WT1 (Wilms tumor protein) is a C2H2 zinc-finger transcription factor that plays essential roles in urogenital and cardiac development. The protein contains an N-terminal proline/glutamine-rich regulatory domain (with separate repression and activation domains) and four C-terminal C2H2 zinc fingers (encoded by exons 7-10) that mediate sequence-specific DNA binding to the motif 5'-GCG(T/G)GGGCG-3' with Kd ~1.14 nM. Alternative splicing at intron 9 produces two major isoform classes with distinct functions: the -KTS isoform functions as a classical DNA-binding transcription factor (both activator and repressor depending on cofactors like BASP1/p53 and cellular context), while the +KTS isoform has reduced DNA affinity (due to increased linker flexibility between ZnF3-4) and participates in RNA processing, localizing to nuclear speckles and interacting with splicing factors (U2AF65, RBM4). The normal +KTS/-KTS ratio of ~2:1 is critical; Frasier syndrome results from altered ratio. WT1 functions as a tumor suppressor in kidney (loss causes Wilms tumor) but can act as an oncogene in AML/leukemias. Key transcriptional targets include nephrin/NPHS1 and podocalyxin (activation in podocytes), PAX2 (repression during differentiation), BCL2 and MYC (repression for tumor suppression), DNMT3A (activation), and SF1/SRY (activation in sex determination). WT1 is essential for: (1) mesenchymal-to-epithelial transition during nephrogenesis and podocyte maintenance, (2) gonadal development and sex determination, and (3) epicardial epithelial-to-mesenchymal transition for coronary vasculature formation via Wnt/beta-catenin and retinoic acid signaling.
Curated functional classes representing distinct biological activities. These may be splice variants, cleavage products, or other forms with different functions.
WT1_MINUS_KTSWT1_PLUS_KTS| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: WT1 is well-established as a sequence-specific DNA-binding transcription factor. The -KTS isoform binds with high affinity to the consensus 5'-GCG(T/G)GGGCG-3' motif via its C2H2 zinc fingers [PMID:7862533, PMID:25258363]. Multiple studies demonstrate direct binding to cis-regulatory regions of target genes including PAX2, BCL2, MYC, EGFR, PDGFA, SRY, and DNMT3A promoters. Reason: Core molecular function well-supported by extensive biochemical and structural evidence. Crystal structures confirm zinc finger-DNA interactions [PMID:25258363]. This is a fundamental function of the -KTS isoform. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: WT1 functions as both a transcriptional activator and repressor depending on target gene and cellular context. The -KTS isoform is the primary transcription factor form. WT1 activates genes like SRY, DNMT3A, and EPO, while repressing PAX2, BCL2, MYC, and EGFR [PMID:9815658, PMID:7720589, PMID:7585606, PMID:23042785]. Reason: Core molecular function. WT1's role as an RNA Pol II transcription factor is foundational to its developmental and tumor suppressor functions. The dual activator/repressor activity is isoform-dependent and context-dependent. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: WT1 is predominantly nuclear, consistent with its role as a transcription factor. Multiple IDA studies confirm nuclear localization [PMID:1662794, PMID:8306891, PMID:7588596]. Both -KTS and +KTS isoforms localize to the nucleus, though with different subnuclear distributions. Reason: Core cellular component annotation well-supported by immunofluorescence and biochemical fractionation studies. Nuclear localization is essential for WT1's transcriptional regulatory function. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: WT1 regulates transcription of numerous target genes via RNA Pol II machinery. It can both activate and repress transcription depending on target and context. Documented targets include PAX2 (repression), BCL2/MYC (repression), DNMT3A (activation), EPO (activation), SRY (activation), and many others [PMID:23042785, PMID:7720589, PMID:7585606, PMID:9815658]. Reason: Core biological process. Transcriptional regulation is the primary function of WT1, underlying its roles in development and tumor suppression. |
| GO:0008285 negative regulation of cell population proliferation | IBA GO_REF:0000033 | ACCEPT | Summary: WT1 functions as a tumor suppressor and inhibits cell proliferation. This is mediated through transcriptional repression of growth-promoting genes like BCL2, MYC, and growth factor receptors, as well as through interaction with Hsp70 [PMID:9553041, PMID:7585606]. Reason: Well-supported tumor suppressor function. WT1 loss leads to uncontrolled proliferation in Wilms tumor. The antiproliferative effect is demonstrated through inducible expression studies [PMID:9553041]. |
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: WT1 has complex effects on apoptosis. While it represses BCL2 which would promote apoptosis [PMID:7585606], developmental studies show that WT1 is required for cell survival during nephrogenesis - Wt1 null embryos show apoptosis in the urogenital ridge [PMID:10101119]. Reason: WT1's role in apoptosis regulation is context-dependent and likely secondary to its primary transcriptional regulatory functions. The anti-apoptotic effect observed in development may reflect regulation of survival factors rather than direct apoptosis pathway involvement. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000117 | ACCEPT | Summary: WT1 functions as a transcriptional repressor for multiple target genes including PAX2, BCL2, MYC, EGFR, and AR [PMID:7720589, PMID:7585606, PMID:7588596, PMID:9815658]. This is a well-documented core function, particularly for the -KTS isoform. Reason: Although this is an IEA annotation, transcriptional repression is extensively documented by experimental evidence. This represents a core molecular function. |
| GO:0003677 DNA binding | IEA GO_REF:0000043 | ACCEPT | Summary: WT1 contains four C2H2 zinc fingers that mediate DNA binding. This is a core molecular function, though the more specific term GO:0043565 (sequence-specific DNA binding) is preferable. Reason: Valid annotation. While more specific terms exist (GO:0043565, GO:0000978), this general DNA binding annotation is correct and supported by extensive evidence. |
| GO:0003723 RNA binding | IEA GO_REF:0000043 | ACCEPT | Summary: The +KTS isoform of WT1 has documented RNA-binding activity. The zinc finger domain provides overlapping surfaces for DNA and RNA binding [bardeesy1998]. The +KTS isoform associates with splicing factors and participates in RNA processing [PMID:16934801]. Reason: Valid annotation for the +KTS isoform specifically. RNA binding is part of WT1's post-transcriptional regulatory functions. Note this is isoform-specific. Supporting Evidence: PMID:16934801 Epub 2006 Jul 25. WT1 interacts with the splicing protein RBM4 and regulates its ability to modulate alternative splicing in vivo. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization is well-established for WT1, consistent with its role as a transcription factor. Reason: Duplicate of IBA annotation above. Nuclear localization is well-supported. |
