Wilms tumor protein","aliases":["WT33"],"length_aa":449,"mass_kda":49.2,"function":"Transcription factor that plays an important role in cellular development and cell survival (PubMed:7862533). Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3' (PubMed:17716689, PubMed:25258363, PubMed:7862533). Regulates the expression of numerous target genes, including EPO. Plays an essential role for development of the urogenital system. It has a tumor suppressor as well as an oncogenic role in tumor formation. Function may be isoform-specific: isoforms lacking the KTS motif may act as transcription factors (PubMed:15520190). Isoforms containing the KTS motif may bind mRNA and play a role in mRNA metabolism or splicing (PubMed:16934801). Isoform 1 has lower affinity for DNA, and can bind RNA (PubMed:19123921)","subcellular_location":"Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/P19544/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WT1","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WT1","total_profiled":1310},"omim":[{"mim_id":"621332","title":"WILMS TUMOR 7; WT7","url":"https://www.omim.org/entry/621332"},{"mim_id":"619327","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 15; LRRC15","url":"https://www.omim.org/entry/619327"},{"mim_id":"616806","title":"WILMS TUMOR 6; WT6","url":"https://www.omim.org/entry/616806"},{"mim_id":"616425","title":"46,XY SEX REVERSAL 10; SRXY10","url":"https://www.omim.org/entry/616425"},{"mim_id":"614790","title":"WT1-INTERACTING PROTEIN; WTIP","url":"https://www.omim.org/entry/614790"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"endometrium 1","ntpm":41.8},{"tissue":"fallopian tube","ntpm":49.2},{"tissue":"ovary","ntpm":27.9},{"tissue":"smooth muscle","ntpm":30.9}],"url":"https://www.proteinatlas.org/search/WT1"},"hgnc":{"alias_symbol":["WAGR","WIT-2","AWT1","NPHS4","WT-1"],"prev_symbol":["GUD"]},"alphafold":{"accession":"P19544","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P19544","model_url":"https://alphafold.ebi.ac.uk/files/AF-P19544-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P19544-F1-predicted_aligned_error_v6.png","plddt_mean":50.78},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WT1","jax_strain_url":"https://www.jax.org/strain/search?query=WT1"},"sequence":{"accession":"P19544","fasta_url":"https://rest.uniprot.org/uniprotkb/P19544.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P19544/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P19544"}},"corpus_meta":[{"pmid":"8395349","id":"PMC_8395349","title":"WT-1 is required for early kidney development.","date":"1993","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8395349","citation_count":1599,"is_preprint":false},{"pmid":"17361230","id":"PMC_17361230","title":"A tumor suppressor and oncogene: the WT1 story.","date":"2007","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/17361230","citation_count":398,"is_preprint":false},{"pmid":"8389468","id":"PMC_8389468","title":"Physical and functional interaction between WT1 and p53 proteins.","date":"1993","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8389468","citation_count":323,"is_preprint":false},{"pmid":"16987884","id":"PMC_16987884","title":"The many facets of the Wilms' tumour gene, WT1.","date":"2006","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16987884","citation_count":290,"is_preprint":false},{"pmid":"9090524","id":"PMC_9090524","title":"A clinical overview of WT1 gene 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histological and developmental analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with specific developmental phenotype, widely replicated as foundational result\",\n      \"pmids\": [\"8395349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"WT1 protein physically associates with p53 in transfected cells; this interaction modulates transcriptional activity: in the absence of p53, WT1 acts as a transcriptional activator of EGR1 sites rather than a repressor, and WT1 cooperatively enhances p53-mediated transactivation of the muscle creatine kinase promoter.\",\n      \"method\": \"Co-immunoprecipitation in transfected cells; transient transfection transcriptional reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional reporter assays, single lab\",\n      \"pmids\": [\"8389468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"WT1 can self-associate in vitro and in vivo through its amino-terminal domain; mutant WT1 alleles that impair DNA recognition can oligomerize with wild-type WT1 and antagonize WT1-mediated transcriptional repression, providing a molecular mechanism for dominant-negative action of Denys-Drash syndrome mutations.