{"gene":"WT1","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":1990,"finding":"WT1 was isolated as a zinc finger polypeptide gene at chromosome 11p13, with expression restricted predominantly to kidney and hematopoietic cells, and predicted to function as a transcriptional regulator based on its four zinc finger domains and proline/glutamine-rich region.","method":"Positional cloning, cDNA isolation, Northern blot expression analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — original cloning paper with multiple orthogonal methods; foundational, highly cited","pmids":["2154335","2154702"],"is_preprint":false},{"year":1991,"finding":"WT1 gene consists of 10 exons generating four alternatively spliced transcripts: two splice sites produce isoforms with/without a 17-amino-acid insertion (exon 5) and with/without 3 amino acids (KTS) between zinc fingers 3 and 4, with the relative ratios conserved between normal tissue and Wilms tumors.","method":"RNase protection analysis, genomic and cDNA cloning","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — direct molecular characterization of genomic and transcript structure, highly cited","pmids":["1658787"],"is_preprint":false},{"year":1991,"finding":"Germline point mutations in WT1 zinc finger domains (exons 8 and 9) cause Denys-Drash syndrome, with these mutations directly affecting DNA sequence recognition, demonstrating WT1's essential role in urogenital development.","method":"Exon sequencing, functional analysis of zinc finger mutations","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — germline mutation analysis with functional annotation, highly cited foundational paper","pmids":["1655284"],"is_preprint":false},{"year":1991,"finding":"Constitutional mutations in WT1 zinc finger domains contribute to abnormal genital system development, establishing WT1 as essential for both kidney and gonadal development.","method":"Constitutional mutation analysis of WT1 coding exons","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — germline mutation-phenotype analysis, replicated across cases, highly cited","pmids":["1654525"],"is_preprint":false},{"year":1991,"finding":"Mouse WT1 protein is greater than 95% conserved with human WT1, with developmental expression in fetal kidney peaking just before birth and declining postpartum, consistent with a role as a negative regulator of nephroblast growth.","method":"Murine Wt1 cDNA isolation, developmental Northern blot expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — cross-species characterization with developmental expression profiling, highly cited","pmids":["1671709"],"is_preprint":false},{"year":1992,"finding":"WT1 protein functions as a transcriptional repressor of the PDGF-A chain promoter by binding to multiple sites in the PDGF-A promoter, as demonstrated by gel-shift analysis and DNase I footprinting, achieving >50-fold repression.","method":"Gel-shift analysis, DNase I footprinting, transient transfection reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — direct DNA binding and transcriptional repression shown by multiple orthogonal biochemical methods","pmids":["1332065"],"is_preprint":false},{"year":1993,"finding":"WT1 physically associates with p53 in transfected cells, modulating their transcriptional activity: in the absence of p53, WT1 acts as a transcriptional activator of the EGR1 site, and WT1 cooperatively enhances p53 transactivation of the muscle creatine kinase promoter.","method":"Co-immunoprecipitation in transfected cells, transcriptional reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional reporter assays, highly cited","pmids":["8389468"],"is_preprint":false},{"year":1993,"finding":"WT1 protein is exclusively nuclear, localizing to podocytes during mesonephric and metanephric development and persisting in adult podocytes, supporting its role as a transcription factor during urogenital development and adult kidney homeostasis.","method":"Immunohistochemistry, immunofluorescence, confocal laser microscopy, in situ hybridization","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — direct subcellular localization by multiple imaging methods with developmental and adult tissue context","pmids":["8306891"],"is_preprint":false},{"year":1993,"finding":"A point mutation in WT1 converting glycine to aspartic acid in the putative trans-activation domain converts the protein from a transcriptional repressor to an activator of its target DNA sequence, providing the 'second hit' mechanism in WAGR-associated Wilms tumorigenesis.","method":"Mutant WT1 functional analysis in transfection reporter assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — functional mutation analysis in reporter assays, single study","pmids":["8402654"],"is_preprint":false},{"year":1995,"finding":"WT1 induces apoptosis in osteosarcoma cell lines via an inducible system, mediating transcriptional repression of the EGFR promoter at two TC-rich repeat sequences and reducing EGFR synthesis; constitutive EGFR expression rescued WT1-induced apoptosis.","method":"Tetracycline-inducible WT1 expression, EGFR promoter reporter assays, apoptosis assays, EGFR rescue experiment","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — inducible system with gain/loss-of-function, epistasis via rescue, and promoter assays in same study","pmids":["7588596"],"is_preprint":false},{"year":1995,"finding":"WT1 directly represses Pax-2 transcription by binding to three high-affinity sites in the 5' untranslated Pax-2 leader sequence (demonstrated by DNase I footprinting), coinciding with down-regulation of Pax-2 during glomerular precursor differentiation in vivo.","method":"DNase I footprinting, co-transfection reporter assays, immunofluorescence in mouse kidney sections","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 — direct DNA binding demonstrated by footprinting plus in vivo correlation and functional reporter assays","pmids":["7720589"],"is_preprint":false},{"year":1995,"finding":"WT1 can self-associate in vitro and in vivo through its amino-terminal domain, and mutant WT1 proteins impaired in DNA recognition can antagonize WT1-mediated transcriptional repression through these oligomeric interactions.","method":"In vitro binding assays, co-immunoprecipitation in vivo, transcriptional repression assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution and in vivo Co-IP with functional read-out","pmids":["7479946"],"is_preprint":false},{"year":1995,"finding":"GATA-1 transactivates the WT1 hematopoietic-specific 3' enhancer by binding to a GATA-binding site, as demonstrated by gel shift competition experiments and transactivation assays, linking GATA-1 to regulation of WT1 expression in hematopoiesis.","method":"Gel shift competition assays, transactivation reporter assays, RT-PCR co-expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct DNA binding and functional transactivation shown, single study","pmids":["7890725"],"is_preprint":false},{"year":1996,"finding":"WT1 was found by structural modeling to contain an N-terminal RNA recognition motif (RRM) similar to the splicing factor U1A, and WT1 co-immunoprecipitates with spliceosomal proteins, with nuclear RNA degradation abolishing the speckled WT1 localization pattern.","method":"Structural modeling, co-immunoprecipitation with spliceosomal proteins, RNA degradation experiment","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 — structural prediction plus Co-IP and localization, single study","pmids":["8589729"],"is_preprint":false},{"year":1996,"finding":"WT1 (both isoforms WT1 and WT1+KTS) represses transcription of the novH (nov) promoter through intact zinc finger regions and the NH2 transcription repression domain, with constitutive WT1 expression decreasing endogenous NOVH protein levels in 293 cells.","method":"Transient co-transfection reporter assays, in vitro footprinting, Western blot of NOVH protein","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — promoter reporter, in vitro DNA binding, and endogenous protein level analysis","pmids":["8622864"],"is_preprint":false},{"year":1998,"finding":"Constitutive WT1 expression in the myeloid progenitor cell line 32D cl3 blocked G-CSF-induced differentiation and instead promoted proliferation, accompanied by constitutive activation of both Stat3α and Stat3β downstream of G-CSF receptor signaling.","method":"Retroviral WT1 transduction of 32D cl3 cells, differentiation assay, Western blot of Stat3 activation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with defined cellular phenotype and signaling pathway read-out","pmids":["9531608"],"is_preprint":false},{"year":1999,"finding":"WT1(-KTS) isoform directly binds to the amphiregulin promoter and potently activates its transcription; amphiregulin, an EGF family member, mirrors WT1 expression during fetal kidney development and stimulates epithelial branching in embryonic kidney organ cultures.","method":"High-density oligonucleotide array after inducible WT1 expression, promoter binding assays, organ culture branching assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — genome-wide target identification with direct promoter binding and in vivo organotypic functional validation","pmids":["10490105"],"is_preprint":false},{"year":1999,"finding":"Wt1 is required for development of the epicardium and subepicardial mesenchymal cells, and is expressed in the proepicardium; Wt1-null embryos show severe epicardial defects and absence of SEMCs leading to embryonic lethality; a human WT1 YAC rescues heart defects completely but only partially rescues urogenital defects.","method":"LacZ reporter YAC, Wt1 knockout mouse analysis, YAC complementation","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — genetic rescue experiment in knockout mouse model with reporter gene","pmids":["10101119"],"is_preprint":false},{"year":2000,"finding":"WT1 directly activates E-cadherin transcription by binding to a conserved GC-rich EGR1-like site in the E-cadherin promoter; stable WT1 expression in NIH 3T3 fibroblasts induces epithelial differentiation features including E-cadherin upregulation.","method":"Retroviral WT1 expression, transient transfection reporter assays, in vitro binding with nuclear extracts, dominant-negative WT1 block","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — direct DNA binding, promoter reporter, dominant-negative, and stable gain-of-function","pmids":["10753894"],"is_preprint":false},{"year":2002,"finding":"WT1 is a key regulator of podocyte function: reduced WT1 levels in mice result in crescentic glomerulonephritis or mesangial sclerosis depending on gene dosage, with downstream podocyte-specific genes nphs1 and podocalyxin dramatically downregulated.","method":"Wt1 knockout and inducible YAC transgenic mouse models, gene expression analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic dose-response experiment in mouse models with defined molecular targets","pmids":["11912180"],"is_preprint":false},{"year":2006,"finding":"The 17AA(+) WT1 isoforms exert antiapoptotic functions in leukemia cells by acting upstream of mitochondria in the intrinsic apoptosis pathway; 17AA(+)WT1-specific siRNA activates caspase-3 and -9 and Bax, while constitutive 17AA(+)WT1 expression protects mitochondrial membrane integrity and decreases proapoptotic Bak expression. The zinc-finger DNA-binding region is essential for these antiapoptotic functions.","method":"Isoform-specific siRNA knockdown, constitutive expression, caspase activation assays, mitochondrial membrane assays, Western blot for Bak/Bax","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — isoform-specific loss- and gain-of-function with multiple mechanistic readouts","pmids":["16518414"],"is_preprint":false},{"year":2006,"finding":"hnRNP-U directly interacts with WT1 endogenously without requiring other proteins or nucleic acids; the interaction 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":"Co-immunoprecipitation of endogenous proteins, domain-mapping pulldown assays, transcriptional reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — endogenous Co-IP and domain mapping with functional consequence, single study","pmids":["16924231"],"is_preprint":false},{"year":2008,"finding":"Brain Acid Soluble Protein 1 (BASP1) acts as a transcriptional cosuppressor blocking WT1 transcriptional activation; during podocyte differentiation, WT1 and BASP1 co-occupy the Bak, c-myc, and podocalyxin promoters, and BASP1 promoter occupancy is dynamically regulated by sumoylation of BASP1.","method":"Chromatin immunoprecipitation (ChIP), podocyte differentiation assay, BASP1 sumoylation analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP of endogenous complex during differentiation with post-translational modification analysis","pmids":["19050011"],"is_preprint":false},{"year":2009,"finding":"WT1(+KTS) isoform cell-autonomously regulates Sry expression in the gonad; XY mice lacking WT1(+KTS) show reduced SRY protein per cell, decreased SRY-expressing cells, blocked Sertoli cell differentiation (loss of SOX9 and Fgf9), and male-to-female sex reversal; addition of recombinant FGF9 to ex vivo gonad cultures rescues the Sertoli cell differentiation defect.","method":"Wt1(+KTS)-null mouse model, immunofluorescence, ex vivo gonad culture with recombinant FGF9 rescue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — isoform-specific knockout with cellular and molecular phenotyping and functional rescue","pmids":["19549635"],"is_preprint":false},{"year":2013,"finding":"Prohibitin is part of the WT1-BASP1 transcriptional repression complex; prohibitin interacts with BASP1, is recruited to WT1 target gene promoters in a BASP1-dependent manner, and cooperates with BASP1 to recruit the chromatin remodeling factor BRG1 and displace CBP from promoters; this complex also recruits PIP2 and HDAC1 to WT1 target genes.","method":"Co-immunoprecipitation, ChIP, promoter reporter assays, nuclear colocalization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP with mechanistic chromatin remodeling readouts, single study","pmids":["24166496"],"is_preprint":false},{"year":2013,"finding":"WT1 is required to repress expression of inhibitory chemokines Ccl5 and Cxcl10 in epicardial cells, partly directly and partly by increasing IRF7 levels; CXCL10 inhibits epicardial cell migration and CCL5 inhibits cardiomyocyte proliferation, linking WT1 to heart morphogenesis via chemokine regulation.","method":"Transcriptome analysis of Wt1-KO epicardial cells, functional chemokine assays (migration, proliferation), expression correlation","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — knockout transcriptome with functional chemokine assays, single study","pmids":["23900076"],"is_preprint":false},{"year":2011,"finding":"PINCH1 interacts with WT1 in podocyte nuclei after TGF-β1-induced nuclear translocation; the interaction is mediated by the LIM1 domain of PINCH1 and the C-terminal zinc-finger domain of WT1, and PINCH1-WT1 interaction suppresses WT1-mediated podocalyxin expression.","method":"Co-immunoprecipitation, pulldown assays, promoter-luciferase reporter, nuclear translocation imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP, domain mapping, and functional reporter, single study","pmids":["21390327"],"is_preprint":false},{"year":2015,"finding":"WT1 physically interacts with and recruits TET2 to WT1 target genes to activate their expression and suppress leukemia cell proliferation; multiple AML-derived TET2 mutations disrupt the WT1-TET2 interaction; WT1 and TET2 are mutated in a mutually exclusive manner in AML, suggesting a shared IDH1/2-TET2-WT1 pathway.","method":"Co-immunoprecipitation, ChIP, colony formation assay, AML mutation analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — physical interaction plus ChIP recruitment and functional proliferation assays with clinical mutation validation","pmids":["25601757"],"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), establishing a role for WT1 in mitotic checkpoint control and genomic stability.","method":"WT1-MAD2 interaction assays, APC/C ubiquitination assay, chromosome segregation analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 — protein interaction and enzymatic activity assay with defined cellular phenotype, single study","pmids":["25789599"],"is_preprint":false},{"year":2018,"finding":"Wt1 haploinsufficiency enhances hematopoietic stem cell self-renewal in an age-dependent manner and cooperates with Flt3-ITD mutation to induce fully penetrant AML, demonstrating that Wt1 loss contributes to leukemogenesis through progressive genetic and epigenetic alterations.","method":"Wt1 heterozygous knockout mouse model, stem cell functional assays, genetic cooperation with Flt3-ITD","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic cooperation and stem cell functional assays, single study","pmids":["30064973"],"is_preprint":false},{"year":2018,"finding":"Loss of Wt1 in mature podocytes activates Notch1 signaling (upregulation of Notch1 and Nrarp), represses FoxC2, and upregulates Hey2 and HES1; HES1 induction is associated with upregulation of epithelial-mesenchymal transition genes and mediates podocyte EMT; pharmacological inhibition of Notch signaling ameliorates glomerular scarring in Wt1-deleted mice.","method":"Tamoxifen-inducible Cre-LoxP Wt1 deletion, immunofluorescence, Notch inhibitor rescue experiment","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 — conditional knockout with temporal control, pathway analysis, and pharmacological