| GO:0005654 nucleoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: WT1 is present in the nucleoplasm. The -KTS isoform has a diffuse nuclear distribution [PMID:15520190], while +KTS localizes more to nuclear speckles. Reason: Supported by localization studies. The -KTS isoform particularly shows nucleoplasmic distribution. |
| GO:0005730 nucleolus | IEA GO_REF:0000044 | UNDECIDED | Summary: UniProt indicates nucleolar localization. WT1 has been reported in various nuclear subcompartments. Reason: Nucleolar localization is not prominently featured in the primary literature. The primary nuclear localizations are nucleoplasm (-KTS) and nuclear speckles (+KTS). This annotation may represent a minor or transient localization. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: WT1 can shuttle between nucleus and cytoplasm. Cytoplasmic WT1 has been associated with polysome-bound mRNPs, supporting post-transcriptional roles. Reason: While WT1 can be cytoplasmic, the primary localization and function is nuclear. Cytoplasmic localization may relate to RNA processing or shuttling. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: WT1 is a transcription factor that regulates expression of numerous target genes. This is a core biological process annotation. Reason: Core function. Equivalent to the more specific GO:0006357 (regulation of transcription by RNA Pol II). |
| GO:0008270 zinc ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: WT1 contains four C2H2 zinc finger domains that coordinate zinc ions for structural integrity and DNA binding. Zinc binding is experimentally demonstrated [PMID:15518539, PMID:25258363]. Reason: Core molecular function. The zinc fingers are essential for DNA binding activity. Structural studies confirm zinc coordination [PMID:15518539]. |
| GO:0016607 nuclear speck | IEA GO_REF:0000044 | ACCEPT | Summary: The +KTS isoform of WT1 localizes to nuclear speckles, which are sites of pre-mRNA splicing factor storage and modification [PMID:9553041, PMID:15520190, PMID:16934801]. Reason: Well-documented localization for the +KTS isoform, consistent with its role in RNA processing. Colocalization with RBM4 in speckles is demonstrated. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: WT1 binds zinc ions via its C2H2 zinc finger domains. This is correct but redundant with the more specific GO:0008270 (zinc ion binding). Reason: Valid but less informative than GO:0008270. Both terms are appropriate. |
| GO:0072078 nephron tubule morphogenesis | IEA GO_REF:0000117 | ACCEPT | Summary: WT1 is essential for nephrogenesis. Wt1 knockout mice show complete failure of kidney development [PMID:10101119]. WT1 regulates genes required for nephron formation and glomerular development. Reason: Well-supported developmental role. WT1 is required throughout nephrogenesis, including tubule formation. This is a core biological process for WT1. |
| GO:0072359 circulatory system development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: WT1 is expressed in the epicardium and is required for heart development. Wt1 null mice die at E13.5 due to heart failure with pericardial bleeding [PMID:10101119]. Reason: Valid annotation but represents a secondary developmental role. The primary functions of WT1 are in kidney and gonad development. Heart involvement is through epicardial/mesothelial functions. |
| GO:1990837 sequence-specific double-stranded DNA binding | IEA GO_REF:0000117 | ACCEPT | Summary: WT1 binds sequence-specifically to double-stranded DNA containing the motif 5'-GCG(T/G)GGGCG-3'. Crystal structures confirm this binding mode [PMID:25258363]. Reason: Core molecular function. Equivalent to GO:0043565 which has experimental support. |
| GO:0005515 protein binding | IPI PMID:19447967 Shifted Transversal Design smart-pooling for high coverage i... | KEEP AS NON CORE | Summary: High-throughput interaction study (Shifted Transversal Design smart-pooling). Interaction with DVL3 (Dishevelled 3) reported. Reason: "Protein binding" is an uninformative term. The specific interaction partner (DVL3) is identified but functional significance for WT1 is unclear. Retain as evidence of protein interaction capacity but not informative about core function. Supporting Evidence: PMID:19447967 Shifted Transversal Design smart-pooling for high coverage interactome mapping. |
| GO:0005515 protein binding | IPI PMID:21900206 A directed protein interaction network for investigating int... | KEEP AS NON CORE | Summary: High-throughput directed protein interaction network study. Interaction with DVL3. Reason: Uninformative term from high-throughput study. The specific interaction (DVL3) lacks clear functional context for WT1 biology. Supporting Evidence: PMID:21900206 A directed protein interaction network for investigating intracellular signal transduction. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Large-scale human interactome mapping study. Interactions with KRTAP10-8 and KRT40. Reason: High-throughput study. Keratin-associated proteins are not obviously relevant to known WT1 biology. May represent non-specific interactions. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:25601757 WT1 recruits TET2 to regulate its target gene expression and... | MODIFY | Summary: WT1 recruits TET2 to regulate target gene expression and suppress leukemia cell proliferation. This represents a functionally important interaction. Reason: This is a functionally significant interaction with TET2 (methylcytosine dioxygenase) involved in epigenetic regulation. The generic "protein binding" term does not capture the functional significance. Proposed replacements: molecular function activator activity Supporting Evidence: PMID:25601757 2015 Jan 15. WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. |
| GO:0005515 protein binding | IPI PMID:27229929 Systematic interactome mapping of acute lymphoblastic leukem... | KEEP AS NON CORE | Summary: Interactome mapping of ALL cancer gene products. WT1-DVL3 interaction. Reason: Uninformative term. Part of cancer gene product interactome study. DVL3 interaction functional significance unclear. Supporting Evidence: PMID:27229929 Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: Study of genetic variants disrupting protein interactions. Interaction with KRT40. Reason: Uninformative term. Keratin interaction not obviously relevant to WT1 function. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. |
| GO:0005515 protein binding | IPI PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp... | MODIFY | Summary: WT1 interacts with Hsp70 (HSPA1A/HSPA1B). This is a functionally important interaction required for WT1's growth suppression activity [PMID:9553041]. Reason: Functionally significant interaction. Hsp70 binding is required for WT1 antiproliferative function. Should be annotated with a more specific term. Proposed replacements: chaperone binding Supporting Evidence: PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. |