\",\n      \"method\": \"In vitro binding assay; co-immunoprecipitation in cells; transcriptional repression reporter assay with mutant alleles\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro assay plus Co-IP plus functional reporter, single lab\",\n      \"pmids\": [\"7479946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Denys-Drash syndrome missense and truncating mutations in the WT1 zinc finger domain abolish DNA binding to all tested WT1 targets (EGR1 consensus, IGF2P2, PDGFA-chain promoter, and +P5 genomic fragment) for both -KTS and +KTS isoforms, indicating these mutations act as dominant-negative antimorphs or through disturbed isoform dosage.\",\n      \"method\": \"GST fusion protein DNA-binding assay with recombinant wild-type and mutant WT1 zinc finger domains\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted DNA-binding assay with mutagenesis, multiple targets tested, single lab\",\n      \"pmids\": [\"7795587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Structural modelling identified an evolutionarily conserved N-terminal RNA recognition motif (RRM) in all known WT1 isoforms, similar to the constitutive splicing factor U1A; WT1 co-immunoprecipitates with spliceosomal proteins and its subnuclear speckled localization is abolished by RNA degradation, indicating WT1 binds RNA and associates with the splicing machinery.\",\n      \"method\": \"Structural modelling; co-immunoprecipitation with spliceosomal proteins; RNA degradation experiment affecting subnuclear localization\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — structural modelling plus Co-IP plus localization experiment, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"8589729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"E-cadherin is a direct transcriptional target of WT1; WT1 activates E-cadherin promoter activity through a conserved GC-rich EGR1-like binding site and a CAAT box, and WT1 protein produced in vitro or from nuclear extracts directly binds the WT1-response element in the E-cadherin promoter.\",\n      \"method\": \"Transient transfection reporter assays; retroviral overexpression in NIH 3T3 cells; in vitro transcription/translation and nuclear extract DNA-binding assay (EMSA)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro DNA binding reconstitution plus promoter reporter assays plus gain-of-function cellular assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"10753894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"WT1 directly interacts with heterogeneous nuclear ribonucleoprotein U (hnRNP-U); this interaction is direct (does not require other proteins or nucleic acids), involves the zinc fingers of WT1 and the middle domain of hnRNP-U, and hnRNP-U modulates WT1 transcriptional activation of a bona fide WT1 target gene.\",\n      \"method\": \"Genetic and biochemical approaches including co-immunoprecipitation of endogenous proteins; domain-mapping pulldown; transcriptional reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP of endogenous proteins plus domain mapping plus functional reporter, single lab\",\n      \"pmids\": [\"16924231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"WT1 and its transcriptional cosuppressor BASP1 co-occupy promoters of Bak, c-myc, and podocalyxin genes in podocyte precursor cells; during differentiation, BASP1 occupancy is selectively reduced at the podocalyxin promoter allowing activation, while the repressive WT1/BASP1 complex is maintained at c-myc and Bak promoters; regulation of BASP1 promoter occupancy involves sumoylation of BASP1.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) in podocyte precursor cell line during differentiation; sumoylation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in differentiating cells with multiple promoters examined, single lab\",\n      \"pmids\": [\"19050011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Histone deacetylase inhibitor Trichostatin A (TSA) downregulates Wt1 expression primarily by cessation of transcription mediated by sequences in intron 3, and also enhances Wt1 protein degradation by the proteasome, at least partly through induction of the ubiquitin-conjugating enzyme UBCH8.