rescue","pmids":["29398135"],"is_preprint":false},{"year":2020,"finding":"WT1 undergoes highly dynamic changes in binding to target genes during podocyte injury and repair, affecting chromatin state and expression of target genes; WT1 binds nearly all genes crucial for maintenance of the glomerular filtration barrier and mediates epigenetic transcriptional reprogramming during injury.","method":"ChIP-seq in murine podocytes and human kidney organoids, transcriptome analysis during injury/repair","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-seq in multiple model systems with chromatin state and transcriptome analysis","pmids":["32754639"],"is_preprint":false},{"year":2020,"finding":"Heterozygous WT1 variants affecting zinc finger 4 (ZF4) cause 46,XX testicular/ovotesticular DSD; ZF4 mutant proteins physically interact with and sequester β-CATENIN, leading to upregulation of testis-specific pathways and masculinization of XX gonads.","method":"Exome sequencing, co-immunoprecipitation, human granulosa cell line transfection, Wt1-XX mouse gonad phenotyping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — Co-IP of protein interaction plus in vitro and in vivo functional validation","pmids":["32493750"],"is_preprint":false},{"year":2021,"finding":"PRMT5 facilitates IRES-dependent translation of Wt1 mRNA by methylating HnRNPA1; loss of Prmt5 in granulosa cells dramatically reduces WT1 protein expression, arrests follicle development, and derepresses steroidogenic gene expression, which is rescued by Wt1 overexpression.","method":"Conditional Prmt5 knockout in granulosa cells, mechanistic studies of HnRNPA1 methylation, Wt1 overexpression rescue","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with defined molecular mechanism and rescue experiment","pmids":["34448450"],"is_preprint":false},{"year":2022,"finding":"Autophagy regulates granulosa cell differentiation by degrading WT1 protein; disruption of autophagy (via ATG5/BECN1 siRNA or chloroquine) causes WT1 accumulation, which inhibits GC differentiation (suppressing CYP19A1/Aromatase and FSHR expression and estradiol synthesis).","method":"siRNA knockdown of ATG5/BECN1, pharmacological autophagy inhibition, WT1 protein accumulation assay, co-immunoprecipitation","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological loss-of-function with defined molecular mechanism and phenotypic readout","pmids":["35025698"],"is_preprint":false},{"year":1995,"finding":"EWS-WT1 chimeric transcripts result from a t(11;22)(p13;q12) translocation fusing EWS exons 1–7 to WT1 exons 8–10 (the last three zinc fingers), generating a predicted transcriptional modulator at WT1 target sites that underlies desmoplastic small round cell tumor.","method":"Genomic DNA fusion breakpoint isolation and sequencing, chimeric transcript RT-PCR analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — direct molecular characterization of fusion gene and chimeric transcripts","pmids":["7862627"],"is_preprint":false},{"year":2016,"finding":"Osr1 interacts with Wt1 in the developing kidney (demonstrated by CRISPR-labeled endogenous proteins); mice heterozygous for both Osr1 and Wt1 null alleles show synergistic kidney development defects including agenesis and hypoplasia, with reduced nephron progenitor cells and decreased Gdnf expression, demonstrating genetic epistasis between these two factors.","method":"CRISPR protein labeling, double heterozygous mouse model, nephron progenitor cell counting, Gdnf expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with endogenous protein interaction, single study","pmids":["27442016"],"is_preprint":false},{"year":2016,"finding":"WT1 is a major repressor of the CMIP gene in podocytes by directly binding to two WT1 response elements in the human CMIP proximal promoter (at -290/-274 and -57/-41); WT1 silencing promotes Cmip expression, and Cmip is early and significantly increased in podocytes with primary Wt1 defects (Denys-Drash and Frasier syndromes).","method":"ChIP assay, EMSA, luciferase reporter assay, decoy oligonucleotide competition, WT1 siRNA knockdown","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 1–2 — direct DNA binding by EMSA and ChIP, functional repression by reporter and competition assay, with human disease validation","pmids":["27650733"],"is_preprint":false},{"year":2017,"finding":"CUG-translated WT1 (cugWT1), an N-terminally extended isoform, functions as an oncogene promoting cell transformation and activating c-myc, bcl-2, and egfr expression; AKT phosphorylates cugWT1 on Ser62 to protect it from FBXW8-mediated proteasomal degradation. In contrast, AUG-WT1 acts as a tumor suppressor and represses the same target genes by recruiting HDAC1 and inhibiting cugWT1 function.","method":"CUG vs AUG translation start site analysis, AKT phosphorylation assay, FBXW8 ubiquitination assay, colony formation assay, target gene reporter assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanistic assays in a single study identifying novel isoform, single lab","pmids":["29040381"],"is_preprint":false}],"current_model":"WT1 is a zinc finger transcription factor (with at least four alternatively spliced isoforms including ±KTS and ±17AA variants) that binds TC/GC-rich promoter sequences to repress or activate target genes (including PDGF-A, Pax-2, EGFR, E-cadherin, amphiregulin, CMIP, and Bak), physically interacts with p53, BASP1 (and co-repressor prohibitin), hnRNP-U, TET2, MAD2, PINCH1, and β-CATENIN to modulate transcription, chromatin state, RNA processing, and mitotic checkpoint fidelity; it also undergoes autophagy-mediated degradation and PRMT5-facilitated IRES-dependent translation, and its distinct isoforms have context-specific roles in kidney podocyte survival, gonadal sex determination (with +KTS regulating Sry and ZF4 variants sequestering β-CATENIN), epicardial development, hematopoietic progenitor differentiation (blocking G-CSF-induced differentiation via constitutive Stat3 activation), and apoptosis (17AA+ isoforms being anti-apoptotic via the intrinsic pathway)."},"narrative":{"teleology":[{"year":1990,"claim":"Positional cloning of the 11p13 Wilms tumor locus identified WT1 as a zinc finger gene with restricted kidney and hematopoietic expression, establishing it as a candidate transcriptional regulator and tumor suppressor.","evidence":"cDNA isolation, Northern blot, and sequence analysis of the 11p13 region","pmids":["2154335","2154702"],"confidence":"High","gaps":["No direct transcriptional activity demonstrated","No target genes identified","No loss-of-function phenotype yet shown"]},{"year":1991,"claim":"Characterization of WT1 exon–intron structure revealed four conserved splice isoforms (±17AA, ±KTS), raising the question of whether these isoforms have distinct functions, while germline zinc finger mutations in Denys-Drash patients proved WT1 is essential for urogenital development.","evidence":"RNase protection, genomic cloning of splice variants; exon sequencing of DDS patients","pmids":["1658787","1655284","1654525"],"confidence":"High","gaps":["Isoform-specific functions not yet dissected","Mechanism by which zinc finger mutations cause disease unknown"]},{"year":1992,"claim":"Demonstration that WT1 directly binds and represses the PDGF-A chain promoter established its biochemical activity as a sequence-specific transcriptional repressor of growth factor genes.","evidence":"Gel-shift, DNase I footprinting, and transient transfection reporter assays","pmids":["1332065"],"confidence":"High","gaps":["Whether WT1 also activates transcription not yet tested","In vivo relevance of PDGF-A repression not confirmed"]},{"year":1993,"claim":"Physical interaction with p53 and the finding that WT1 can switch between repressor and activator modes—depending on p53 availability and point mutations in the transactivation domain—revealed WT1 as a context-dependent transcriptional regulator rather than a simple repressor.","evidence":"Co-immunoprecipitation, reporter assays with wild-type and mutant WT1","pmids":["8389468","8402654"],"confidence":"High","gaps":["Structural basis of WT1–p53 interaction unresolved","In vivo relevance of the repressor-to-activator switch unclear"]},{"year":1995,"claim":"Identification of multiple direct target genes—Pax-2 (repressed), EGFR (repressed, mediating WT1-induced apoptosis), and amphiregulin (activated)—and self-association of WT1 through its N-terminal domain expanded the repertoire of WT1 transcriptional functions and dominant-negative mechanisms, while the EWS-WT1 fusion was characterized in desmoplastic small round cell tumor.","evidence":"DNase I footprinting, inducible expression with EGFR rescue of apoptosis, oligonucleotide arrays, in vitro/in vivo binding assays, fusion transcript cloning","pmids":["7720589","7588596","7479946","7862627"],"confidence":"High","gaps":["Genome-wide target repertoire unknown","Self-association stoichiometry and structural basis unresolved"]},{"year":1996,"claim":"Evidence that WT1 harbors an RNA recognition motif and co-immunoprecipitates with spliceosomal proteins suggested a post-transcriptional role, though this remained less well characterized than its transcriptional functions.","evidence":"Structural modeling, spliceosomal Co-IP, RNA degradation–localization experiment","pmids":["8589729"],"confidence":"Medium","gaps":["No direct RNA-binding assay performed","No specific RNA targets identified","Functional consequence of spliceosomal association not demonstrated"]},{"year":1999,"claim":"Wt1-null mouse studies showed WT1 is required for epicardial and subepicardial mesenchymal cell development; YAC complementation fully rescued cardiac but only partially rescued urogenital defects, revealing tissue-specific regulatory requirements.","evidence":"Wt1 knockout mouse, LacZ YAC reporter, YAC rescue","pmids":["10101119"],"confidence":"High","gaps":["Epicardial target genes not identified","Mechanism of tissue-specific rescue differences unknown"]},{"year":2002,"claim":"Gene-dosage experiments in mice established WT1 as a master regulator of podocyte identity, with reduced Wt1 levels causing glomerulonephritis or mesangial sclerosis and loss of podocyte-specific genes nphs1 and podocalyxin.","evidence":"Wt1 heterozygous knockout and inducible transgenic mice","pmids":["11912180"],"confidence":"High","gaps":["Direct versus indirect regulation of nphs1 and podocalyxin not distinguished","Chromatin-level mechanism not explored"]},{"year":2006,"claim":"Isoform-specific studies resolved that 17AA+ WT1 suppresses apoptosis via the intrinsic mitochondrial pathway by repressing Bak, while hnRNP-U was identified as a direct zinc-finger–dependent interaction partner modulating WT1 transcriptional activation.","evidence":"Isoform-specific siRNA, caspase and mitochondrial assays; endogenous Co-IP and domain mapping","pmids":["16518414","16924231"],"confidence":"High","gaps":["Full set of 17AA+-specific targets not defined","In vivo role of hnRNP-U–WT1 interaction untested"]},{"year":2008,"claim":"Discovery of the BASP1 co-repressor complex on WT1 target promoters during podocyte differentiation provided the first chromatin-level mechanism for WT1-mediated gene repression, with sumoylation dynamically regulating BASP1 recruitment.","evidence":"ChIP in differentiating podocytes, BASP1 sumoylation analysis","pmids":["19050011"],"confidence":"Medium","gaps":["Genome-wide extent of BASP1 co-occupancy unknown","Whether sumoylation is necessary in vivo untested"]},{"year":2009,"claim":"The +KTS isoform was shown to cell-autonomously regulate Sry expression, with its loss causing male-to-female sex reversal rescued by exogenous FGF9, mechanistically linking alternative splicing to gonadal sex determination.","evidence":"Wt1(+KTS)-specific knockout mice, immunofluorescence, ex vivo gonad culture rescue","pmids":["19549635"],"confidence":"High","gaps":["Whether +KTS acts via transcriptional or post-transcriptional mechanisms on Sry unresolved","Direct binding to Sry locus not demonstrated"]},{"year":2013,"claim":"The WT1-BASP1-prohibitin repressor complex was shown to recruit BRG1 and HDAC1 while displacing CBP from target promoters, and WT1 was found to repress epicardial chemokines Ccl5/Cxcl10 to promote heart morphogenesis, broadening the chromatin-remodeling and developmental scope of WT1 function.","evidence":"Co-IP, ChIP, reporter assays; Wt1-KO epicardial transcriptome with functional chemokine assays","pmids":["24166496","23900076"],"confidence":"Medium","gaps":["Whether prohibitin-BRG1 recruitment is universal across WT1 targets unknown","Direct WT1 binding at chemokine promoters not confirmed"]},{"year":2015,"claim":"WT1 was found to recruit the DNA demethylase TET2 to target genes—with AML-derived TET2 mutations disrupting this interaction—and to regulate mitotic fidelity through MAD2 interaction and APC/C inhibition, revealing non-transcriptional roles and linking WT1/TET2 to a shared leukemogenic pathway.","evidence":"Co-IP, ChIP, colony formation, AML mutation exclusivity analysis; MAD2 interaction and APC/C ubiquitination assays","pmids":["25601757","25789599"],"confidence":"High","gaps":["Genome-wide WT1-TET2 co-occupancy map not generated","In vivo significance of WT1-MAD2 interaction not confirmed in animal models"]},{"year":2016,"claim":"WT1 directly represses CMIP via two response elements in podocytes, and genetic epistasis between Wt1 and Osr1 in kidney development further defined the transcription factor network governing nephron progenitor maintenance.","evidence":"ChIP, EMSA, luciferase reporter, WT1 siRNA; CRISPR-labeled Osr1-Wt1 double-heterozygous mice","pmids":["27650733","27442016"],"confidence":"High","gaps":["Whether CMIP derepression is sufficient to cause glomerular disease not tested","Molecular basis of Osr1-Wt1 interaction not defined"]},{"year":2018,"claim":"Conditional Wt1 deletion in podocytes revealed Notch1 pathway activation and HES1-mediated EMT as a downstream disease mechanism amenable to pharmacological rescue, while Wt1 haploinsufficiency was shown to cooperate with Flt3-ITD to drive AML, establishing Wt1 as a bona fide leukemia tumor suppressor gene in vivo.","evidence":"Tamoxifen-inducible podocyte Wt1 deletion with Notch inhibitor rescue; Wt1-het × Flt3-ITD mouse leukemia model","pmids":["29398135","30064973"],"confidence":"High","gaps":["Whether Notch pathway activation is the primary mediator versus a bystander in podocyte injury unknown","Epigenetic versus genetic mechanisms of Wt1-haploinsufficiency-driven leukemogenesis not dissected"]},{"year":2020,"claim":"Genome-wide ChIP-seq demonstrated that WT1 binds nearly all genes essential for the glomerular filtration barrier and undergoes dynamic chromatin reprogramming during podocyte injury and repair, while ZF4 mutations were shown to sequester β-catenin and cause 46,XX testicular DSD.","evidence":"ChIP-seq in murine podocytes and human kidney organoids; exome sequencing, Co-IP, and Wt1-XX mouse gonad analysis","pmids":["32754639","32493750"],"confidence":"High","gaps":["Causal hierarchy of WT1 chromatin changes versus injury signals not resolved","Whether β-catenin sequestration is the sole mechanism of ZF4-mediated sex reversal untested"]},{"year":2021,"claim":"PRMT5-mediated methylation of hnRNPA1 was shown to facilitate IRES-dependent translation of Wt1 mRNA, establishing a post-transcriptional layer of WT1 regulation essential for granulosa cell function and follicle development.","evidence":"Conditional Prmt5 knockout in granulosa cells, hnRNPA1 methylation analysis, Wt1 overexpression rescue","pmids":["34448450"],"confidence":"High","gaps":["Whether IRES-dependent translation is relevant outside granulosa cells unknown","Structural basis of hnRNPA1-WT1 IRES interaction not defined"]},{"year":2022,"claim":"Autophagy-mediated degradation of WT1 protein was identified as a mechanism controlling granulosa cell differentiation, adding a protein-turnover layer to WT1 regulation.","evidence":"ATG5/BECN1 siRNA and chloroquine-mediated autophagy inhibition with WT1 accumulation and differentiation assays","pmids":["35025698"],"confidence":"High","gaps":["Autophagy receptor or ubiquitin signal targeting WT1 for degradation not identified","Whether autophagy-mediated WT1 turnover operates in podocytes or other WT1-dependent lineages unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis of WT1 isoform-specific DNA versus RNA recognition, the genome-wide co-occupancy maps for WT1 with TET2 and the BASP1-prohibitin complex across cell types, and whether the mitotic checkpoint role of WT1 via MAD2 contributes to tumor suppression in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of full-length WT1 or isoform-specific complexes","Comprehensive WT1 interactome across developmental contexts not available","In vivo relevance of WT1-MAD2 axis in tumorigenesis untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,5,10,16,18,37]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,6,9,10,16,18,22,27,37]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,26]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[7,13]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,9,10,16,18,22,24,27,37]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3,17,19,23,36]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,20]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[24,27,31]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[29,35]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[34]}],"complexes":["WT1-BASP1-prohibitin repressor complex"],"partners":["TP53","BASP1","TET2","MAD2L1","HNRNPU","LIMS1","CTNNB1","OSR1"],"other_free_text":[]},"mechanistic_narrative":"WT1 is a zinc finger transcription factor that governs urogenital development, hematopoietic differentiation, and epicardial morphogenesis by binding GC/TC-rich promoter elements to repress or activate context-dependent target genes. Four major isoforms arising from alternative splicing of exon 5 (±17AA) and the KTS insertion between zinc fingers 3 and 4 confer distinct functions: the −KTS isoform drives canonical DNA-binding–dependent transcriptional regulation of targets such as PDGF-A, Pax-2, EGFR, amphiregulin, E-cadherin, and CMIP [PMID:1332065, PMID:7720589, PMID:10490105, PMID:27650733], while the +KTS isoform regulates Sry expression and gonadal sex determination [PMID:19549635]; the 17AA+ isoform suppresses apoptosis through the intrinsic mitochondrial pathway by repressing Bak [PMID:16518414]. WT1 recruits chromatin-modifying co-factors—including the BASP1–prohibitin–HDAC1 repressor complex and the DNA demethylase TET2—to target promoters, dynamically reprogramming chromatin during podocyte injury and repair [PMID:19050011, PMID:24166496, PMID:25601757, PMID:32754639]. Germline WT1 mutations cause Denys-Drash syndrome and other disorders of sex development, and somatic WT1 loss cooperates with oncogenic lesions such as FLT3-ITD to drive acute myeloid leukemia [PMID:1655284, PMID:30064973]."