| GO:0005515 protein binding | IPI PMID:7720589 Repression of Pax-2 by WT1 during normal kidney development. | MODIFY | Summary: WT1 interacts with PAX2, its transcriptional target. The study demonstrates WT1 binding to PAX2 regulatory sequences and repression of PAX2 expression. Reason: This represents DNA binding to PAX2 promoter rather than protein-protein interaction. The IPI annotation may be misattributed. Proposed replacements: transcription cis-regulatory region binding Supporting Evidence: PMID:7720589 Repression of Pax-2 by WT1 during normal kidney development. |
| GO:0005515 protein binding | IPI PMID:16934801 WT1 interacts with the splicing protein RBM4 and regulates i... | MODIFY | Summary: WT1 interacts with RBM4, a splicing regulator. The +KTS isoform specifically modulates RBM4's effect on alternative splicing [PMID:16934801]. Reason: Functionally significant interaction related to WT1's RNA processing function. Should use a more specific MF term. Proposed replacements: molecular function activator activity Supporting Evidence: PMID:16934801 Epub 2006 Jul 25. WT1 interacts with the splicing protein RBM4 and regulates its ability to modulate alternative splicing in vivo. |
| GO:0005515 protein binding | IPI PMID:21390327 PINCH1 is transcriptional regulator in podocytes that intera... | KEEP AS NON CORE | Summary: WT1 interacts with PINCH1 (LIMS1). PINCH1 represses podocalyxin expression and interacts with WT1 in podocytes. Reason: PINCH1 interaction is documented but the term "protein binding" is uninformative. The functional significance relates to podocyte gene regulation. Supporting Evidence: PMID:21390327 PINCH1 is transcriptional regulator in podocytes that interacts with WT1 and represses podocalyxin expression. |
| GO:0005515 protein binding | IPI PMID:14701728 BASP1 is a transcriptional cosuppressor for the Wilms' tumor... | MODIFY | Summary: WT1 interacts with BASP1, a transcriptional cosuppressor. BASP1 binding converts WT1 from an activator to a repressor at specific promoters. Reason: Functionally important interaction that modulates WT1's transcriptional activity. BASP1 is a documented WT1 cofactor. Proposed replacements: transcription corepressor activity Supporting Evidence: PMID:14701728 BASP1 is a transcriptional cosuppressor for the Wilms' tumor suppressor protein WT1. |
| GO:0005515 protein binding | IPI PMID:9178767 Differential regulation of the human Wilms tumour suppressor... | KEEP AS NON CORE | Summary: WT1 interacts with PAX2. PAX2 regulates WT1 promoter activity in a reciprocal regulatory relationship. Reason: Documents interaction between two kidney development transcription factors. Generic term is uninformative. Supporting Evidence: PMID:9178767 Differential regulation of the human Wilms tumour suppressor gene (WT1) promoter by two isoforms of PAX2. |
| GO:0005515 protein binding | IPI PMID:8119964 The Wilms' tumor suppressor gene WT1 is negatively autoregul... | ACCEPT | Summary: WT1 can form homodimers and binds to its own promoter for autoregulation. The interaction is via the zinc finger domain (C2H2 zinc finger domain binding). Reason: Documents WT1 homodimerization. Also annotated with GO:0070742 (C2H2 zinc finger domain binding) which is more specific. Supporting Evidence: PMID:8119964 The Wilms' tumor suppressor gene WT1 is negatively autoregulated. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence data showing nucleoplasmic localization. Reason: Supported by imaging data. Consistent with WT1's nuclear transcription factor function. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence data indicating cytosolic presence. Reason: WT1 can shuttle to cytoplasm but primary function is nuclear. Cytosolic localization may relate to shuttling or RNA processing functions. |
| GO:0008270 zinc ion binding | IDA PMID:25258363 Wilms tumor protein recognizes 5-carboxylcytosine within a s... | ACCEPT | Summary: Crystal structure of WT1 zinc finger domain bound to DNA confirms zinc coordination in C2H2 zinc fingers [PMID:25258363]. Reason: Core molecular function confirmed by structural biology. Supporting Evidence: PMID:25258363 Sep 25. Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence. |
| GO:0010385 double-stranded methylated DNA binding | IDA PMID:25258363 Wilms tumor protein recognizes 5-carboxylcytosine within a s... | ACCEPT | Summary: WT1 can bind to methylated DNA. The study shows WT1 has slightly higher affinity for 5mC-containing sequences compared to unmethylated, but much lower affinity for oxidized forms (5hmC, 5fC, 5caC) [PMID:25258363]. Reason: Directly demonstrated by biochemical and structural studies. This is a specialized aspect of WT1's DNA binding activity. Supporting Evidence: PMID:25258363 Sep 25. Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:25258363 Wilms tumor protein recognizes 5-carboxylcytosine within a s... | ACCEPT | Summary: WT1 binds to the consensus sequence 5'-GCG(T/G)GGGCG-3' with high affinity and specificity [PMID:25258363, PMID:7862533]. Reason: Core molecular function demonstrated by multiple methods including gel shift, footprinting, and X-ray crystallography. Supporting Evidence: PMID:25258363 Sep 25. Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence. |
| GO:0044729 hemi-methylated DNA-binding | IDA PMID:25258363 Wilms tumor protein recognizes 5-carboxylcytosine within a s... | ACCEPT | Summary: Study demonstrates WT1 can bind hemi-methylated DNA substrates [PMID:25258363]. Reason: Directly demonstrated in the structural/biochemical study. Supporting Evidence: PMID:25258363 Sep 25. Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence. |
| GO:0016607 nuclear speck | IDA PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp... | ACCEPT | Summary: WT1 localizes to nuclear speckles, particularly the +KTS isoform which colocalizes with splicing factors [PMID:9553041, PMID:16934801]. Reason: Isoform-specific localization related to RNA processing function. Supporting Evidence: PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:23042785 Control of epigenetic states by WT1 via regulation of de nov... | ACCEPT | Summary: ChIP assays demonstrate WT1 recruitment to the DNMT3A promoter region [PMID:23042785]. Reason: Core molecular function demonstrated by chromatin immunoprecipitation. Supporting Evidence: PMID:23042785 Chromatin immunoprecipitation assays demonstrate WT1 recruitment to the DNMT3A promoter region |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:23042785 Control of epigenetic states by WT1 via regulation of de nov... | ACCEPT | Summary: WT1 directly transactivates DNMT3A expression. Reporter assays confirm transcriptional activation [PMID:23042785]. Reason: Core molecular function. WT1 activates transcription of multiple target genes including DNMT3A, EPO, and SRY. Supporting Evidence: PMID:23042785 reporter assays confirm that WT1 directly transactivates DNMT3A expression |
| GO:0005634 nucleus | IDA PMID:16934801 WT1 interacts with the splicing protein RBM4 and regulates i... | ACCEPT | Summary: Immunofluorescence shows nuclear localization of WT1 [PMID:16934801]. Reason: Duplicate of multiple other annotations. Nuclear localization is core. Supporting Evidence: PMID:16934801 Epub 2006 Jul 25. WT1 interacts with the splicing protein RBM4 and regulates its ability to modulate alternative splicing in vivo. |