\",\n      \"method\": \"Cell line treatment with TSA; transcriptional run-on/reporter assays; proteasome inhibitor experiments; UBCH8 induction analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays (transcriptional, proteasomal, ubiquitin pathway), single lab\",\n      \"pmids\": [\"18535006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"WT1(+KTS) isoform cell-autonomously regulates Sry expression in XY gonads; Wt1(+KTS)-null mice show reduced SRY protein per cell and fewer SRY-expressing cells, reduced cell proliferation at the coelomic epithelium, and blocked Sertoli cell differentiation (loss of SOX9/Fgf9); addition of recombinant FGF9 to ex vivo gonad cultures rescued the mutant phenotype, indicating WT1(+KTS) acts upstream of Sry, which in turn drives cell proliferation and Sertoli differentiation via FGF9.\",\n      \"method\": \"Immunofluorescence analysis; targeted Wt1(+KTS)-null mouse model; ex vivo gonad culture with recombinant FGF9 rescue experiment\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific genetic model with defined rescue experiment and multiple cellular readouts\",\n      \"pmids\": [\"19549635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WT1 is a critical regulator of senescence and proliferation downstream of oncogenic KRAS signaling; deletion or suppression of Wt1 leads to senescence of mouse primary cells expressing physiological levels of oncogenic Kras, decreases tumor burden in a Kras-driven lung cancer mouse model, and in human lung cancer lines dependent on KRAS, WT1 loss decreases proliferation and induces senescence.\",\n      \"method\": \"Functional genomics screen; mouse genetics (Wt1 conditional deletion in Kras-driven lung cancer model); shRNA knockdown in human cell lines; senescence assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — combination of functional genomics, in vivo mouse model, and human cell line validation with specific phenotypic readouts\",\n      \"pmids\": [\"20972333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WT1 activates transcription of CXXC5/WID, a gene that negatively regulates WNT/β-catenin signaling through Dishevelled; WT1 acts through an upstream enhancer region of WID; WID protein interacts with Dishevelled via its C-terminal CXXC zinc finger and Dishevelled-binding domains, inhibiting WNT/β-catenin signaling in vitro and in vivo.\",\n      \"method\": \"Transcriptional reporter assay; promoter/enhancer deletion analysis; co-immunoprecipitation; antisense morpholino knockdown in zebrafish; in vivo WNT signaling assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays plus Co-IP plus in vivo rescue, single lab, multiple methods\",\n      \"pmids\": [\"20220130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Prohibitin is part of the WT1-BASP1 transcriptional repression complex; prohibitin interacts with BASP1, co-localizes with BASP1 in the nucleus, and is recruited to WT1 target gene promoters to elicit BASP1-dependent transcriptional repression; BASP1 and prohibitin cooperate to recruit chromatin remodeling factor BRG1 and to cause dissociation of CBP from WT1-responsive promoters, and are also required for recruitment of PIP2 and HDAC1 to these promoters.\",\n      \"method\": \"Co-immunoprecipitation; ChIP; immunofluorescence co-localization; transcriptional reporter assays; knockdown experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ChIP plus functional reporter assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24166496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WT1 regulates expression of inhibitory chemokines CCL5 and CXCL10 in epicardial cells by direct and indirect (via IRF7) transcriptional repression; CXCL10 inhibits epicardial cell migration and CCL5 inhibits cardiomyocyte proliferation, revealing a role for WT1 in heart morphogenesis through chemokine repression.\",\n      \"method\": \"Transcriptome analysis of Wt1KO epicardial cells; functional migration and proliferation assays with recombinant chemokines; ChIP; IRF7 expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomics plus functional assays plus ChIP, single lab\",\n      \"pmids\": [\"23900076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WT1 regulates the fidelity of chromosome segregation through interaction with the spindle assembly checkpoint protein MAD2; WT1 delays anaphase entry by inhibiting the ubiquitination activity of the Anaphase Promoting Complex/Cyclosome (APC/C).\",\n      \"method\": \"Co-immunoprecipitation; functional cell division assays; APC/C ubiquitination assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional APC/C assay, single lab\",\n      \"pmids\": [\"25789599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of WT1 in mature podocytes activates Notch signaling (upregulation of Notch1 and transcriptional targets including Nrarp, HES1), with repression of FoxC2 and upregulation of Hey2, implicating a WT1/FoxC2/Notch transcriptional network in podocyte injury; HES1 induction was associated with upregulation of epithelial-mesenchymal transition genes; pharmacological Notch inhibition ameliorated glomerular scarring and albuminuria.