},"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":"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":397,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1317488","id":"PMC_1317488","title":"Expression of the Wilms' tumor gene (WT1) in human leukemias.","date":"1992","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/1317488","citation_count":329,"is_preprint":false,"source_track":"pubmed_title"},{"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":322,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9028964","id":"PMC_9028964","title":"Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia.","date":"1997","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9028964","citation_count":298,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9090524","id":"PMC_9090524","title":"A clinical overview of WT1 gene mutations.","date":"1997","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/9090524","citation_count":281,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11595161","id":"PMC_11595161","title":"WT1 proteins: functions in growth and differentiation.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11595161","citation_count":274,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18753648","id":"PMC_18753648","title":"Brain-derived neurotrophic factor and obesity in the WAGR syndrome.","date":"2008","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18753648","citation_count":246,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11237525","id":"PMC_11237525","title":"Wilms tumor and the WT1 gene.","date":"2001","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/11237525","citation_count":224,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8012395","id":"PMC_8012395","title":"Mosaic and polymorphic imprinting of the WT1 gene in humans.","date":"1994","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8012395","citation_count":175,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7856747","id":"PMC_7856747","title":"Wilms' tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma.","date":"1995","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/7856747","citation_count":167,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9531608","id":"PMC_9531608","title":"Wilms' tumor gene (WT1) competes with differentiation-inducing signal in hematopoietic progenitor cells.","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9531608","citation_count":156,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28811308","id":"PMC_28811308","title":"Wilms' tumour 1 (WT1) in development, homeostasis and disease.","date":"2017","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28811308","citation_count":154,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8393819","id":"PMC_8393819","title":"The role of WT1 in Wilms tumorigenesis.","date":"1993","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/8393819","citation_count":147,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9531607","id":"PMC_9531607","title":"Wilms' tumor (WT1) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance.","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9531607","citation_count":146,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9131006","id":"PMC_9131006","title":"Expression of the Wilms' tumor gene (WT1) in normal hemopoiesis.","date":"1997","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/9131006","citation_count":144,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16927106","id":"PMC_16927106","title":"WT1 and glomerular diseases.","date":"2006","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/16927106","citation_count":128,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12835718","id":"PMC_12835718","title":"WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies.","date":"2003","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/12835718","citation_count":127,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24402088","id":"PMC_24402088","title":"Genotype-phenotype associations in WT1 glomerulopathy.","date":"2014","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/24402088","citation_count":112,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35025698","id":"PMC_35025698","title":"Autophagy regulates differentiation of ovarian granulosa cells through degradation of WT1.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35025698","citation_count":111,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12665546","id":"PMC_12665546","title":"The complex life of WT1.","date":"2003","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/12665546","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10753894","id":"PMC_10753894","title":"E-cadherin is a WT1 target gene.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10753894","citation_count":106,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1327525","id":"PMC_1327525","title":"Inherited WT1 mutation in Denys-Drash syndrome.","date":"1992","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/1327525","citation_count":98,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8019557","id":"PMC_8019557","title":"Infrequent mutation of the WT1 gene in 77 Wilms' Tumors.","date":"1994","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/8019557","citation_count":97,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8589729","id":"PMC_8589729","title":"An RNA recognition motif in Wilms' tumour protein (WT1) revealed by structural modelling.","date":"1996","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8589729","citation_count":95,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17524167","id":"PMC_17524167","title":"The role of the Wilms tumour gene (WT1) in normal and malignant haematopoiesis.","date":"2007","source":"Expert reviews in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17524167","citation_count":93,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16099645","id":"PMC_16099645","title":"Transcriptional regulation by WT1 in development.","date":"2005","source":"Current opinion in genetics & development","url":"https://pubmed.ncbi.nlm.nih.gov/16099645","citation_count":91,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7479946","id":"PMC_7479946","title":"Antagonism of WT1 activity by protein self-association.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7479946","citation_count":90,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1331933","id":"PMC_1331933","title":"Identification of mutations in the WT1 gene in tumours from patients with the WAGR syndrome.","date":"1992","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/1331933","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1722569","id":"PMC_1722569","title":"Cell types expressing the Wilms' tumour gene (WT1) in Wilms' tumours: implications for tumour histogenesis.","date":"1991","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/1722569","citation_count":85,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16518414","id":"PMC_16518414","title":"Antiapoptotic function of 17AA(+)WT1 (Wilms' tumor gene) isoforms on the intrinsic apoptosis pathway.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16518414","citation_count":85,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15920488","id":"PMC_15920488","title":"Wilms' tumour gene 1 (WT1) in human neoplasia.","date":"2005","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/15920488","citation_count":73,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16263157","id":"PMC_16263157","title":"Expression of Wilms tumor gene (WT1) in epithelial ovarian cancer.","date":"2005","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16263157","citation_count":72,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20963411","id":"PMC_20963411","title":"Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909.","date":"2010","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/20963411","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14681303","id":"PMC_14681303","title":"Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours.","date":"2003","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14681303","citation_count":66,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1314370","id":"PMC_1314370","title":"Inactivation of the remaining allele of the WT1 gene in a Wilms' tumour from a WAGR patient.","date":"1992","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/1314370","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19050011","id":"PMC_19050011","title":"Dynamic interaction between WT1 and BASP1 in transcriptional regulation during differentiation.","date":"2008","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19050011","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2539014","id":"PMC_2539014","title":"A deletion map of the WAGR region on chromosome 11.","date":"1989","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2539014","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20885852","id":"PMC_20885852","title":"WT1 and kidney progenitor cells.","date":"2010","source":"Organogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/20885852","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8290269","id":"PMC_8290269","title":"Antisense transcripts and protein binding motifs within the Wilms tumour (WT1) locus.","date":"1994","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8290269","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8622864","id":"PMC_8622864","title":"Regulation of nov by WT1: a potential role for nov in nephrogenesis.","date":"1996","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8622864","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19549635","id":"PMC_19549635","title":"A cell-autonomous role for WT1 in regulating Sry in vivo.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19549635","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8530399","id":"PMC_8530399","title":"The transcriptional effect of WT1 is modulated by choice of expression vector.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8530399","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7833922","id":"PMC_7833922","title":"The Wilms tumour (WT1) gene is mutated in a secondary leukaemia in a WAGR patient.","date":"1994","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7833922","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12215009","id":"PMC_12215009","title":"The role of WT1 in oncogenesis: tumor suppressor or oncogene?","date":"2002","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/12215009","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7890725","id":"PMC_7890725","title":"GATA-1 transactivates the WT1 hematopoietic specific enhancer.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7890725","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26462627","id":"PMC_26462627","title":"WT1-AS promotes cell apoptosis in hepatocellular carcinoma through down-regulating of WT1.","date":"2015","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/26462627","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32493750","id":"PMC_32493750","title":"Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 (WT1) gene.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32493750","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15213600","id":"PMC_15213600","title":"Endometrial stromal neoplasms are immunoreactive with WT-1 antibody.","date":"2004","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/15213600","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28859078","id":"PMC_28859078","title":"The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28859078","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34634995","id":"PMC_34634995","title":"LINC00839/miR-144-3p/WTAP (WT1 Associated protein) axis is involved in regulating hepatocellular carcinoma progression.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34634995","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27417957","id":"PMC_27417957","title":"The Role of WT1 in Embryonic Development and Normal Organ Homeostasis.","date":"2016","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/27417957","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30064973","id":"PMC_30064973","title":"Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis.","date":"2018","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/30064973","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9361029","id":"PMC_9361029","title":"Paternal expression of WT1 in human fibroblasts and lymphocytes.","date":"1997","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9361029","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8402654","id":"PMC_8402654","title":"Altered trans-activational properties of a mutated WT1 gene product in a WAGR-associated Wilms' tumor.","date":"1993","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/8402654","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1322241","id":"PMC_1322241","title":"Role of the WT1 gene in Wilms' tumour.","date":"1992","source":"Cancer surveys","url":"https://pubmed.ncbi.nlm.nih.gov/1322241","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15510596","id":"PMC_15510596","title":"Overexpression of the Wilms' tumor gene WT1 in esophageal cancer.","date":"2004","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15510596","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20013787","id":"PMC_20013787","title":"The clinical relevance of Wilms Tumour 1 (WT1) gene mutations in acute leukaemia.","date":"2010","source":"Hematological oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20013787","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15540161","id":"PMC_15540161","title":"Upregulation of Wilms' tumor gene 1 (WT1) in desmoid tumors.","date":"2005","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15540161","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17531467","id":"PMC_17531467","title":"Upregulation of Wilms' tumour gene 1 (WT1) in uterine sarcomas.","date":"2007","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/17531467","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17137506","id":"PMC_17137506","title":"FGFR1 and WT1 are markers of human prostate cancer progression.","date":"2006","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17137506","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15779010","id":"PMC_15779010","title":"Congenital diaphragmatic hernia in WAGR syndrome.","date":"2005","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/15779010","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12215010","id":"PMC_12215010","title":"Cancer immunotherapy targeting WT1 protein.","date":"2002","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/12215010","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19196508","id":"PMC_19196508","title":"Wilms' tumour gene 1 (WT1) as a target in curcumin treatment of pancreatic cancer cells.","date":"2009","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/19196508","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16924231","id":"PMC_16924231","title":"hnRNP-U directly interacts with WT1 and modulates WT1 transcriptional activation.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16924231","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29398135","id":"PMC_29398135","title":"Activation of podocyte Notch mediates early Wt1 glomerulopathy.","date":"2018","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/29398135","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18929401","id":"PMC_18929401","title":"Wilms' tumor gene 1 (WT1) in endometrial carcinoma.","date":"2008","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18929401","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23791475","id":"PMC_23791475","title":"Immunolocalization of Wilms' Tumor protein (WT1) in developing human peripheral sympathetic and gastroenteric nervous system.","date":"2013","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/23791475","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24166496","id":"PMC_24166496","title":"Prohibitin is required for transcriptional repression by the WT1-BASP1 complex.