| GO:0016607 nuclear speck | IDA PMID:16934801 WT1 interacts with the splicing protein RBM4 and regulates i... | ACCEPT | Summary: WT1 colocalizes with RBM4 in nuclear speckles [PMID:16934801]. Reason: Consistent with +KTS isoform's role in RNA processing. Supporting Evidence: PMID:16934801 Epub 2006 Jul 25. WT1 interacts with the splicing protein RBM4 and regulates its ability to modulate alternative splicing in vivo. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:7720589 Repression of Pax-2 by WT1 during normal kidney development. | ACCEPT | Summary: DNase I footprinting demonstrates WT1 binding to specific sites in the PAX2 promoter [PMID:7720589]. Reason: Core molecular function demonstrated by direct biochemical assay. Supporting Evidence: PMID:7720589 Repression of Pax-2 by WT1 during normal kidney development. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:7720589 Repression of Pax-2 by WT1 during normal kidney development. | ACCEPT | Summary: WT1 represses PAX2 transcription. Co-transfection assays demonstrate WT1-dependent transcriptional repression [PMID:7720589]. Reason: Core function. WT1 represses multiple target genes. PAX2 repression is important for kidney development. Supporting Evidence: PMID:7720589 Repression of Pax-2 by WT1 during normal kidney development. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:9815658 The Wilms' tumor gene WT1 can regulate genes involved in sex... | ACCEPT | Summary: EMSA shows WT1 binding to promoter elements of SRY, MIS, and androgen receptor genes [PMID:9815658]. Reason: Core molecular function demonstrated for multiple target gene promoters. Supporting Evidence: PMID:9815658 The Wilms' tumor gene WT1 can regulate genes involved in sex determination and differentiation: SRY, Müllerian-inhibiting substance, and the androgen receptor. |
| GO:0007530 sex determination | IDA PMID:9815658 The Wilms' tumor gene WT1 can regulate genes involved in sex... | ACCEPT | Summary: WT1 regulates transcription of sex determination genes SRY, MIS, and androgen receptor [PMID:9815658]. Genital abnormalities in DDS patients and Wt1 knockout mice support this role. Reason: Core biological process. WT1 is essential for gonadal development and sex determination, regulating key genes in the pathway. Supporting Evidence: PMID:9815658 The Wilms' tumor gene WT1 can regulate genes involved in sex determination and differentiation: SRY, Müllerian-inhibiting substance, and the androgen receptor. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:1662794 Characterization of the zinc finger protein encoded by the W... | ACCEPT | Summary: WT1 binds to the EGR consensus sequence in gel-retardation assays [PMID:1662794]. Reason: One of the earliest demonstrations of WT1's sequence-specific DNA binding. Supporting Evidence: PMID:1662794 Characterization of the zinc finger protein encoded by the WT1 Wilms' tumor locus. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:8132626 Transcriptional regulation of the human Wilms' tumor gene (W... | ACCEPT | Summary: WT1 activates transcription in certain contexts. Reason: Core function. WT1 can act as both activator and repressor. Supporting Evidence: PMID:8132626 Transcriptional regulation of the human Wilms' tumor gene (WT1). |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:21390327 PINCH1 is transcriptional regulator in podocytes that intera... | ACCEPT | Summary: WT1 regulates podocalyxin expression in podocytes. Reason: Supports WT1's role in podocyte gene regulation. Supporting Evidence: PMID:21390327 PINCH1 is transcriptional regulator in podocytes that interacts with WT1 and represses podocalyxin expression. |
| GO:0008285 negative regulation of cell population proliferation | IDA PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp... | ACCEPT | Summary: Inducible WT1 expression inhibits cellular proliferation. This requires association with Hsp70 [PMID:9553041]. Reason: Core tumor suppressor function demonstrated by inducible expression studies. Supporting Evidence: PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. |
| GO:0030308 negative regulation of cell growth | IDA PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp... | ACCEPT | Summary: WT1 inhibits cell growth [PMID:9553041]. Reason: Related to tumor suppressor function. Equivalent to GO:0008285. Supporting Evidence: PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9178767 Differential regulation of the human Wilms tumour suppressor... | REMOVE | Summary: PMID:9178767 investigates PAX2 regulation of the WT1 promoter, not WT1's transcriptional activity. The study shows "PAX2 transactivated the WT1 promoter up to 35-fold" - this is PAX2's function, not WT1's. Reason: This annotation is incorrectly attributed. The referenced paper demonstrates that PAX2 activates WT1 transcription (PAX2 -> WT1), not that WT1 positively regulates other genes. This should be an annotation on PAX2, not WT1. Supporting Evidence: PMID:9178767 Differential regulation of the human Wilms tumour suppressor gene (WT1) promoter by two isoforms of PAX2. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor supp... | ACCEPT | Summary: WT1 can activate transcription of certain target genes. Reason: WT1 has dual activator/repressor function. Supporting Evidence: PMID:9553041 Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:7588596 WT1 suppresses synthesis of the epidermal growth factor rece... | ACCEPT | Summary: WT1 binds to EGFR promoter elements [PMID:7588596]. Reason: Core molecular function for regulation of EGFR. Supporting Evidence: PMID:7588596 WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA P19544-1 PMID:9815658 The Wilms' tumor gene WT1 can regulate genes involved in sex... | ACCEPT | Summary: WT1 represses transcription of MIS and androgen receptor genes [PMID:9815658]. Reason: Core repressor function on sex determination genes. Supporting Evidence: PMID:9815658 The Wilms' tumor gene WT1 can regulate genes involved in sex determination and differentiation: SRY, Müllerian-inhibiting substance, and the androgen receptor. |