\",\n      \"method\": \"Tamoxifen-inducible CRE-LoxP Wt1 deletion in adult mice; immunofluorescence; gene expression analysis; pharmacological Notch inhibition\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined molecular pathway, pharmacological rescue, single lab\",\n      \"pmids\": [\"29398135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT5 regulates WT1 protein levels in granulosa cells by facilitating IRES-dependent translation of Wt1 mRNA through methylation of HnRNPA1; loss of PRMT5 dramatically reduces WT1 protein without affecting mRNA levels, and Wt1 overexpression rescues the premature differentiation phenotype caused by Prmt5 deletion.\",\n      \"method\": \"Conditional Prmt5 knockout mice; western blot and qRT-PCR; IRES-dependent translation assay; WT1 overexpression rescue experiment; HnRNPA1 methylation analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined rescue, IRES translation assay, methylation of identified substrate, single lab\",\n      \"pmids\": [\"34448450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Autophagy degrades WT1 protein in ovarian granulosa cells; inhibition of autophagy (by siRNA knockdown of ATG5/BECN1 or chloroquine treatment) causes WT1 accumulation and inhibits granulosa cell differentiation (reduced CYP19A1/FSHR expression and estradiol synthesis), establishing autophagy-mediated degradation of WT1 as a mechanism regulating granulosa cell differentiation.\",\n      \"method\": \"siRNA knockdown of ATG5 and BECN1; pharmacological autophagy inhibition with chloroquine; co-immunoprecipitation; cycloheximide chase assay; western blot for autophagy markers\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological inhibition of autophagy with defined protein accumulation and functional differentiation readout, single lab\",\n      \"pmids\": [\"35025698\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WT1 is a multi-isoform zinc finger protein that functions as both a transcriptional activator/repressor (binding EGR1-like DNA sequences to regulate target genes including E-cadherin, CXXC5/WID, and chemokines CCL5/CXCL10) and an RNA-binding/processing factor (via an N-terminal RRM, association with spliceosomal proteins, and IRES-dependent translation regulation); its transcriptional repression is executed through a complex with BASP1 and prohibitin that recruits BRG1, HDAC1, and PIP2 to promoters; WT1 physically interacts with p53 and hnRNP-U to modulate their activities, self-associates through its N-terminal domain enabling dominant-negative inhibition by Denys-Drash mutations, interacts with MAD2 to inhibit APC/C and regulate chromosome segregation, and is regulated post-translationally by autophagy-mediated degradation and proteasomal degradation facilitated by UBCH8; the +KTS isoform cell-autonomously regulates Sry expression upstream of FGF9-driven Sertoli cell differentiation, while WT1 is essential for kidney morphogenesis (metanephric blastema survival and ureteric bud outgrowth) and acts as a downstream effector of oncogenic KRAS signaling to suppress cellular senescence.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WT1 is a zinc finger transcription factor that orchestrates organogenesis of the kidney and gonad and modulates cellular proliferation, with loss-of-function causing metanephric blastema apoptosis, failure of ureteric bud outgrowth, and absence of kidney and gonad [#0]. Through its zinc fingers it binds EGR1-like GC-rich elements to control specific target genes, directly activating E-cadherin via a conserved WT1-response element [#5] and CXXC5/WID to restrain WNT/\\u03b2-catenin signaling [#11], while repressing other targets; its repressive output is executed by a BASP1\\u2013prohibitin corepressor module that recruits BRG1, HDAC1, and PIP2 and displaces CBP from WT1-responsive promoters [#7, #12]. WT1 activity is further shaped by direct protein partners: it associates with p53 to switch between activation and repression [#1], binds hnRNP-U through its zinc fingers to modulate transactivation [#6], and self-associates via its N-terminal domain, the basis for dominant-negative action of Denys-Drash zinc finger mutations that abolish DNA binding [#2, #3]. Beyond transcription, WT1 contains a conserved N-terminal RNA recognition motif and associates with spliceosomal proteins in an RNA-dependent