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24166496","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19443388","id":"PMC_19443388","title":"Immunohistochemical detection of WT1 protein in endometrial cancer.","date":"2009","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19443388","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9669676","id":"PMC_9669676","title":"Wilms tumor gene (WT1) as a new marker for the detection of minimal residual disease in leukemia.","date":"1998","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/9669676","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11739471","id":"PMC_11739471","title":"Expression of Wilms' tumor suppressor gene (WT1) in human endometrium: regulation through decidual differentiation.","date":"2001","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/11739471","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32754639","id":"PMC_32754639","title":"Epigenetic transcriptional reprogramming by WT1 mediates a repair response during podocyte injury.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/32754639","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7569406","id":"PMC_7569406","title":"Transcription factors in renal development: the WT1 and Pax-2 story.","date":"1995","source":"Seminars in nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/7569406","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9402320","id":"PMC_9402320","title":"The Wilms tumour gene WT1 in leukaemia.","date":"1997","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/9402320","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10092116","id":"PMC_10092116","title":"Coordinate action of Wt1 and a modifier gene supports embryonic survival in the oviduct.","date":"1999","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/10092116","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15761866","id":"PMC_15761866","title":"Genome-wide loss of heterozygosity analysis of WT1-wild-type and WT1-mutant Wilms tumors.","date":"2005","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15761866","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19004815","id":"PMC_19004815","title":"Characterization of an evolutionarily conserved metallophosphoesterase that is expressed in the fetal brain and associated with the WAGR syndrome.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19004815","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24778040","id":"PMC_24778040","title":"High levels of Wilms' tumor 1 (WT1) expression were associated with aggressive clinical features in ovarian cancer.","date":"2014","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24778040","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20619457","id":"PMC_20619457","title":"Structures of native and affinity-enhanced WT1 epitopes bound to HLA-A*0201: implications for WT1-based cancer therapeutics.","date":"2010","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20619457","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25881478","id":"PMC_25881478","title":"Wilms tumor 1 (WT1) protein: Diagnostic utility in pediatric tumors.","date":"2015","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/25881478","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9001425","id":"PMC_9001425","title":"Mutation analysis of the WT1 gene in sporadic childhood leukaemia.","date":"1997","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/9001425","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23900076","id":"PMC_23900076","title":"WT1 regulates the expression of inhibitory chemokines during heart development.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23900076","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12215007","id":"PMC_12215007","title":"Wilms tumor gene (WT1) expression as a panleukemic marker.","date":"2002","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/12215007","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25018051","id":"PMC_25018051","title":"The development of Wilms tumor: from WT1 and microRNA to animal models.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25018051","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21390327","id":"PMC_21390327","title":"PINCH1 is transcriptional regulator in podocytes that interacts with WT1 and represses podocalyxin expression.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21390327","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24607494","id":"PMC_24607494","title":"WT1 expression increases with malignancy and indicates unfavourable outcome in astrocytoma.","date":"2014","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24607494","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34448450","id":"PMC_34448450","title":"PRMT5 regulates ovarian follicle development by facilitating Wt1 translation.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34448450","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7527372","id":"PMC_7527372","title":"A WAGR region gene between PAX-6 and FSHB expressed in fetal brain.","date":"1994","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7527372","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22244202","id":"PMC_22244202","title":"RNAa-mediated overexpression of WT1 induces apoptosis in HepG2 cells.","date":"2012","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22244202","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18466223","id":"PMC_18466223","title":"Diagnostic value of WT1 in neuroepithelial tumours.","date":"2008","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/18466223","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25789599","id":"PMC_25789599","title":"A role of WT1 in cell division and genomic stability.","date":"2015","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/25789599","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10100271","id":"PMC_10100271","title":"Expression of Wilms tumor gene (WT1) in children with acute leukemia.","date":"1999","source":"Pediatric hematology and oncology","url":"https://pubmed.ncbi.nlm.nih.gov/10100271","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27650733","id":"PMC_27650733","title":"Repression of CMIP transcription by WT1 is relevant to podocyte health.","date":"2016","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/27650733","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34786213","id":"PMC_34786213","title":"lncRNA DDGC participates in premature ovarian insufficiency through regulating RAD51 and WT1.","date":"2021","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/34786213","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19856421","id":"PMC_19856421","title":"Combination of MUC5ac and WT-1 immunohistochemistry is useful in distinguishing pancreatic ductal carcinoma from ovarian serous carcinoma in effusion cytology.","date":"2010","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/19856421","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11196418","id":"PMC_11196418","title":"Requirement of WT1 for gonad and adrenal development: insights from transgenic animals.","date":"2000","source":"Endocrine research","url":"https://pubmed.ncbi.nlm.nih.gov/11196418","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17935232","id":"PMC_17935232","title":"Complete sex reversal in a WAGR syndrome patient.","date":"2007","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/17935232","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29040381","id":"PMC_29040381","title":"The CUG-translated WT1, not AUG-WT1, is an oncogene.","date":"2017","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/29040381","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36923529","id":"PMC_36923529","title":"WT1+ glomerular parietal epithelial progenitors promote renal proximal tubule regeneration after severe acute kidney injury.","date":"2023","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/36923529","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27442016","id":"PMC_27442016","title":"Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27442016","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23788249","id":"PMC_23788249","title":"ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.","date":"2013","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23788249","citation_count":1945,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2154335","id":"PMC_2154335","title":"Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus.","date":"1990","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/2154335","citation_count":1805,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2154702","id":"PMC_2154702","title":"Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping.","date":"1990","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2154702","citation_count":1267,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19274049","id":"PMC_19274049","title":"A census of human transcription factors: function, expression and evolution.","date":"2009","source":"Nature reviews. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19274049","citation_count":1191,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1655284","id":"PMC_1655284","title":"Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.","date":"1991","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1655284","citation_count":795,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1658787","id":"PMC_1658787","title":"Alternative splicing and genomic structure of the Wilms tumor gene WT1.","date":"1991","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1658787","citation_count":605,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15365188","id":"PMC_15365188","title":"Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15365188","citation_count":457,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1654525","id":"PMC_1654525","title":"WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour.","date":"1991","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1654525","citation_count":430,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10101119","id":"PMC_10101119","title":"YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis.","date":"1999","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10101119","citation_count":425,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19752335","id":"PMC_19752335","title":"Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study.","date":"2009","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19752335","citation_count":372,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17371932","id":"PMC_17371932","title":"Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).","date":"2007","source":"Pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/17371932","citation_count":315,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7588596","id":"PMC_7588596","title":"WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7588596","citation_count":308,"is_preprint":false,"source_track":"gene2pubmed"},{"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,"source_track":"gene2pubmed"},{"pmid":"8306891","id":"PMC_8306891","title":"Nuclear localization of the protein encoded by the Wilms' tumor gene WT1 in embryonic and adult tissues.","date":"1993","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8306891","citation_count":284,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21900206","id":"PMC_21900206","title":"A directed protein interaction network for investigating intracellular signal transduction.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21900206","citation_count":258,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7862627","id":"PMC_7862627","title":"Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7862627","citation_count":249,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25601757","id":"PMC_25601757","title":"WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation.","date":"2015","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/25601757","citation_count":245,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1671709","id":"PMC_1671709","title":"Isolation, characterization, and expression of the murine Wilms' tumor gene (WT1) during kidney development.","date":"1991","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1671709","citation_count":242,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10490105","id":"PMC_10490105","title":"The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin.","date":"1999","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/10490105","citation_count":238,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7720589","id":"PMC_7720589","title":"Repression of Pax-2 by WT1 during normal kidney development.","date":"1995","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/7720589","citation_count":233,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1332065","id":"PMC_1332065","title":"Human platelet-derived growth factor A chain is transcriptionally repressed by the Wilms tumor suppressor WT1.","date":"1992","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1332065","citation_count":227,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11912180","id":"PMC_11912180","title":"WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis.","date":"2002","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11912180","citation_count":225,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8393820","id":"PMC_8393820","title":"The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor.","date":"1993","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/8393820","citation_count":221,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12200377","id":"PMC_12200377","title":"CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12200377","citation_count":219,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44591,"output_tokens":6869,"usd":0.118404},"stage2":{"model":"claude-opus-4-6","input_tokens":10516,"output_tokens":4940,"usd":0.26412},"total_usd":0.796209,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":57090,"output_tokens":8462,"usd":0.1491},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":12573,"output_tokens":4541,"usd":0.264585}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"WT1 protein physically associates with p53 in transfected cells (co-immunoprecipitation), and this interaction modulates their transcriptional activities: in the absence of p53, WT1 acts as a transcriptional activator of the EGR1 site rather than a repressor, while WT1 enhances p53-mediated transactivation of the muscle creatine kinase promoter.\",\n      \"method\": \"Co-immunoprecipitation in transfected cells; transient transfection transcriptional assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional interaction shown by Co-IP and multiple transcriptional readouts in a single study; highly cited foundational paper\",\n      \"pmids\": [\"8389468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"WT1 can self-associate in vitro and in vivo; the self-association domain maps to the amino-terminal region. Mutant WT1 alleles that impair DNA recognition can oligomerize with full-length WT1 and antagonize WT1-mediated transcriptional repression, providing a dominant-negative mechanism for Denys-Drash syndrome mutations.\",\n      \"method\": \"In vitro binding assays; co-immunoprecipitation in vivo; transient transfection transcriptional repression assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of self-association plus in vivo Co-IP and functional transcriptional assays; domain mapping included\",\n      \"pmids\": [\"7479946\"],\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 WT1 isoforms similar to the constitutive splicing factor U1A; experimental co-immunoprecipitation showed WT1 associates with spliceosomal proteins, and nuclear RNA degradation abolishes the speckled subnuclear localization of WT1, indicating WT1 binds RNA and localizes to nuclear speckles in an RNA-dependent manner.\",\n      \"method\": \"Structural modelling; co-immunoprecipitation with spliceosomal proteins; nuclear RNA degradation experiment with immunofluorescence\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — structural prediction combined with Co-IP and localization experiment; single study\",\n      \"pmids\": [\"8589729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"WT1 directly represses the novH (CCN3/NOV) promoter through its zinc finger domain and N-terminal repression domain; repression requires intact zinc fingers and the NH2 transcriptional repression domain; constitutive expression of WT1 in 293 cells decreased endogenous NOVH protein levels, identifying novH as a physiological target gene of WT1.\",\n      \"method\": \"Transient co-transfection reporter assays; in vitro footprinting; western blotting of endogenous protein\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter assay, domain mutagenesis, endogenous protein levels) in a single study\",\n      \"pmids\": [\"8622864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Constitutive expression of wild-type WT1 in myeloid progenitor 32D cl3 cells blocks G-CSF-induced differentiation and promotes proliferation; WT1 expression leads to constitutive activation of both Stat3α and Stat3β downstream of the G-CSF receptor, whereas Stat3 activation is only transient in WT1-uninfected cells, demonstrating that WT1 interferes with differentiation signaling via the G-CSF receptor/Stat3 axis.