| GO:0008270 zinc ion binding | IDA PMID:15518539 Why zinc fingers prefer zinc: ligand-field symmetry and the ... | ACCEPT | Summary: NMR structure of WT1 zinc fingers in complex with zinc [PMID:15518539]. Reason: Structural confirmation of zinc binding. Supporting Evidence: PMID:15518539 Why zinc fingers prefer zinc: ligand-field symmetry and the hidden thermodynamics of metal ion selectivity. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:1332065 Human platelet-derived growth factor A chain is transcriptio... | ACCEPT | Summary: WT1 binds to PDGFA promoter [PMID:1332065]. Reason: Core molecular function. Supporting Evidence: PMID:1332065 Human platelet-derived growth factor A chain is transcriptionally repressed by the Wilms tumor suppressor WT1. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:7585606 Regulation of the proto-oncogenes bcl-2 and c-myc by the Wil... | ACCEPT | Summary: WT1 binds to BCL2 and MYC promoter elements [PMID:7585606]. Reason: Core molecular function for tumor suppressor activity. Supporting Evidence: PMID:7585606 Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms' tumor suppressor gene WT1. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:1332065 Human platelet-derived growth factor A chain is transcriptio... | ACCEPT | Summary: WT1 represses PDGFA transcription. Reason: Core repressor function. Supporting Evidence: PMID:1332065 Human platelet-derived growth factor A chain is transcriptionally repressed by the Wilms tumor suppressor WT1. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:7585606 Regulation of the proto-oncogenes bcl-2 and c-myc by the Wil... | ACCEPT | Summary: WT1 represses BCL2 and MYC transcription [PMID:7585606]. Reason: Core tumor suppressor function. Supporting Evidence: PMID:7585606 Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms' tumor suppressor gene WT1. |
| GO:0005634 nucleus | IDA PMID:7588596 WT1 suppresses synthesis of the epidermal growth factor rece... | ACCEPT | Summary: Nuclear localization confirmed. Reason: Duplicate annotation. Nuclear localization is core. Supporting Evidence: PMID:7588596 WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. |
| GO:0005634 nucleus | IDA PMID:14701728 BASP1 is a transcriptional cosuppressor for the Wilms' tumor... | ACCEPT | Summary: Nuclear localization confirmed. Reason: Duplicate annotation. Supporting Evidence: PMID:14701728 BASP1 is a transcriptional cosuppressor for the Wilms' tumor suppressor protein WT1. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:14701728 BASP1 is a transcriptional cosuppressor for the Wilms' tumor... | ACCEPT | Summary: WT1 with BASP1 represses transcription [PMID:14701728]. Reason: Core function. BASP1 modulates WT1's repressor activity. Supporting Evidence: PMID:14701728 BASP1 is a transcriptional cosuppressor for the Wilms' tumor suppressor protein WT1. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:19050011 Dynamic interaction between WT1 and BASP1 in transcriptional... | ACCEPT | Summary: Dynamic WT1-BASP1 interaction regulates transcription during differentiation. Reason: Supports repressor function. Supporting Evidence: PMID:19050011 Dec 2. Dynamic interaction between WT1 and BASP1 in transcriptional regulation during differentiation. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:14701728 BASP1 is a transcriptional cosuppressor for the Wilms' tumor... | ACCEPT | Summary: WT1 without BASP1 can activate transcription. Reason: Dual activator/repressor function depends on cofactor context. Supporting Evidence: PMID:14701728 BASP1 is a transcriptional cosuppressor for the Wilms' tumor suppressor protein WT1. |
| GO:0008285 negative regulation of cell population proliferation | IDA PMID:9765217 Induction of Rb-associated protein (RbAp46) by Wilms' tumor ... | ACCEPT | Summary: WT1 induces RbAp46 which mediates growth inhibition [PMID:9765217]. Reason: Tumor suppressor mechanism. Supporting Evidence: PMID:9765217 Induction of Rb-associated protein (RbAp46) by Wilms' tumor suppressor WT1 mediates growth inhibition. |
| GO:0030308 negative regulation of cell growth | IDA PMID:9765217 Induction of Rb-associated protein (RbAp46) by Wilms' tumor ... | ACCEPT | Summary: WT1-induced growth inhibition via RbAp46. Reason: Related to tumor suppressor function. Supporting Evidence: PMID:9765217 Induction of Rb-associated protein (RbAp46) by Wilms' tumor suppressor WT1 mediates growth inhibition. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9765217 Induction of Rb-associated protein (RbAp46) by Wilms' tumor ... | ACCEPT | Summary: WT1 activates RbAp46 transcription. Reason: WT1 can activate transcription of certain targets. Supporting Evidence: PMID:9765217 Induction of Rb-associated protein (RbAp46) by Wilms' tumor suppressor WT1 mediates growth inhibition. |
| GO:0005634 nucleus | IDA PMID:1662794 Characterization of the zinc finger protein encoded by the W... | ACCEPT | Summary: Immunofluorescence shows nuclear localization [PMID:1662794]. Reason: Core localization. Supporting Evidence: PMID:1662794 Characterization of the zinc finger protein encoded by the WT1 Wilms' tumor locus. |
| GO:0005634 nucleus | IDA PMID:8306891 Nuclear localization of the protein encoded by the Wilms' tu... | ACCEPT | Summary: Nuclear localization in embryonic and adult tissues. Reason: Core localization. Supporting Evidence: PMID:8306891 Nuclear localization of the protein encoded by the Wilms' tumor gene WT1 in embryonic and adult tissues. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:8119964 The Wilms' tumor suppressor gene WT1 is negatively autoregul... | ACCEPT | Summary: WT1 binds specifically to its own promoter for autoregulation. Reason: Core molecular function. Supporting Evidence: PMID:8119964 The Wilms' tumor suppressor gene WT1 is negatively autoregulated. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:12802290 Upregulation of c-MYC in WT1-mutant tumors: assessment of WT... | ACCEPT | Summary: WT1 regulates c-MYC expression. c-MYC is upregulated in WT1-mutant tumors. Reason: Core tumor suppressor mechanism. Supporting Evidence: PMID:12802290 Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:8119964 The Wilms' tumor suppressor gene WT1 is negatively autoregul... | ACCEPT | Summary: WT1 negatively autoregulates its own expression. Reason: Autoregulatory repression. Supporting Evidence: PMID:8119964 The Wilms' tumor suppressor gene WT1 is negatively autoregulated. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:12802290 Upregulation of c-MYC in WT1-mutant tumors: assessment of WT... | REMOVE | Summary: PMID:12802290 shows "c-MYC...was upregulated in WT1-mutant tumors", meaning WT1 normally represses c-MYC. The paper states WT1 "represses or activates the expression of a variety of putative target genes" but the specific finding for c-MYC supports repression. Reason: This annotation contradicts the evidence in the referenced paper. PMID:12802290 demonstrates that c-MYC is upregulated when WT1 is mutated, indicating WT1 normally represses (not activates) c-MYC transcription. The negative regulation annotation from this paper is correct; this positive regulation annotation is erroneous. Supporting Evidence: PMID:12802290 Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors. |
| GO:0070742 C2H2 zinc finger domain binding | IPI PMID:8119964 The Wilms' tumor suppressor gene WT1 is negatively autoregul... | ACCEPT | Summary: WT1 homodimerizes via zinc finger domains. Reason: Specific molecular function for homodimerization. Supporting Evidence: PMID:8119964 The Wilms' tumor suppressor gene WT1 is negatively autoregulated. |