subnuclear distribution, linking it to RNA processing [#4], and it safeguards chromosome segregation by binding the spindle checkpoint protein MAD2 to inhibit APC/C ubiquitination activity [#14]. The +KTS isoform cell-autonomously drives Sry expression upstream of FGF9-dependent Sertoli cell differentiation [#9], and WT1 acts as a downstream effector of oncogenic KRAS that suppresses senescence to sustain tumor growth [#10]. WT1 protein abundance is controlled post-translationally by proteasomal degradation involving UBCH8 [#8], by autophagy [#17], and by PRMT5-dependent IRES-mediated translation [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established WT1 as essential for the inductive events of kidney and gonad development, defining its physiological importance before its molecular targets were known.\",\n      \"evidence\": \"Knockout mouse with histological and developmental analysis\",\n      \"pmids\": [\"8395349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the transcriptional targets mediating blastema survival\", \"Does not distinguish isoform-specific contributions\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Showed WT1 activity is context-dependent on p53, explaining how the same protein can act as activator or repressor.\",\n      \"evidence\": \"Co-IP in transfected cells plus reporter assays\",\n      \"pmids\": [\"8389468\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction shown in overexpression context\", \"Endogenous relevance and interface not mapped\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined the molecular basis of dominant-negative Denys-Drash mutations through N-terminal self-association and zinc-finger DNA-binding loss.\",\n      \"evidence\": \"In vitro binding, Co-IP, GST DNA-binding assays with mutant alleles across multiple targets\",\n      \"pmids\": [\"7479946\", \"7795587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish in vivo dosage consequences across tissues\", \"Self-association interface not structurally resolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Revealed an RNA-binding facet of WT1 via a conserved RRM and spliceosomal association, broadening its function beyond transcription.\",\n      \"evidence\": \"Structural modelling, Co-IP with spliceosomal proteins, RNA-dependent localization\",\n      \"pmids\": [\"8589729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined RNA substrate identified\", \"Functional consequence for splicing not demonstrated\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified E-cadherin as a direct WT1 target, linking WT1 to epithelial adhesion programs.\",\n      \"evidence\": \"Reporter assays, overexpression, in vitro/nuclear-extract DNA binding (EMSA)\",\n      \"pmids\": [\"10753894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous regulation in developing tissue not shown\", \"Isoform dependence not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated a direct WT1\\u2013hnRNP-U interaction that modulates WT1 transactivation, connecting WT1 to an RNA/chromatin-associated partner.\",\n      \"evidence\": \"Endogenous Co-IP, domain mapping, reporter assay\",\n      \"pmids\": [\"16924231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target gene scope of modulation limited\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the BASP1-based repressive mechanism and its promoter-selective regulation during differentiation.\",\n      \"evidence\": \"ChIP across multiple promoters in differentiating podocyte precursors plus sumoylation analysis\",\n      \"pmids\": [\"19050011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sumoylation enzymes not identified\", \"Generality beyond examined promoters unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established post-transcriptional control of WT1 abundance via proteasomal degradation and UBCH8 induction.\",\n      \"evidence\": \"TSA treatment, transcriptional and proteasome inhibitor assays, UBCH8 induction analysis\",\n      \"pmids\": [\"18535006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination of WT1 by UBCH8 not reconstituted\", \"Physiological trigger unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed the +KTS isoform cell-autonomously drives Sry upstream of FGF9, placing WT1 at the top of the male sex-determination cascade.\",\n      \"evidence\": \"Isoform-specific null mouse, immunofluorescence, ex vivo FGF9 rescue\",\n      \"pmids\": [\"19549635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding to Sry regulatory elements not mapped here\", \"Mechanism of +KTS isoform specificity unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed WT1 downstream of oncogenic KRAS as a suppressor of senescence required for tumor maintenance.