\",\n      \"method\": \"Retroviral transduction of WT1 into myeloid progenitor cell line; G-CSF stimulation; western blot for Stat3 phosphorylation; differentiation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean gain-of-function in a defined cell system with specific signaling readout (Stat3 activation) and cellular phenotype (differentiation block); highly cited\",\n      \"pmids\": [\"9531608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"WT1 transcriptionally activates the E-cadherin promoter through a conserved GC-rich EGR-1-like binding site and a CAAT box; WT1 produced in vitro or from nuclear extracts binds the WT1-response element within the murine E-cadherin promoter; stable WT1 expression in NIH 3T3 fibroblasts induces growth suppression and epithelial differentiation features including up-regulation of E-cadherin mRNA, identifying E-cadherin as a WT1 target gene.\",\n      \"method\": \"Stable and retroviral WT1 expression in NIH 3T3; transient transfection reporter assays; in vitro/nuclear extract gel-shift/DNA-binding assays; dominant-negative WT1 blockade\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro DNA binding, promoter reporter assay, dominant-negative control, and endogenous gene induction; multiple orthogonal methods\",\n      \"pmids\": [\"10753894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The 17AA(+) WT1 isoforms (but not 17AA(−) isoforms) exert anti-apoptotic functions via the intrinsic (mitochondrial) apoptosis pathway; 17AA(+)WT1-specific siRNA activates caspase-3 and -9 and Bax in leukemia cells; the zinc-finger DNA-binding region of 17AA(+)WT1 is essential for anti-apoptotic activity; 17AA(+)KTS(−)WT1 isoform decreases pro-apoptotic Bak expression.\",\n      \"method\": \"Isoform-specific siRNA knockdown; caspase activation assays; mitochondrial membrane potential measurement; constitutive WT1 isoform expression in K562 cells; western blotting\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific loss-of-function and gain-of-function with multiple mechanistic readouts; domain mutagenesis identifies zinc finger as essential\",\n      \"pmids\": [\"16518414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"WT1 directly interacts with heterogeneous nuclear ribonucleoprotein U (hnRNP-U); the interaction does not require other proteins or nucleic acids, involves the zinc fingers of WT1 and the middle domain of hnRNP-U; hnRNP-U modulates WT1 transcriptional activation of a bona fide WT1 target gene.\",\n      \"method\": \"Reciprocal Co-immunoprecipitation of endogenous proteins; genetic and biochemical domain-mapping; transcriptional reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal endogenous Co-IP with domain mapping and functional transcriptional consequence; multiple methods in one study\",\n      \"pmids\": [\"16924231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Brain Acid Soluble Protein 1 (BASP1) and WT1 co-occupy the promoters of the Bak, c-myc, and podocalyxin genes in podocyte precursor cells (chromatin immunoprecipitation); during differentiation, BASP1 occupancy of the podocalyxin promoter decreases while WT1 remains, allowing podocalyxin upregulation, whereas the repressive WT1/BASP1 complex is maintained at c-myc and Bak promoters; BASP1 promoter occupancy is regulated by sumoylation of BASP1.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); differentiation induction in podocyte precursor cell line; sumoylation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP at multiple endogenous promoters in a relevant differentiation model with functional gene expression outcomes; multiple orthogonal approaches\",\n      \"pmids\": [\"19050011\"],\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 have reduced SRY protein per cell and fewer SRY-expressing cells, correlated with decreased cell proliferation near the coelomic epithelium at 11.5 dpc; Sertoli cell differentiation (SOX9, Fgf9) is blocked; addition of recombinant FGF9 to ex vivo cultures rescues the mutant phenotype and restores anti-Müllerian hormone expression.\",\n      \"method\": \"Immunofluorescence in knockout mice; cell counting; ex vivo gonad culture rescue with recombinant FGF9; marker analysis by immunofluorescence\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific knockout with specific cellular phenotype, cell-autonomy established, and rescue experiment; multiple orthogonal readouts\",\n      \"pmids\": [\"19549635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PINCH1 interacts with WT1 (co-immunoprecipitation and pull-down); the interaction is mediated by the LIM1 domain of PINCH1 and the C-terminal zinc-finger domain of WT1; PINCH1–WT1 interaction suppresses WT1-mediated podocalyxin expression in podocytes, as shown by promoter-luciferase reporter assays; PINCH1 translocates to the nucleus in response to TGF-β1.\",\n      \"method\": \"Co-immunoprecipitation; GST pull-down; promoter-luciferase reporter assay; immunofluorescence localization; domain deletion mapping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP and pull-down with domain mapping and functional consequence in podocytes; single lab study\",\n      \"pmids\": [\"21390327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Prohibitin is a component of the WT1–BASP1 transcriptional repression complex; prohibitin interacts with BASP1 and colocalizes with it in the nucleus; prohibitin is recruited to WT1 target gene promoters to elicit BASP1-dependent transcriptional repression; prohibitin and BASP1 cooperate to recruit chromatin remodeling factor BRG1 and dissociate CBP from WT1-responsive promoters; the complex also recruits PIP2 and HDAC1 to WT1 target genes in a BASP1-and prohibitin-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation; ChIP; transcriptional reporter assays; nuclear colocalization studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, reporter assay, colocalization) demonstrating a multiprotein complex mechanism; strong mechanistic detail\",\n      \"pmids\": [\"24166496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WT1 directly represses the expression of chemokines Ccl5 and Cxcl10 in epicardial cells both directly (binding to gene promoters) and indirectly by increasing IRF7 levels; CXCL10 inhibits epicardial cell migration and CCL5 inhibits cardiomyocyte proliferation; an inverse correlation between Wt1 and chemokine expression exists during epicardium development.\",\n      \"method\": \"Wt1 knockout transcriptome analysis; functional migration/proliferation assays; inverse expression correlation; promoter binding/reporter analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptome plus functional assays showing downstream consequences; some mechanistic detail for IRF7 indirect pathway; single lab\",\n      \"pmids\": [\"23900076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WT1 interacts with the spindle assembly checkpoint protein MAD2 and delays anaphase entry by inhibiting the ubiquitination activity of the Anaphase Promoting Complex/cyclosome (APC/C), thereby regulating chromosome segregation fidelity and genomic stability.\",\n      \"method\": \"Co-immunoprecipitation of WT1-MAD2 interaction; APC/C ubiquitination assay; cell division assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — interaction shown by Co-IP with biochemical APC/C ubiquitination assay; single lab study; limited methodological detail in abstract\",\n      \"pmids\": [\"25789599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WT1 binds two WT1 response elements in the human CMIP promoter (at positions −290/−274 and −57/−41) as shown by ChIP and EMSA; WT1 dose-dependently inhibits CMIP promoter transcription in luciferase assays; WT1 silencing promotes Cmip expression in podocytes; Cmip is elevated early in podocytes with primary WT1 defects (Denys-Drash and Frasier syndromes), establishing WT1 as a major repressor of CMIP.\",\n      \"method\": \"ChIP; electrophoretic mobility shift assay (EMSA); luciferase reporter assay; WT1 siRNA knockdown; patient tissue analysis\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct DNA binding (EMSA + ChIP) with promoter reporter and loss-of-function; validated in disease patient tissue\",\n      \"pmids\": [\"27650733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CUG-initiated WT1 (cugWT1), an N-terminally extended isoform, functions as an oncogene and increases c-myc, bcl-2 and egfr expression; AUG-initiated WT1 (augWT1) represses the same target genes by recruiting HDAC1 and inhibits cugWT1 function; AKT phosphorylates cugWT1 on Ser62, protecting it from FBXW8-mediated proteasomal degradation.\",\n      \"method\": \"CUG vs AUG WT1 isoform expression constructs; colony formation assays; gene expression analysis; HDAC1 recruitment assays; AKT phosphorylation assay; proteasomal degradation assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple isoform-specific functional assays with molecular mechanisms identified; single lab; AKT phosphorylation site identified\",\n      \"pmids\": [\"29040381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wt1 haploinsufficiency in mice enhances hematopoietic stem cell self-renewal in an age-dependent manner and cooperates with Flt3-ITD mutation to induce fully penetrant AML, demonstrating that WT1 loss contributes to leukemogenesis through progressive genetic and epigenetic alterations.\",\n      \"method\": \"Wt1 heterozygous mouse model; stem cell functional assays; Flt3-ITD double mutant model; epigenetic profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic mouse models with epistasis (Wt1 × Flt3-ITD) and defined cellular/molecular phenotypes; genetic cooperation established\",\n      \"pmids\": [\"30064973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Deletion of Wt1 in adult mouse podocytes triggers podocyte apoptosis (from day 4 post-induction), activates Notch1 signaling with upregulation of Nrarp, Hey2, and HES1, represses FoxC2, and induces epithelial-mesenchymal transition markers; pharmacological Notch inhibition early after Wt1 deletion ameliorates glomerular scarring and albuminuria, placing WT1 upstream of a Wt1/FoxC2/Notch transcriptional network in podocyte injury.\",\n      \"method\": \"Tamoxifen-inducible Cre-LoxP Wt1 deletion in adult mice; immunostaining; Notch inhibitor treatment; marker gene analysis\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with specific early phenotypic readouts, pathway placement via pharmacological rescue, and transcriptional network characterization\",\n      \"pmids\": [\"29398135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WT1 fourth zinc finger (ZF4) missense mutations cause 46,XX testicular/ovotesticular DSD by physically interacting with and sequestering the pro-ovary factor β-CATENIN; introduction of ZF4 mutants into a human granulosa cell line upregulates endogenous Sertoli cell transcripts; Wt1 XX gain-of-function mice display masculinization of fetal gonads.\",\n      \"method\": \"Exome sequencing; cell line transfection with ZF4 mutants; gene expression analysis; protein-protein interaction (physical interaction with β-CATENIN); Wt1 XX mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (human genetics, cell line functional assay, protein interaction, mouse model); de novo variant association; epistasis with β-CATENIN\",\n      \"pmids\": [\"32493750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WT1 acts as a master regulator of podocyte gene expression, binding nearly all genes crucial for glomerular filtration barrier maintenance; during podocyte injury WT1 dynamically redistributes its binding across target genes, reprogramming chromatin state and gene expression levels as part of a reparative injury response.\",\n      \"method\": \"ChIP-seq in murine podocytes and human kidney organoids; murine injury models; genome-wide occupancy analysis during injury\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide ChIP-seq in two independent model systems (mouse and human organoid) with dynamic occupancy changes correlated to gene expression reprogramming\",\n      \"pmids\": [\"32754639\"],\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 reduces WT1 protein and causes premature granulosa cell differentiation with upregulation of steroidogenic genes; Wt1 overexpression rescues the steroidogenic gene upregulation in Prmt5-deficient cells.\",\n      \"method\": \"Conditional Prmt5 knockout in granulosa cells; western blot; rescue with Wt1 overexpression; IRES-dependent translation assay; HnRNPA1 methylation analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with rescue experiment, mechanistic pathway (PRMT5→HnRNPA1 methylation→IRES-dependent WT1 translation) supported by multiple assays\",\n      \"pmids\": [\"34448450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Autophagy degrades the WT1 protein in ovarian granulosa cells; inhibition of autophagy (via ATG5/BECN1 siRNA or chloroquine) causes WT1 accumulation which inhibits granulosa cell differentiation (reduced CYP19A1/Aromatase, FSHR expression and estradiol synthesis); WT1 is identified as a substrate of autophagic degradation via an LC3-interacting region (LIR motif).\",\n      \"method\": \"siRNA knockdown of ATG5 and BECN1; chloroquine treatment; western blot for LC3-II:LC3-I and SQSTM1/p62; Co-IP; cycloheximide chase; LIR motif identification; gene expression analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological autophagy inhibition with mechanistic identification of WT1 as autophagy substrate via LIR motif; multiple orthogonal methods\",\n      \"pmids\": [\"35025698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"GATA-1 transactivates the WT1 hematopoietic-specific 3' enhancer by binding a GATA-binding site within the enhancer, as shown by gel-shift competition and transactivation assays; GATA-1 and WT1 are co-expressed in K562 cells and mouse spleen, indicating GATA-1 regulates WT1 during hematopoiesis.\",\n      \"method\": \"Gel-shift competition assays; transient transfection transcriptional assays; co-expression analysis by RT-PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gel shift and reporter assay identify GATA-1 as a direct regulator of WT1 enhancer; single study\",\n      \"pmids\": [\"7890725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"A point mutation within the WT1 putative trans-activation domain (glycine to aspartic acid substitution) converts WT1 from a transcriptional repressor to an activator of its target DNA sequence, providing a molecular mechanism for the 'second hit' in WAGR-associated Wilms tumorigenesis.\",\n      \"method\": \"Sequencing of tumor WT1 allele; transient transfection transcriptional reporter assays comparing wild-type vs mutant WT1\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutation identified from tumor, functional consequence confirmed in transcriptional assay; single study\",\n      \"pmids\": [\"8402654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Osr1 and Wt1 interact genetically and synergistically regulate kidney organogenesis; mice heterozygous for both Osr1 and Wt1 (but not either single heterozygote) show defects in metanephric kidney development with reduced nephron progenitor cells (Pax2+, Six2+) and reduced Gdnf expression in metanephric mesenchyme; CRISPR labeling showed Osr1 protein co-localizes with Wt1 in the developing kidney.\",\n      \"method\": \"Compound heterozygous mouse model; CRISPR endogenous tagging; immunofluorescence; quantification of nephron progenitor cells; Gdnf expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis by double heterozygote showing synergistic interaction, with CRISPR-based co-localization; single lab\",\n      \"pmids\": [\"27442016\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WT1 is a multifunctional zinc finger transcription factor that activates or represses target genes (including E-cadherin, CMIP, novH, Ccl5/Cxcl10) depending on isoform (−KTS vs +KTS; 17AA± ; AUG vs CUG) and interacting partners (p53, BASP1/prohibitin complex recruiting HDAC1/BRG1/PIP2, hnRNP-U, PINCH1, MAD2, β-CATENIN); the +KTS isoform also binds RNA via an N-terminal RRM and associates with spliceosomal proteins; WT1 protein levels are controlled post-translationally by PRMT5-driven IRES-dependent translation and by autophagic degradation via a LIR motif, and by AKT-mediated phosphorylation (Ser62) that protects the oncogenic CUG-WT1 isoform from FBXW8-mediated proteasomal degradation; in signaling, WT1 constitutively activates Stat3 downstream of G-CSFR to block myeloid differentiation, and in mitosis delays anaphase entry by inhibiting APC/C ubiquitination activity through interaction with MAD2.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"WT1 was isolated as a zinc finger polypeptide gene at chromosome 11p13, with expression restricted predominantly to kidney and hematopoietic cells, and predicted to function as a transcriptional regulator based on its four zinc finger domains and proline/glutamine-rich region.\",\n      \"method\": \"Positional cloning, cDNA isolation, Northern blot expression analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning paper with multiple orthogonal methods; foundational, highly cited\",\n      \"pmids\": [\"2154335\", \"2154702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"WT1 gene consists of 10 exons generating four alternatively spliced transcripts: two splice sites produce isoforms with/without a 17-amino-acid insertion (exon 5) and with/without 3 amino acids (KTS) between zinc fingers 3 and 4, with the relative ratios conserved between normal tissue and Wilms tumors.