| GO:0016607 nuclear speck | IDA P19544-1 PMID:15520190 SUMO-1 modification of the Wilms' tumor suppressor WT1. | ACCEPT | Summary: +KTS isoform (isoform 1) localizes to nuclear speckles [PMID:15520190]. Reason: Isoform-specific localization related to RNA processing. Supporting Evidence: PMID:15520190 SUMO-1 modification of the Wilms' tumor suppressor WT1. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:16467207 Wilms tumor suppressor, Wt1, is a transcriptional activator ... | ACCEPT | Summary: WT1 binds to erythropoietin (EPO) gene promoter [PMID:16467207]. Reason: Core molecular function for EPO regulation. Supporting Evidence: PMID:16467207 Feb 7. Wilms tumor suppressor, Wt1, is a transcriptional activator of the erythropoietin gene. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:16467207 Wilms tumor suppressor, Wt1, is a transcriptional activator ... | ACCEPT | Summary: WT1 activates EPO gene transcription [PMID:16467207]. Reason: Core activator function. Supporting Evidence: PMID:16467207 Feb 7. Wilms tumor suppressor, Wt1, is a transcriptional activator of the erythropoietin gene. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:7585606 Regulation of the proto-oncogenes bcl-2 and c-myc by the Wil... | ACCEPT | Summary: WT1 represses BCL2 and MYC via RNA Pol II [PMID:7585606]. Reason: Core repressor function. Supporting Evidence: PMID:7585606 Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms' tumor suppressor gene WT1. |
| GO:0044027 negative regulation of gene expression via chromosomal CpG island methylation | IMP PMID:23042785 Control of epigenetic states by WT1 via regulation of de nov... | ACCEPT | Summary: WT1 regulates DNMT3A, leading to DNA methylation changes at specific promoters. WT1 overexpression causes hypermethylation and silencing [PMID:23042785]. Reason: Novel regulatory function linking WT1 to epigenetic regulation via DNMT3A. Well-supported by the study. Supporting Evidence: PMID:23042785 human embryonal kidney cells over-expressing WT1 acquire DNA methylation changes at specific gene promoters where DNMT3A recruitment is increased, with hypermethylation being associated with silencing of gene expression |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:23042785 Control of epigenetic states by WT1 via regulation of de nov... | ACCEPT | Summary: WT1 depletion affects transcription of methylated genes. Reason: Supported by knockdown studies in the paper. Supporting Evidence: PMID:23042785 depletion of WT1 in Wilms' tumour cells can lead to reactivation of gene expression from methylated promoters |
| GO:0010628 positive regulation of gene expression | IMP PMID:23042785 Control of epigenetic states by WT1 via regulation of de nov... | ACCEPT | Summary: WT1 positively regulates DNMT3A expression. Reason: Direct evidence from the study. Supporting Evidence: PMID:23042785 depletion of WT1 by short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:23042785 Control of epigenetic states by WT1 via regulation of de nov... | ACCEPT | Summary: WT1 activates DNMT3A transcription. Reason: Core activator function demonstrated by reporter assays. Supporting Evidence: PMID:23042785 Wilms' tumour 1 (WT1), a developmental master regulator that can also act as a tumour suppressor or oncoprotein, transcriptionally regulates the de novo DNA methyltransferase 3A (DNMT3A) |
| GO:1902895 positive regulation of miRNA transcription | IMP PMID:23042785 Control of epigenetic states by WT1 via regulation of de nov... | UNDECIDED | Summary: WT1 may regulate miRNA transcription through DNMT3A-mediated epigenetic effects. Reason: The PMID:23042785 paper focuses on DNMT3A regulation. The connection to miRNA transcription is not directly documented in the abstract. Need to verify this specific claim. Supporting Evidence: PMID:23042785 Control of epigenetic states by WT1 via regulation of de novo DNA methyltransferase 3A. |
| GO:0032836 glomerular basement membrane development | IMP PMID:19205749 Membranoproliferative glomerulonephritis associated with a m... | ACCEPT | Summary: WT1 mutation associated with glomerular defects. Reason: WT1 is essential for podocyte function and glomerular development. Mutations cause glomerular disease. Supporting Evidence: PMID:19205749 2009 Feb 11. Membranoproliferative glomerulonephritis associated with a mutation in Wilms' tumour suppressor gene 1. |
| GO:0007507 heart development | IGI PMID:10101119 YAC complementation shows a requirement for Wt1 in the devel... | KEEP AS NON CORE | Summary: Wt1 knockout mice show heart defects with pericardial bleeding. YAC rescue experiments demonstrate WT1 requirement for heart development [PMID:10101119]. Reason: Valid developmental role but secondary to kidney/gonad functions. Heart involvement is through epicardial development. Supporting Evidence: PMID:10101119 Lack of WT1 leads to severe defects in the epicardial layer and a concomitant absence of SEMCs, which explains the pericardial bleeding and subsequent embryonic death observed in Wt1 null embryos |
| GO:0030325 adrenal gland development | IGI PMID:10101119 YAC complementation shows a requirement for Wt1 in the devel... | KEEP AS NON CORE | Summary: Partially rescued Wt1 mutant embryos show severely affected adrenal gland development [PMID:10101119]. Reason: Valid developmental role but less prominent than kidney/gonad. Related to WT1's role in intermediate mesoderm-derived organs. Supporting Evidence: PMID:10101119 the development of adrenal glands is also severely affected in partially rescued embryos |
| GO:0072284 metanephric S-shaped body morphogenesis | IGI PMID:10101119 YAC complementation shows a requirement for Wt1 in the devel... | ACCEPT | Summary: WT1 required for nephron morphogenesis including S-shaped body stage. Reason: Core kidney development function. Supporting Evidence: PMID:10101119 Analysis of the observed hypoplastic kidneys demonstrate a continuous requirement for WT1 during nephrogenesis, in particular, in the formation of mature glomeruli |
| GO:0061032 visceral serous pericardium development | IGI PMID:10101119 YAC complementation shows a requirement for Wt1 in the devel... | KEEP AS NON CORE | Summary: WT1 is expressed in epicardium and required for its development. Reason: Valid but secondary to kidney/gonad roles. Supporting Evidence: PMID:10101119 WT1 is expressed in the early proepicardium, the epicardium and the subepicardial mesenchymal cells (SEMC) |
| GO:0001658 branching involved in ureteric bud morphogenesis | IGI PMID:10101119 YAC complementation shows a requirement for Wt1 in the devel... | ACCEPT | Summary: WT1 regulates ureteric bud development. Reason: Core kidney development function. Supporting Evidence: PMID:10101119 a general requirement for this protein in the formation of organs derived from the intermediate mesoderm |
| GO:0001822 kidney development | IGI PMID:11912180 WT1 is a key regulator of podocyte function: reduced express... | ACCEPT | Summary: Reduced WT1 levels cause crescentic glomerulonephritis or mesangial sclerosis depending on dosage. WT1 regulates podocyte genes nphs1 and podocalyxin [PMID:11912180]. Reason: Core biological process. WT1 is essential for all stages of kidney development and podocyte maintenance. Supporting Evidence: PMID:11912180 WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis. |