\",\n      \"evidence\": \"Functional genomics screen, conditional Wt1 deletion in Kras lung model, human cell line knockdown, senescence assays\",\n      \"pmids\": [\"20972333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct WT1 targets enforcing senescence not defined\", \"Connection to KRAS signaling intermediates unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked WT1 to WNT pathway restraint by transactivating CXXC5/WID, which inhibits Dishevelled.\",\n      \"evidence\": \"Reporter/enhancer-deletion assays, Co-IP, zebrafish morpholino, in vivo WNT assays\",\n      \"pmids\": [\"20220130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct WT1 occupancy of WID enhancer in vivo limited\", \"Tissue contexts of this axis not broadly tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Completed the WT1 corepressor architecture, showing prohibitin and BASP1 recruit BRG1, HDAC1 and PIP2 while evicting CBP.\",\n      \"evidence\": \"Co-IP, ChIP, co-localization, reporter assays, knockdowns\",\n      \"pmids\": [\"24166496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and assembly order not resolved\", \"Promoter selectivity determinants unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended WT1's developmental repression program to cardiac chemokines, controlling epicardial migration and cardiomyocyte proliferation.\",\n      \"evidence\": \"Transcriptomics of Wt1KO epicardial cells, functional assays, ChIP, IRF7 analysis\",\n      \"pmids\": [\"23900076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs IRF7-indirect contributions not fully separated\", \"In vivo heart phenotype linkage partial\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Uncovered a mitotic role for WT1 in chromosome segregation through MAD2 binding and APC/C inhibition.\",\n      \"evidence\": \"Co-IP, cell division assays, APC/C ubiquitination assay\",\n      \"pmids\": [\"25789599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of MAD2 interaction unknown\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a WT1/FoxC2/Notch network whose disruption drives podocyte injury, mechanistically connecting WT1 loss to glomerular disease.\",\n      \"evidence\": \"Inducible adult Wt1 deletion, expression analysis, pharmacological Notch inhibition\",\n      \"pmids\": [\"29398135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct WT1 binding to FoxC2/Notch loci not shown here\", \"EMT linkage correlative\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed WT1 protein output is set by IRES-dependent translation under PRMT5 control via hnRNPA1 methylation.\",\n      \"evidence\": \"Conditional Prmt5 KO, IRES translation assay, hnRNPA1 methylation analysis, WT1 rescue\",\n      \"pmids\": [\"34448450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PRMT5 action on the Wt1 IRES not fully isolated\", \"Generality beyond granulosa cells unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified autophagy as a degradation route controlling WT1 levels during granulosa cell differentiation.\",\n      \"evidence\": \"ATG5/BECN1 siRNA, chloroquine, Co-IP, cycloheximide chase, autophagy marker blots\",\n      \"pmids\": [\"35025698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Autophagy receptor recognizing WT1 not identified\", \"Tissue specificity unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WT1 integrates its transcriptional, RNA-processing, and mitotic activities, and what determines isoform- and context-specific choice among activator, repressor, and non-transcriptional roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking RRM-mediated RNA functions to DNA-binding roles\", \"Determinants of activator-vs-repressor switching incompletely defined\", \"Structural basis of partner-selective interactions lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [5, 11, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 7, 11, 12, 13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 7, 12]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 7, 12, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 9, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 11, 15]}\n    ],\n    \"complexes\": [\n      \"WT1-BASP1-prohibitin transcriptional repression complex\"\n    ],\n    \"partners\": [\n      \"BASP1\",\n      \"PHB\",\n      \"TP53\",\n      \"HNRNPU\",\n      \"MAD2\",\n      \"BRG1\",\n      \"HDAC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}