\",\n      \"method\": \"RNase protection analysis, genomic and cDNA cloning\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct molecular characterization of genomic and transcript structure, highly cited\",\n      \"pmids\": [\"1658787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Germline point mutations in WT1 zinc finger domains (exons 8 and 9) cause Denys-Drash syndrome, with these mutations directly affecting DNA sequence recognition, demonstrating WT1's essential role in urogenital development.\",\n      \"method\": \"Exon sequencing, functional analysis of zinc finger mutations\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — germline mutation analysis with functional annotation, highly cited foundational paper\",\n      \"pmids\": [\"1655284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Constitutional mutations in WT1 zinc finger domains contribute to abnormal genital system development, establishing WT1 as essential for both kidney and gonadal development.\",\n      \"method\": \"Constitutional mutation analysis of WT1 coding exons\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — germline mutation-phenotype analysis, replicated across cases, highly cited\",\n      \"pmids\": [\"1654525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Mouse WT1 protein is greater than 95% conserved with human WT1, with developmental expression in fetal kidney peaking just before birth and declining postpartum, consistent with a role as a negative regulator of nephroblast growth.\",\n      \"method\": \"Murine Wt1 cDNA isolation, developmental Northern blot expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cross-species characterization with developmental expression profiling, highly cited\",\n      \"pmids\": [\"1671709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"WT1 protein functions as a transcriptional repressor of the PDGF-A chain promoter by binding to multiple sites in the PDGF-A promoter, as demonstrated by gel-shift analysis and DNase I footprinting, achieving >50-fold repression.\",\n      \"method\": \"Gel-shift analysis, DNase I footprinting, transient transfection reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct DNA binding and transcriptional repression shown by multiple orthogonal biochemical methods\",\n      \"pmids\": [\"1332065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"WT1 physically associates with p53 in transfected cells, modulating their transcriptional activity: in the absence of p53, WT1 acts as a transcriptional activator of the EGR1 site, and WT1 cooperatively enhances p53 transactivation of the muscle creatine kinase promoter.\",\n      \"method\": \"Co-immunoprecipitation in transfected cells, transcriptional reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional reporter assays, highly cited\",\n      \"pmids\": [\"8389468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"WT1 protein is exclusively nuclear, localizing to podocytes during mesonephric and metanephric development and persisting in adult podocytes, supporting its role as a transcription factor during urogenital development and adult kidney homeostasis.\",\n      \"method\": \"Immunohistochemistry, immunofluorescence, confocal laser microscopy, in situ hybridization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization by multiple imaging methods with developmental and adult tissue context\",\n      \"pmids\": [\"8306891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"A point mutation in WT1 converting glycine to aspartic acid in the putative trans-activation domain converts the protein from a transcriptional repressor to an activator of its target DNA sequence, providing the 'second hit' mechanism in WAGR-associated Wilms tumorigenesis.\",\n      \"method\": \"Mutant WT1 functional analysis in transfection reporter assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional mutation analysis in reporter assays, single study\",\n      \"pmids\": [\"8402654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"WT1 induces apoptosis in osteosarcoma cell lines via an inducible system, mediating transcriptional repression of the EGFR promoter at two TC-rich repeat sequences and reducing EGFR synthesis; constitutive EGFR expression rescued WT1-induced apoptosis.\",\n      \"method\": \"Tetracycline-inducible WT1 expression, EGFR promoter reporter assays, apoptosis assays, EGFR rescue experiment\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — inducible system with gain/loss-of-function, epistasis via rescue, and promoter assays in same study\",\n      \"pmids\": [\"7588596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"WT1 directly represses Pax-2 transcription by binding to three high-affinity sites in the 5' untranslated Pax-2 leader sequence (demonstrated by DNase I footprinting), coinciding with down-regulation of Pax-2 during glomerular precursor differentiation in vivo.\",\n      \"method\": \"DNase I footprinting, co-transfection reporter assays, immunofluorescence in mouse kidney sections\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct DNA binding demonstrated by footprinting plus in vivo correlation and functional reporter assays\",\n      \"pmids\": [\"7720589\"],\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, and mutant WT1 proteins impaired in DNA recognition can antagonize WT1-mediated transcriptional repression through these oligomeric interactions.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation in vivo, transcriptional repression assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution and in vivo Co-IP with functional read-out\",\n      \"pmids\": [\"7479946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"GATA-1 transactivates the WT1 hematopoietic-specific 3' enhancer by binding to a GATA-binding site, as demonstrated by gel shift competition experiments and transactivation assays, linking GATA-1 to regulation of WT1 expression in hematopoiesis.\",\n      \"method\": \"Gel shift competition assays, transactivation reporter assays, RT-PCR co-expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct DNA binding and functional transactivation shown, single study\",\n      \"pmids\": [\"7890725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"WT1 was found by structural modeling to contain an N-terminal RNA recognition motif (RRM) similar to the splicing factor U1A, and WT1 co-immunoprecipitates with spliceosomal proteins, with nuclear RNA degradation abolishing the speckled WT1 localization pattern.\",\n      \"method\": \"Structural modeling, co-immunoprecipitation with spliceosomal proteins, RNA degradation experiment\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — structural prediction plus Co-IP and localization, single study\",\n      \"pmids\": [\"8589729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"WT1 (both isoforms WT1 and WT1+KTS) represses transcription of the novH (nov) promoter through intact zinc finger regions and the NH2 transcription repression domain, with constitutive WT1 expression decreasing endogenous NOVH protein levels in 293 cells.\",\n      \"method\": \"Transient co-transfection reporter assays, in vitro footprinting, Western blot of NOVH protein\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter reporter, in vitro DNA binding, and endogenous protein level analysis\",\n      \"pmids\": [\"8622864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Constitutive WT1 expression in the myeloid progenitor cell line 32D cl3 blocked G-CSF-induced differentiation and instead promoted proliferation, accompanied by constitutive activation of both Stat3α and Stat3β downstream of G-CSF receptor signaling.\",\n      \"method\": \"Retroviral WT1 transduction of 32D cl3 cells, differentiation assay, Western blot of Stat3 activation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with defined cellular phenotype and signaling pathway read-out\",\n      \"pmids\": [\"9531608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"WT1(-KTS) isoform directly binds to the amphiregulin promoter and potently activates its transcription; amphiregulin, an EGF family member, mirrors WT1 expression during fetal kidney development and stimulates epithelial branching in embryonic kidney organ cultures.\",\n      \"method\": \"High-density oligonucleotide array after inducible WT1 expression, promoter binding assays, organ culture branching assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genome-wide target identification with direct promoter binding and in vivo organotypic functional validation\",\n      \"pmids\": [\"10490105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Wt1 is required for development of the epicardium and subepicardial mesenchymal cells, and is expressed in the proepicardium; Wt1-null embryos show severe epicardial defects and absence of SEMCs leading to embryonic lethality; a human WT1 YAC rescues heart defects completely but only partially rescues urogenital defects.\",\n      \"method\": \"LacZ reporter YAC, Wt1 knockout mouse analysis, YAC complementation\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue experiment in knockout mouse model with reporter gene\",\n      \"pmids\": [\"10101119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"WT1 directly activates E-cadherin transcription by binding to a conserved GC-rich EGR1-like site in the E-cadherin promoter; stable WT1 expression in NIH 3T3 fibroblasts induces epithelial differentiation features including E-cadherin upregulation.\",\n      \"method\": \"Retroviral WT1 expression, transient transfection reporter assays, in vitro binding with nuclear extracts, dominant-negative WT1 block\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct DNA binding, promoter reporter, dominant-negative, and stable gain-of-function\",\n      \"pmids\": [\"10753894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"WT1 is a key regulator of podocyte function: reduced WT1 levels in mice result in crescentic glomerulonephritis or mesangial sclerosis depending on gene dosage, with downstream podocyte-specific genes nphs1 and podocalyxin dramatically downregulated.\",\n      \"method\": \"Wt1 knockout and inducible YAC transgenic mouse models, gene expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic dose-response experiment in mouse models with defined molecular targets\",\n      \"pmids\": [\"11912180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The 17AA(+) WT1 isoforms exert antiapoptotic functions in leukemia cells by acting upstream of mitochondria in the intrinsic apoptosis pathway; 17AA(+)WT1-specific siRNA activates caspase-3 and -9 and Bax, while constitutive 17AA(+)WT1 expression protects mitochondrial membrane integrity and decreases proapoptotic Bak expression. The zinc-finger DNA-binding region is essential for these antiapoptotic functions.\",\n      \"method\": \"Isoform-specific siRNA knockdown, constitutive expression, caspase activation assays, mitochondrial membrane assays, Western blot for Bak/Bax\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific loss- and gain-of-function with multiple mechanistic readouts\",\n      \"pmids\": [\"16518414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"hnRNP-U directly interacts with WT1 endogenously without requiring other proteins or nucleic acids; the interaction 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\": \"Co-immunoprecipitation of endogenous proteins, domain-mapping pulldown assays, transcriptional reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — endogenous Co-IP and domain mapping with functional consequence, single study\",\n      \"pmids\": [\"16924231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Brain Acid Soluble Protein 1 (BASP1) acts as a transcriptional cosuppressor blocking WT1 transcriptional activation; during podocyte differentiation, WT1 and BASP1 co-occupy the Bak, c-myc, and podocalyxin promoters, and BASP1 promoter occupancy is dynamically regulated by sumoylation of BASP1.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), podocyte differentiation assay, BASP1 sumoylation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP of endogenous complex during differentiation with post-translational modification analysis\",\n      \"pmids\": [\"19050011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"WT1(+KTS) isoform cell-autonomously regulates Sry expression in the gonad; XY mice lacking WT1(+KTS) show reduced SRY protein per cell, decreased SRY-expressing cells, blocked Sertoli cell differentiation (loss of SOX9 and Fgf9), and male-to-female sex reversal; addition of recombinant FGF9 to ex vivo gonad cultures rescues the Sertoli cell differentiation defect.\",\n      \"method\": \"Wt1(+KTS)-null mouse model, immunofluorescence, ex vivo gonad culture with recombinant FGF9 rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific knockout with cellular and molecular phenotyping and functional rescue\",\n      \"pmids\": [\"19549635\"],\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, is recruited to WT1 target gene promoters in a BASP1-dependent manner, and cooperates with BASP1 to recruit the chromatin remodeling factor BRG1 and displace CBP from promoters; this complex also recruits PIP2 and HDAC1 to WT1 target genes.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, promoter reporter assays, nuclear colocalization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP with mechanistic chromatin remodeling readouts, single study\",\n      \"pmids\": [\"24166496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WT1 is required to repress expression of inhibitory chemokines Ccl5 and Cxcl10 in epicardial cells, partly directly and partly by increasing IRF7 levels; CXCL10 inhibits epicardial cell migration and CCL5 inhibits cardiomyocyte proliferation, linking WT1 to heart morphogenesis via chemokine regulation.\",\n      \"method\": \"Transcriptome analysis of Wt1-KO epicardial cells, functional chemokine assays (migration, proliferation), expression correlation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockout transcriptome with functional chemokine assays, single study\",\n      \"pmids\": [\"23900076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PINCH1 interacts with WT1 in podocyte nuclei after TGF-β1-induced nuclear translocation; the interaction is mediated by the LIM1 domain of PINCH1 and the C-terminal zinc-finger domain of WT1, and PINCH1-WT1 interaction suppresses WT1-mediated podocalyxin expression.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, promoter-luciferase reporter, nuclear translocation imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP, domain mapping, and functional reporter, single study\",\n      \"pmids\": [\"21390327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WT1 physically interacts with and recruits TET2 to WT1 target genes to activate their expression and suppress leukemia cell proliferation; multiple AML-derived TET2 mutations disrupt the WT1-TET2 interaction; WT1 and TET2 are mutated in a mutually exclusive manner in AML, suggesting a shared IDH1/2-TET2-WT1 pathway.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, colony formation assay, AML mutation analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction plus ChIP recruitment and functional proliferation assays with clinical mutation validation\",\n      \"pmids\": [\"25601757\"],\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), establishing a role for WT1 in mitotic checkpoint control and genomic stability.\",\n      \"method\": \"WT1-MAD2 interaction assays, APC/C ubiquitination assay, chromosome segregation analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein interaction and enzymatic activity assay with defined cellular phenotype, single study\",\n      \"pmids\": [\"25789599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wt1 haploinsufficiency enhances hematopoietic stem cell self-renewal in an age-dependent manner and cooperates with Flt3-ITD mutation to induce fully penetrant AML, demonstrating that Wt1 loss contributes to leukemogenesis through progressive genetic and epigenetic alterations.\",\n      \"method\": \"Wt1 heterozygous knockout mouse model, stem cell functional assays, genetic cooperation with Flt3-ITD\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic cooperation and stem cell functional assays, single study\",\n      \"pmids\": [\"30064973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of Wt1 in mature podocytes activates Notch1 signaling (upregulation of Notch1 and Nrarp), represses FoxC2, and upregulates Hey2 and HES1; HES1 induction is associated with upregulation of epithelial-mesenchymal transition genes and mediates podocyte EMT; pharmacological inhibition of Notch signaling ameliorates glomerular scarring in Wt1-deleted mice.\",\n      \"method\": \"Tamoxifen-inducible Cre-LoxP Wt1 deletion, immunofluorescence, Notch inhibitor rescue experiment\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional knockout with temporal control, pathway analysis, and pharmacological rescue\",\n      \"pmids\": [\"29398135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WT1 undergoes highly dynamic changes in binding to target genes during podocyte injury and repair, affecting chromatin state and expression of target genes; WT1 binds nearly all genes crucial for maintenance of the glomerular filtration barrier and mediates epigenetic transcriptional reprogramming during injury.