| GO:0032835 glomerulus development | IGI PMID:10101119 YAC complementation shows a requirement for Wt1 in the devel... | ACCEPT | Summary: WT1 required for mature glomeruli formation. Reason: Core kidney development function. Supporting Evidence: PMID:10101119 a continuous requirement for WT1 during nephrogenesis, in particular, in the formation of mature glomeruli |
| GO:0043066 negative regulation of apoptotic process | IGI PMID:10101119 YAC complementation shows a requirement for Wt1 in the devel... | KEEP AS NON CORE | Summary: WT1 prevents apoptosis in developing kidney/epicardium. Reason: Likely secondary to WT1's role in regulating survival genes. Supporting Evidence: PMID:10101119 YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. |
| GO:0045893 positive regulation of DNA-templated transcription | IGI PMID:11912180 WT1 is a key regulator of podocyte function: reduced express... | ACCEPT | Summary: WT1 activates podocyte-specific genes like nphs1 and podocalyxin. Reason: Core function in podocyte gene regulation. Supporting Evidence: PMID:11912180 WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis. |
| GO:0072207 metanephric epithelium development | IEP PMID:7856737 Comparative in situ hybridization analysis of PAX2, PAX8, an... | ACCEPT | Summary: WT1 expressed in developing metanephric epithelium, consistent with role. Reason: Expression pattern supports functional role in kidney development. Supporting Evidence: PMID:7856737 Comparative in situ hybridization analysis of PAX2, PAX8, and WT1 gene transcription in human fetal kidney and Wilms' tumors. |
| GO:0071320 cellular response to cAMP | IEP PMID:15961562 Expression, regulation, and function of paired-box gene 8 in... | KEEP AS NON CORE | Summary: WT1 expression regulated by cAMP signaling in placenta. Reason: IEP evidence only. Expression response to cAMP does not indicate direct function in cAMP signaling pathway. Supporting Evidence: PMID:15961562 Jun 16. Expression, regulation, and function of paired-box gene 8 in the human placenta and placental cancer cell lines. |
| GO:0071371 cellular response to gonadotropin stimulus | IDA PMID:15961562 Expression, regulation, and function of paired-box gene 8 in... | KEEP AS NON CORE | Summary: WT1 expression responsive to gonadotropin in placenta. Reason: Placental expression context. Not a core function but reflects tissue-specific regulation. Supporting Evidence: PMID:15961562 Jun 16. Expression, regulation, and function of paired-box gene 8 in the human placenta and placental cancer cell lines. |
| GO:0008584 male gonad development | IEP PMID:17848411 Developmental changes in human fetal testicular cell numbers... | ACCEPT | Summary: WT1 expressed during fetal testis development. Reason: Supports core role in gonad development. Expression pattern is consistent with functional requirement. Supporting Evidence: PMID:17848411 Epub 2007 Sep 11. Developmental changes in human fetal testicular cell numbers and messenger ribonucleic acid levels during the second trimester. |
| GO:0005634 nucleus | IDA PMID:15961562 Expression, regulation, and function of paired-box gene 8 in... | ACCEPT | Summary: Nuclear localization in placental cells. Reason: Consistent with nuclear localization in all tissues. Supporting Evidence: PMID:15961562 Jun 16. Expression, regulation, and function of paired-box gene 8 in the human placenta and placental cancer cell lines. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from mouse WT1. Well-supported by direct human evidence. Reason: Human WT1 has documented transcription activator activity (IDA evidence exists). |
| GO:0003700 DNA-binding transcription factor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from mouse WT1. Core function. Reason: Well-supported by human experimental evidence. |
| GO:2001076 positive regulation of metanephric ureteric bud development | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from mouse knockout studies. Reason: Consistent with human WT1's role in kidney development. |
| GO:0007356 thorax and anterior abdomen determination | ISS GO_REF:0000024 | REMOVE | Summary: Transfer from mouse. This is a Drosophila-centric term. Reason: This GO term is specific to Drosophila body segmentation. Not applicable to mammalian WT1 biology. Likely annotation error. |
| GO:0008406 gonad development | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from mouse knockout studies. Core function. Reason: Well-supported by human genetics (DDS, Frasier syndrome). |
| GO:0060421 positive regulation of heart growth | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse. Heart involvement via epicardium. Reason: Valid but secondary to kidney/gonad roles. |
| GO:0060539 diaphragm development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse. WT1 mutations cause Meacham syndrome with diaphragm defects. Reason: Documented in Meacham syndrome but not core function. |
| GO:0072075 metanephric mesenchyme development | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from mouse. Core kidney development function. Reason: WT1 essential for metanephric mesenchyme development and MET. |
| GO:0035802 adrenal cortex formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse. Adrenal development affected in Wt1 mutants. Reason: Valid but secondary developmental role. |
| GO:0060923 cardiac muscle cell fate commitment | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse. Epicardial progenitor role. Reason: Secondary to kidney/gonad functions. |
| GO:0001570 vasculogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse. Related to epicardial/heart development. Reason: Secondary developmental role. |
| GO:0001657 ureteric bud development | ISS GO_REF:0000024 | ACCEPT | Summary: Core kidney development function. Reason: Essential for nephrogenesis. |
| GO:0003156 regulation of animal organ formation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Generic term for developmental regulation. Reason: Overly broad term. More specific terms for kidney, gonad, heart development are more appropriate. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: WT1 can be cytoplasmic but primarily nuclear. Reason: Minor localization compared to nucleus. |
| GO:0006355 regulation of DNA-templated transcription | ISS GO_REF:0000024 | ACCEPT | Summary: Core function. Reason: Well-supported by human evidence. |
| GO:0006357 regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: Core function. Reason: Well-supported by human evidence. |
| GO:0007281 germ cell development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: WT1 role in germ cell development via gonad function. Reason: Related to gonad development but indirect. |
| GO:0008380 RNA splicing | ISS GO_REF:0000024 | ACCEPT | Summary: +KTS isoform participates in RNA processing/splicing, interacting with RBM4 and other splicing factors [PMID:16934801]. Reason: Isoform-specific function of +KTS variant. |
| GO:0009888 tissue development | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Generic developmental term. Reason: Too broad. More specific terms exist. |
| GO:0030539 male genitalia development | ISS GO_REF:0000024 | ACCEPT | Summary: WT1 required for male genital development. DDS patients have genital abnormalities. Reason: Core function in sex development. |
| GO:0030855 epithelial cell differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: WT1 drives mesenchymal-to-epithelial transition in nephrogenesis. Reason: Core function in kidney development. |
| GO:0043010 camera-type eye development | ISS GO_REF:0000024 | REMOVE | Summary: Eye involvement in WAGR syndrome includes aniridia, but that is due to PAX6. Reason: WT1 is not the cause of eye defects in WAGR syndrome - that is due to contiguous deletion including PAX6. This appears to be an annotation error. |
| GO:0060231 mesenchymal to epithelial transition | ISS GO_REF:0000024 | ACCEPT | Summary: Core function in nephrogenesis. WT1 required for MET during kidney development. Reason: Well-documented developmental function. |
| GO:0072166 posterior mesonephric tubule development | ISS GO_REF:0000024 | ACCEPT | Summary: WT1 required for mesonephric development. Reason: Part of urogenital development. |
| GO:0072302 negative regulation of metanephric glomerular mesangial cell proliferation | ISS GO_REF:0000024 | ACCEPT | Summary: WT1 regulates mesangial cell proliferation. Reduced WT1 causes mesangial sclerosis. Reason: Consistent with podocyte/glomerular function. |
| GO:2000020 positive regulation of male gonad development | ISS GO_REF:0000024 | ACCEPT | Summary: WT1 activates SRY and promotes male gonad development. Reason: Core function in sex determination. |
| GO:2000195 negative regulation of female gonad development | ISS GO_REF:0000024 | UNDECIDED | Summary: WT1 promotes male development, which indirectly suppresses female pathway. Reason: The relationship is complex. WT1 is required for gonad development of both sexes. The negative regulation of female gonad development may be overstated. |
| GO:0072112 podocyte differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: WT1 essential for podocyte differentiation and maintenance. Reason: Core function. WT1 regulates podocyte-specific genes (nphs1, podocalyxin) [PMID:11912180]. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9767700 | ACCEPT | Summary: Reactome pathway annotation. WT1 binds CDH1 gene promoter. Reason: Consistent with nuclear localization. |
| GO:0003700 DNA-binding transcription factor activity | NAS PMID:7862533 High affinity binding sites for the Wilms' tumour suppressor... | ACCEPT | Summary: Review article documenting WT1 as transcription factor. Reason: Core function with extensive experimental support. Supporting Evidence: PMID:7862533 High affinity binding sites for the Wilms' tumour suppressor protein WT1. |
| GO:0006355 regulation of DNA-templated transcription | NAS PMID:7862533 High affinity binding sites for the Wilms' tumour suppressor... | ACCEPT | Summary: Core function from review. Reason: Well-supported. Supporting Evidence: PMID:7862533 High affinity binding sites for the Wilms' tumour suppressor protein WT1. |
| GO:0003700 DNA-binding transcription factor activity | NAS PMID:8393820 The WT1 Wilms tumor gene product: a developmentally regulate... | ACCEPT | Summary: Review characterizing WT1 as transcription factor. Reason: Core function. Supporting Evidence: PMID:8393820 The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. |
| GO:0006355 regulation of DNA-templated transcription | NAS PMID:8393820 The WT1 Wilms tumor gene product: a developmentally regulate... | ACCEPT | Summary: Core function from review. Reason: Well-supported. Supporting Evidence: PMID:8393820 The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. |
| GO:0003344 pericardium morphogenesis | TAS PMID:10101119 YAC complementation shows a requirement for Wt1 in the devel... | NEW | Summary: WT1 is expressed in proepicardium and epicardium. Wt1 null mice die at E13.5 due to heart failure from defective epicardial development. YAC complementation studies demonstrate continuous requirement for WT1 in epicardial/pericardial development. Reason: Well-supported by knockout studies showing WT1 is essential for epicardial development. The epicardium is the visceral layer of the pericardium. Supporting Evidence: PMID:10101119 YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. file:human/WT1/WT1-deep-research-cyberian.md |
| GO:0060317 cardiac epithelial to mesenchymal transition | TAS PMID:10101119 YAC complementation shows a requirement for Wt1 in the devel... | NEW | Summary: WT1 is required for epicardial epithelial-to-mesenchymal transition (EMT) that generates cardiovascular progenitor cells. WT1 regulates epicardial EMT through Wnt/beta-catenin signaling and retinoic acid signaling via direct Raldh2 regulation. Reason: WT1 drives EMT in epicardium (opposite to MET in kidney), generating cardiac fibroblasts, vascular smooth muscle cells, and coronary endothelial cells. Supporting Evidence: PMID:10101119 YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. file:human/WT1/WT1-deep-research-cyberian.md |
| GO:0060947 cardiac vascular smooth muscle cell differentiation | TAS PMID:10101119 YAC complementation shows a requirement for Wt1 in the devel... | NEW | Summary: Epicardial EMT driven by WT1 generates cardiac vascular smooth muscle cells that contribute to coronary vasculature formation. Wt1 null mice show impaired coronary plexus formation. Reason: WT1-dependent epicardial EMT produces vascular smooth muscle cells for coronary vessels. Supporting Evidence: PMID:10101119 YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. file:human/WT1/WT1-deep-research-cyberian.md |
| GO:0045893 positive regulation of DNA-templated transcription | IDA NOT P19544-1 PMID:9815658 The Wilms' tumor gene WT1 can regulate genes involved in sex... | ACCEPT | Summary: The +KTS isoform (P19544-1) does NOT activate transcription. PMID:9815658 shows the SRY promoter was strongly activated by WT1(-KTS) isoforms but was NOT activated by WT1(+KTS) isoforms. The +KTS tripeptide insertion alters DNA binding capability. This is a classic example of isoform-specific function where the two splice variants have opposite activities. Reason: Well-documented isoform-specific NOT annotation. The +KTS isoform lacks transcriptional activation ability that the -KTS isoform possesses, due to altered DNA binding from the KTS insertion. This is a paradigm case of functional divergence between splice isoforms. Supporting Evidence: PMID:9815658 by the WT1 isoforms without the KTS tripeptide, WT1(-)KTS, but was not activated by the WT1 isoforms with the KTS tripeptide, WT1(+)KTS, in all cells tested |
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Q: What are the distinct RNA targets of the +KTS isoform?
Experiment: ChIP-seq for WT1 isoforms to systematically identify genome-wide binding sites for -KTS vs +KTS isoforms, which would clarify their distinct transcriptional targets.
Experiment: CLIP-seq for +KTS isoform to identify RNA binding targets, which would elucidate its post-transcriptional regulatory functions.
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