\",\n      \"method\": \"ChIP-seq in murine podocytes and human kidney organoids, transcriptome analysis during injury/repair\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq in multiple model systems with chromatin state and transcriptome analysis\",\n      \"pmids\": [\"32754639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Heterozygous WT1 variants affecting zinc finger 4 (ZF4) cause 46,XX testicular/ovotesticular DSD; ZF4 mutant proteins physically interact with and sequester β-CATENIN, leading to upregulation of testis-specific pathways and masculinization of XX gonads.\",\n      \"method\": \"Exome sequencing, co-immunoprecipitation, human granulosa cell line transfection, Wt1-XX mouse gonad phenotyping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of protein interaction plus in vitro and in vivo functional validation\",\n      \"pmids\": [\"32493750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT5 facilitates IRES-dependent translation of Wt1 mRNA by methylating HnRNPA1; loss of Prmt5 in granulosa cells dramatically reduces WT1 protein expression, arrests follicle development, and derepresses steroidogenic gene expression, which is rescued by Wt1 overexpression.\",\n      \"method\": \"Conditional Prmt5 knockout in granulosa cells, mechanistic studies of HnRNPA1 methylation, Wt1 overexpression rescue\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined molecular mechanism and rescue experiment\",\n      \"pmids\": [\"34448450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Autophagy regulates granulosa cell differentiation by degrading WT1 protein; disruption of autophagy (via ATG5/BECN1 siRNA or chloroquine) causes WT1 accumulation, which inhibits GC differentiation (suppressing CYP19A1/Aromatase and FSHR expression and estradiol synthesis).\",\n      \"method\": \"siRNA knockdown of ATG5/BECN1, pharmacological autophagy inhibition, WT1 protein accumulation assay, co-immunoprecipitation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological loss-of-function with defined molecular mechanism and phenotypic readout\",\n      \"pmids\": [\"35025698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"EWS-WT1 chimeric transcripts result from a t(11;22)(p13;q12) translocation fusing EWS exons 1–7 to WT1 exons 8–10 (the last three zinc fingers), generating a predicted transcriptional modulator at WT1 target sites that underlies desmoplastic small round cell tumor.\",\n      \"method\": \"Genomic DNA fusion breakpoint isolation and sequencing, chimeric transcript RT-PCR analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct molecular characterization of fusion gene and chimeric transcripts\",\n      \"pmids\": [\"7862627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Osr1 interacts with Wt1 in the developing kidney (demonstrated by CRISPR-labeled endogenous proteins); mice heterozygous for both Osr1 and Wt1 null alleles show synergistic kidney development defects including agenesis and hypoplasia, with reduced nephron progenitor cells and decreased Gdnf expression, demonstrating genetic epistasis between these two factors.\",\n      \"method\": \"CRISPR protein labeling, double heterozygous mouse model, nephron progenitor cell counting, Gdnf expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with endogenous protein interaction, single study\",\n      \"pmids\": [\"27442016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WT1 is a major repressor of the CMIP gene in podocytes by directly binding to two WT1 response elements in the human CMIP proximal promoter (at -290/-274 and -57/-41); WT1 silencing promotes Cmip expression, and Cmip is early and significantly increased in podocytes with primary Wt1 defects (Denys-Drash and Frasier syndromes).\",\n      \"method\": \"ChIP assay, EMSA, luciferase reporter assay, decoy oligonucleotide competition, WT1 siRNA knockdown\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct DNA binding by EMSA and ChIP, functional repression by reporter and competition assay, with human disease validation\",\n      \"pmids\": [\"27650733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CUG-translated WT1 (cugWT1), an N-terminally extended isoform, functions as an oncogene promoting cell transformation and activating c-myc, bcl-2, and egfr expression; AKT phosphorylates cugWT1 on Ser62 to protect it from FBXW8-mediated proteasomal degradation. In contrast, AUG-WT1 acts as a tumor suppressor and represses the same target genes by recruiting HDAC1 and inhibiting cugWT1 function.\",\n      \"method\": \"CUG vs AUG translation start site analysis, AKT phosphorylation assay, FBXW8 ubiquitination assay, colony formation assay, target gene reporter assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic assays in a single study identifying novel isoform, single lab\",\n      \"pmids\": [\"29040381\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WT1 is a zinc finger transcription factor (with at least four alternatively spliced isoforms including ±KTS and ±17AA variants) that binds TC/GC-rich promoter sequences to repress or activate target genes (including PDGF-A, Pax-2, EGFR, E-cadherin, amphiregulin, CMIP, and Bak), physically interacts with p53, BASP1 (and co-repressor prohibitin), hnRNP-U, TET2, MAD2, PINCH1, and β-CATENIN to modulate transcription, chromatin state, RNA processing, and mitotic checkpoint fidelity; it also undergoes autophagy-mediated degradation and PRMT5-facilitated IRES-dependent translation, and its distinct isoforms have context-specific roles in kidney podocyte survival, gonadal sex determination (with +KTS regulating Sry and ZF4 variants sequestering β-CATENIN), epicardial development, hematopoietic progenitor differentiation (blocking G-CSF-induced differentiation via constitutive Stat3 activation), and apoptosis (17AA+ isoforms being anti-apoptotic via the intrinsic pathway).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"WT1 is a zinc finger transcription factor that functions as a context-dependent transcriptional activator or repressor governing kidney organogenesis, gonadal sex determination, podocyte homeostasis, and hematopoietic differentiation. WT1 self-associates via its N-terminal domain and binds target gene promoters (E-cadherin, CMIP, novH, Ccl5/Cxcl10, podocalyxin, c-myc, Bak) either activating or repressing them depending on isoform (−KTS vs +KTS; 17AA±; AUG vs CUG), interacting cofactors such as BASP1/prohibitin (which recruit HDAC1, BRG1, and PIP2 for repression) or hnRNP-U (which modulates activation), and partners including p53, PINCH1, and β-catenin [PMID:8389468, PMID:7479946, PMID:24166496, PMID:16924231, PMID:10753894, PMID:27650733, PMID:21390327, PMID:32493750]. Beyond transcription, the +KTS isoform harbors an N-terminal RRM that associates with spliceosomal proteins and localizes to nuclear speckles in an RNA-dependent manner, while WT1 also delays mitotic anaphase by interacting with MAD2 to inhibit APC/C ubiquitination activity [PMID:8589729, PMID:25789599]. WT1 protein levels are controlled post-translationally through PRMT5-driven IRES-dependent translation, autophagic degradation via an LC3-interacting region motif, and AKT-mediated Ser62 phosphorylation of the oncogenic CUG-WT1 isoform that protects it from FBXW8-dependent proteasomal turnover; loss-of-function mutations cause Denys-Drash syndrome and contribute to Wilms tumorigenesis, while gain-of-function zinc finger 4 mutations cause 46,XX testicular/ovotesticular DSD [PMID:34448450, PMID:35025698, PMID:29040381, PMID:7479946, PMID:32493750].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that WT1 is not simply a repressor but a context-dependent transcriptional regulator whose activity is modulated by protein-protein interactions — physical association with p53 converts WT1 from repressor to activator on EGR1 sites, while a tumor-derived point mutation in the transactivation domain similarly switches WT1 from repressor to activator, explaining a 'second hit' mechanism in WAGR-associated Wilms tumor.\",\n      \"evidence\": \"Co-immunoprecipitation of WT1–p53 in transfected cells with reporter assays; sequencing of tumor WT1 allele with functional transcriptional assays\",\n      \"pmids\": [\"8389468\", \"8402654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of WT1–p53 interaction not determined\", \"Whether WT1–p53 co-regulation occurs at endogenous loci in vivo not shown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defining WT1 self-association as a mechanism for dominant-negative pathogenesis — WT1 oligomerizes through its N-terminal domain, and DNA-binding-defective Denys-Drash mutants antagonize wild-type WT1 transcriptional repression through hetero-oligomerization, providing a molecular explanation for the dominant inheritance pattern.\",\n      \"evidence\": \"In vitro binding and in vivo co-immunoprecipitation with domain mapping; transcriptional repression assays with mutant/wild-type coexpression\",\n      \"pmids\": [\"7479946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and quaternary structure of WT1 oligomers unknown\", \"In vivo relevance in developing kidney tissue not tested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Revealing a dual DNA/RNA-binding capability — identification of an N-terminal RRM homologous to U1A in all WT1 isoforms, with experimental demonstration that WT1 associates with spliceosomal proteins and localizes to nuclear speckles in an RNA-dependent manner, expanding WT1 function beyond transcription.\",\n      \"evidence\": \"Structural modelling of RRM; co-immunoprecipitation with spliceosomal proteins; RNase treatment abolishes speckle localization by immunofluorescence\",\n      \"pmids\": [\"8589729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific RNA targets of WT1 not identified\", \"Functional consequence of WT1 association with spliceosomes on mRNA processing not demonstrated\", \"RRM structural prediction not validated by crystallography\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linking WT1 to hematopoietic differentiation signaling — WT1 expression in myeloid progenitors constitutively activates Stat3α/β downstream of the G-CSF receptor, blocking G-CSF-induced differentiation and promoting proliferation, establishing a mechanism for WT1 overexpression in leukemia.\",\n      \"evidence\": \"Retroviral WT1 transduction into 32D cl3 myeloid progenitor cells; Stat3 phosphorylation western blot; differentiation assays\",\n      \"pmids\": [\"9531608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WT1 directly activates Stat3 transcription or acts post-translationally on Stat3 signaling not resolved\", \"Mechanism by which WT1 sustains Stat3 phosphorylation not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying E-cadherin as a direct WT1 transcriptional target linked epithelial differentiation — WT1 binds a GC-rich element in the E-cadherin promoter and induces E-cadherin expression, growth suppression, and epithelial differentiation features in fibroblasts.\",\n      \"evidence\": \"In vitro/nuclear extract gel-shift; promoter reporter assays; stable WT1 expression induces E-cadherin mRNA and epithelial morphology in NIH 3T3 cells\",\n      \"pmids\": [\"10753894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WT1-dependent E-cadherin regulation occurs in native mesenchymal-to-epithelial transition during nephrogenesis not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Dissecting isoform-specific functions — the 17AA(+) isoforms are specifically anti-apoptotic via the intrinsic mitochondrial pathway (suppressing Bak, inhibiting caspase-9/3 activation), while hnRNP-U was identified as a direct nucleic-acid-independent binding partner of WT1 zinc fingers that modulates transcriptional activation.\",\n      \"evidence\": \"Isoform-specific siRNA and overexpression in leukemia cells with caspase/Bax readouts; reciprocal endogenous co-IP of WT1–hnRNP-U with domain mapping and reporter assays\",\n      \"pmids\": [\"16518414\", \"16924231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific transcriptional targets mediating the anti-apoptotic effect of 17AA(+) isoform not fully characterized\", \"Whether hnRNP-U modulates WT1 at all target promoters or selectively unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Elucidating the BASP1-dependent repression mechanism — ChIP demonstrated that WT1 and BASP1 co-occupy endogenous promoters (Bak, c-myc, podocalyxin), and during podocyte differentiation BASP1 dynamically dissociates from the podocalyxin promoter to allow activation while maintaining repression at c-myc and Bak.\",\n      \"evidence\": \"ChIP at multiple endogenous promoters in podocyte precursor cells during differentiation; sumoylation analysis of BASP1\",\n      \"pmids\": [\"19050011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BASP1 sumoylation is the signal for promoter-selective dissociation not fully established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing the +KTS isoform as essential for male sex determination upstream of SRY — Wt1(+KTS)-null XY mice have reduced SRY protein and fewer SRY-expressing cells, blocking Sertoli cell differentiation; recombinant FGF9 rescues the phenotype, placing WT1(+KTS) in a Wt1→Sry→Sox9→Fgf9 hierarchy.\",\n      \"evidence\": \"Isoform-specific Wt1(+KTS) knockout mice; immunofluorescence quantification; ex vivo gonad culture with FGF9 rescue\",\n      \"pmids\": [\"19549635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WT1(+KTS) regulates Sry transcriptionally or post-transcriptionally not resolved\", \"Direct binding of WT1(+KTS) to Sry regulatory elements not shown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Building the full WT1–BASP1 co-repressor complex architecture — prohibitin was identified as a BASP1-dependent component that recruits BRG1 chromatin remodeling, HDAC1, and PIP2 to WT1 target promoters while dissociating CBP, establishing a multiprotein mechanism converting WT1 from activator to repressor.\",\n      \"evidence\": \"Co-IP; ChIP at WT1 target promoters; reporter assays; nuclear colocalization\",\n      \"pmids\": [\"24166496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the BASP1–prohibitin–HDAC1–BRG1 assembly not determined\", \"Whether PIP2 has a direct enzymatic or structural role in this complex unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extending WT1 function beyond transcription into mitotic regulation — WT1 interacts with MAD2 and inhibits APC/C ubiquitination activity, delaying anaphase onset and regulating chromosome segregation fidelity.\",\n      \"evidence\": \"Co-immunoprecipitation of WT1–MAD2; APC/C ubiquitination assay; cell division assays\",\n      \"pmids\": [\"25789599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which WT1 inhibits APC/C activity (direct or via MAD2 stabilization) not resolved\", \"Whether this mitotic role is relevant in non-cancer cells not tested\", \"Not independently confirmed by a second group\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying CMIP as a direct repression target of WT1 relevant to podocyte disease and demonstrating genetic synergy between Osr1 and Wt1 in kidney organogenesis — WT1 binds two response elements in the CMIP promoter and represses transcription, with derepression validated in Denys-Drash/Frasier patient tissue; compound Osr1/Wt1 heterozygotes reveal synergistic regulation of nephron progenitors and Gdnf.\",\n      \"evidence\": \"ChIP, EMSA, luciferase reporter, siRNA knockdown, patient tissue for CMIP; compound heterozygous mouse model with CRISPR co-localization for Osr1–Wt1\",\n      \"pmids\": [\"27650733\", \"27442016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WT1 and OSR1 physically interact or regulate shared targets not determined\", \"Mechanism of CMIP derepression in disease beyond WT1 loss not explored\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealing opposing functions of alternative translation-initiation WT1 isoforms — CUG-WT1 acts as an oncogene upregulating c-myc/bcl-2/EGFR while AUG-WT1 represses these genes via HDAC1 recruitment; AKT-mediated Ser62 phosphorylation stabilizes CUG-WT1 by protecting it from FBXW8-mediated proteasomal degradation.\",\n      \"evidence\": \"CUG vs AUG isoform expression constructs; colony formation; AKT phosphorylation assay; proteasomal degradation assays\",\n      \"pmids\": [\"29040381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AKT–FBXW8 regulation of CUG-WT1 is relevant in primary tumors not validated\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating WT1 haploinsufficiency as a cooperating event in leukemogenesis and placing WT1 upstream of a Notch1/FoxC2 transcriptional network in podocyte survival — Wt1 heterozygosity enhances HSC self-renewal and synergizes with Flt3-ITD to cause AML; conditional Wt1 deletion in adult podocytes triggers apoptosis and Notch1 pathway activation that can be pharmacologically rescued.\",\n      \"evidence\": \"Wt1 heterozygous and Wt1/Flt3-ITD double mutant mouse models; tamoxifen-inducible podocyte-specific Wt1 knockout with Notch inhibitor rescue\",\n      \"pmids\": [\"30064973\", \"29398135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WT1 directly represses Notch1 pathway genes or acts indirectly via FoxC2 not fully resolved\", \"Epigenetic alterations underlying age-dependent HSC self-renewal enhancement not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing WT1 as a genome-wide master regulator of podocyte identity and revealing a gain-of-function mechanism for DSD — ChIP-seq showed WT1 binds nearly all genes critical for the glomerular filtration barrier and dynamically redistributes during injury; independently, ZF4 missense mutations cause 46,XX testicular/ovotesticular DSD by enabling WT1 to sequester β-catenin, a pro-ovary factor.\",\n      \"evidence\": \"ChIP-seq in murine podocytes and human kidney organoids during injury; exome sequencing of DSD patients with ZF4 mutant functional assays and Wt1 gain-of-function mouse model\",\n      \"pmids\": [\"32754639\", \"32493750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin remodeling mechanisms underlying WT1 redistribution during injury not characterized\", \"Whether β-catenin sequestration by ZF4 mutants is stoichiometric or involves altered DNA binding not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying PRMT5-dependent IRES translation and autophagy as two independent post-translational regulators of WT1 protein levels — PRMT5 methylates HnRNPA1 to facilitate IRES-dependent Wt1 translation in granulosa cells, while WT1 is also degraded by selective autophagy via a LIR motif, with both pathways controlling granulosa cell differentiation.\",\n      \"evidence\": \"Conditional Prmt5 KO in granulosa cells with Wt1 rescue; IRES translation assay; ATG5/BECN1 siRNA and chloroquine autophagy inhibition; LIR motif identification; cycloheximide chase\",\n      \"pmids\": [\"34448450\", \"35025698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRMT5-IRES and autophagic degradation pathways are coordinated or independent not addressed\", \"Structural basis of WT1 LIR motif recognition by LC3 not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the identity of specific RNA targets bound by the WT1 +KTS isoform and the functional consequence for mRNA splicing/processing; the structural basis for isoform-specific (−KTS vs +KTS, 17AA±, CUG vs AUG) interactions with distinct cofactors; and how WT1 integrates its transcriptional, post-transcriptional, and mitotic functions within a single cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No CLIP-seq or equivalent identification of WT1 RNA targets\", \"No high-resolution structure of full-length WT1 or WT1-cofactor complexes\", \"Relative contribution of transcriptional vs post-transcriptional WT1 functions in vivo not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 3, 5, 8, 12, 14, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3, 5, 7, 8, 11, 12, 14, 15]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 8, 11, 19]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 5, 7, 8, 11, 12, 14, 15, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 17, 18, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 17]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 23]}\n    ],\n    \"complexes\": [\n      \"WT1-BASP1-prohibitin-HDAC1-BRG1 co-repressor complex\"\n    ],\n    \"partners\": [\n      \"TP53\",\n      \"BASP1\",\n      \"PHB\",\n      \"HNRNPU\",\n      \"PINCH1\",\n      \"MAD2L1\",\n      \"CTNNB1\",\n      \"FBXW8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"WT1 is a zinc finger transcription factor that governs urogenital development, hematopoietic differentiation, and epicardial morphogenesis by binding GC/TC-rich promoter elements to repress or activate context-dependent target genes. Four major isoforms arising from alternative splicing of exon 5 (±17AA) and the KTS insertion between zinc fingers 3 and 4 confer distinct functions: the −KTS isoform drives canonical DNA-binding–dependent transcriptional regulation of targets such as PDGF-A, Pax-2, EGFR, amphiregulin, E-cadherin, and CMIP [PMID:1332065, PMID:7720589, PMID:10490105, PMID:27650733], while the +KTS isoform regulates Sry expression and gonadal sex determination [PMID:19549635]; the 17AA+ isoform suppresses apoptosis through the intrinsic mitochondrial pathway by repressing Bak [PMID:16518414]. WT1 recruits chromatin-modifying co-factors—including the BASP1–prohibitin–HDAC1 repressor complex and the DNA demethylase TET2—to target promoters, dynamically reprogramming chromatin during podocyte injury and repair [PMID:19050011, PMID:24166496, PMID:25601757, PMID:32754639]. Germline WT1 mutations cause Denys-Drash syndrome and other disorders of sex development, and somatic WT1 loss cooperates with oncogenic lesions such as FLT3-ITD to drive acute myeloid leukemia [PMID:1655284, PMID:30064973].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Positional cloning of the 11p13 Wilms tumor locus identified WT1 as a zinc finger gene with restricted kidney and hematopoietic expression, establishing it as a candidate transcriptional regulator and tumor suppressor.\",\n      \"evidence\": \"cDNA isolation, Northern blot, and sequence analysis of the 11p13 region\",\n      \"pmids\": [\"2154335\", \"2154702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct transcriptional activity demonstrated\", \"No target genes identified\", \"No loss-of-function phenotype yet shown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Characterization of WT1 exon–intron structure revealed four conserved splice isoforms (±17AA, ±KTS), raising the question of whether these isoforms have distinct functions, while germline zinc finger mutations in Denys-Drash patients proved WT1 is essential for urogenital development.\",\n      \"evidence\": \"RNase protection, genomic cloning of splice variants; exon sequencing of DDS patients\",\n      \"pmids\": [\"1658787\", \"1655284\", \"1654525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform-specific functions not yet dissected\", \"Mechanism by which zinc finger mutations cause disease unknown\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Demonstration that WT1 directly binds and represses the PDGF-A chain promoter established its biochemical activity as a sequence-specific transcriptional repressor of growth factor genes.\",\n      \"evidence\": \"Gel-shift, DNase I footprinting, and transient transfection reporter assays\",\n      \"pmids\": [\"1332065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WT1 also activates transcription not yet tested\", \"In vivo relevance of PDGF-A repression not confirmed\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Physical interaction with p53 and the finding that WT1 can switch between repressor and activator modes—depending on p53 availability and point mutations in the transactivation domain—revealed WT1 as a context-dependent transcriptional regulator rather than a simple repressor.\",\n      \"evidence\": \"Co-immunoprecipitation, reporter assays with wild-type and mutant WT1\",\n      \"pmids\": [\"8389468\", \"8402654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of WT1–p53 interaction unresolved\", \"In vivo relevance of the repressor-to-activator switch unclear\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of multiple direct target genes—Pax-2 (repressed), EGFR (repressed, mediating WT1-induced apoptosis), and amphiregulin (activated)—and self-association of WT1 through its N-terminal domain expanded the repertoire of WT1 transcriptional functions and dominant-negative mechanisms, while the EWS-WT1 fusion was characterized in desmoplastic small round cell tumor.\",\n      \"evidence\": \"DNase I footprinting, inducible expression with EGFR rescue of apoptosis, oligonucleotide arrays, in vitro/in vivo binding assays, fusion transcript cloning\",\n      \"pmids\": [\"7720589\", \"7588596\", \"7479946\", \"7862627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide target repertoire unknown\", \"Self-association stoichiometry and structural basis unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Evidence that WT1 harbors an RNA recognition motif and co-immunoprecipitates with spliceosomal proteins suggested a post-transcriptional role, though this remained less well characterized than its transcriptional functions.\",\n      \"evidence\": \"Structural modeling, spliceosomal Co-IP, RNA degradation–localization experiment\",\n      \"pmids\": [\"8589729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct RNA-binding assay performed\", \"No specific RNA targets identified\", \"Functional consequence of spliceosomal association not demonstrated\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Wt1-null mouse studies showed WT1 is required for epicardial and subepicardial mesenchymal cell development; YAC complementation fully rescued cardiac but only partially rescued urogenital defects, revealing tissue-specific regulatory requirements.\",\n      \"evidence\": \"Wt1 knockout mouse, LacZ YAC reporter, YAC rescue\",\n      \"pmids\": [\"10101119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Epicardial target genes not identified\", \"Mechanism of tissue-specific rescue differences unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Gene-dosage experiments in mice established WT1 as a master regulator of podocyte identity, with reduced Wt1 levels causing glomerulonephritis or mesangial sclerosis and loss of podocyte-specific genes nphs1 and podocalyxin.\",\n      \"evidence\": \"Wt1 heterozygous knockout and inducible transgenic mice\",\n      \"pmids\": [\"11912180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect regulation of nphs1 and podocalyxin not distinguished\", \"Chromatin-level mechanism not explored\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Isoform-specific studies resolved that 17AA+ WT1 suppresses apoptosis via the intrinsic mitochondrial pathway by repressing Bak, while hnRNP-U was identified as a direct zinc-finger–dependent interaction partner modulating WT1 transcriptional activation.\",\n      \"evidence\": \"Isoform-specific siRNA, caspase and mitochondrial assays; endogenous Co-IP and domain mapping\",\n      \"pmids\": [\"16518414\", \"16924231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of 17AA+-specific targets not defined\", \"In vivo role of hnRNP-U–WT1 interaction untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery of the BASP1 co-repressor complex on WT1 target promoters during podocyte differentiation provided the first chromatin-level mechanism for WT1-mediated gene repression, with sumoylation dynamically regulating BASP1 recruitment.\",\n      \"evidence\": \"ChIP in differentiating podocytes, BASP1 sumoylation analysis\",\n      \"pmids\": [\"19050011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide extent of BASP1 co-occupancy unknown\", \"Whether sumoylation is necessary in vivo untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The +KTS isoform was shown to cell-autonomously regulate Sry expression, with its loss causing male-to-female sex reversal rescued by exogenous FGF9, mechanistically linking alternative splicing to gonadal sex determination.\",\n      \"evidence\": \"Wt1(+KTS)-specific knockout mice, immunofluorescence, ex vivo gonad culture rescue\",\n      \"pmids\": [\"19549635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether +KTS acts via transcriptional or post-transcriptional mechanisms on Sry unresolved\", \"Direct binding to Sry locus not demonstrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The WT1-BASP1-prohibitin repressor complex was shown to recruit BRG1 and HDAC1 while displacing CBP from target promoters, and WT1 was found to repress epicardial chemokines Ccl5/Cxcl10 to promote heart morphogenesis, broadening the chromatin-remodeling and developmental scope of WT1 function.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assays; Wt1-KO epicardial transcriptome with functional chemokine assays\",\n      \"pmids\": [\"24166496\", \"23900076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether prohibitin-BRG1 recruitment is universal across WT1 targets unknown\", \"Direct WT1 binding at chemokine promoters not confirmed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"WT1 was found to recruit the DNA demethylase TET2 to target genes—with AML-derived TET2 mutations disrupting this interaction—and to regulate mitotic fidelity through MAD2 interaction and APC/C inhibition, revealing non-transcriptional roles and linking WT1/TET2 to a shared leukemogenic pathway.\",\n      \"evidence\": \"Co-IP, ChIP, colony formation, AML mutation exclusivity analysis; MAD2 interaction and APC/C ubiquitination assays\",\n      \"pmids\": [\"25601757\", \"25789599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide WT1-TET2 co-occupancy map not generated\", \"In vivo significance of WT1-MAD2 interaction not confirmed in animal models\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"WT1 directly represses CMIP via two response elements in podocytes, and genetic epistasis between Wt1 and Osr1 in kidney development further defined the transcription factor network governing nephron progenitor maintenance.\",\n      \"evidence\": \"ChIP, EMSA, luciferase reporter, WT1 siRNA; CRISPR-labeled Osr1-Wt1 double-heterozygous mice\",\n      \"pmids\": [\"27650733\", \"27442016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CMIP derepression is sufficient to cause glomerular disease not tested\", \"Molecular basis of Osr1-Wt1 interaction not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Conditional Wt1 deletion in podocytes revealed Notch1 pathway activation and HES1-mediated EMT as a downstream disease mechanism amenable to pharmacological rescue, while Wt1 haploinsufficiency was shown to cooperate with Flt3-ITD to drive AML, establishing Wt1 as a bona fide leukemia tumor suppressor gene in vivo.\",\n      \"evidence\": \"Tamoxifen-inducible podocyte Wt1 deletion with Notch inhibitor rescue; Wt1-het × Flt3-ITD mouse leukemia model\",\n      \"pmids\": [\"29398135\", \"30064973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Notch pathway activation is the primary mediator versus a bystander in podocyte injury unknown\", \"Epigenetic versus genetic mechanisms of Wt1-haploinsufficiency-driven leukemogenesis not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genome-wide ChIP-seq demonstrated that WT1 binds nearly all genes essential for the glomerular filtration barrier and undergoes dynamic chromatin reprogramming during podocyte injury and repair, while ZF4 mutations were shown to sequester β-catenin and cause 46,XX testicular DSD.\",\n      \"evidence\": \"ChIP-seq in murine podocytes and human kidney organoids; exome sequencing, Co-IP, and Wt1-XX mouse gonad analysis\",\n      \"pmids\": [\"32754639\", \"32493750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal hierarchy of WT1 chromatin changes versus injury signals not resolved\", \"Whether β-catenin sequestration is the sole mechanism of ZF4-mediated sex reversal untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PRMT5-mediated methylation of hnRNPA1 was shown to facilitate IRES-dependent translation of Wt1 mRNA, establishing a post-transcriptional layer of WT1 regulation essential for granulosa cell function and follicle development.\",\n      \"evidence\": \"Conditional Prmt5 knockout in granulosa cells, hnRNPA1 methylation analysis, Wt1 overexpression rescue\",\n      \"pmids\": [\"34448450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IRES-dependent translation is relevant outside granulosa cells unknown\", \"Structural basis of hnRNPA1-WT1 IRES interaction not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Autophagy-mediated degradation of WT1 protein was identified as a mechanism controlling granulosa cell differentiation, adding a protein-turnover layer to WT1 regulation.\",\n      \"evidence\": \"ATG5/BECN1 siRNA and chloroquine-mediated autophagy inhibition with WT1 accumulation and differentiation assays\",\n      \"pmids\": [\"35025698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Autophagy receptor or ubiquitin signal targeting WT1 for degradation not identified\", \"Whether autophagy-mediated WT1 turnover operates in podocytes or other WT1-dependent lineages unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of WT1 isoform-specific DNA versus RNA recognition, the genome-wide co-occupancy maps for WT1 with TET2 and the BASP1-prohibitin complex across cell types, and whether the mitotic checkpoint role of WT1 via MAD2 contributes to tumor suppression in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of full-length WT1 or isoform-specific complexes\", \"Comprehensive WT1 interactome across developmental contexts not available\", \"In vivo relevance of WT1-MAD2 axis in tumorigenesis untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 5, 10, 16, 18, 37]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 6, 9, 10, 16, 18, 22, 27, 37]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 26]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [7, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 9, 10, 16, 18, 22, 24, 27, 37]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3, 17, 19, 23, 36]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 20]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [24, 27, 31]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [29, 35]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [34]}\n    ],\n    \"complexes\": [\n      \"WT1-BASP1-prohibitin repressor complex\"\n    ],\n    \"partners\": [\n      \"TP53\",\n      \"BASP1\",\n      \"TET2\",\n      \"MAD2L1\",\n      \"HNRNPU\",\n      \"LIMS1\",\n      \"CTNNB1\",\n      \"OSR1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}