FOXE3 is a nuclear forkhead transcription factor that maintains lens epithelial cells and coordinates anterior-eye development. Human FOXE3 associates with DNAJB1 regulatory chromatin in lens epithelial cells and stimulates DNAJB1 promoter activity and RNA expression in transfected HEK293FT cells. Mouse Foxe3 promotes lens epithelial proliferation and restrains premature lens-fiber differentiation during development. Human FOXE3 variants cause a spectrum of congenital lens and anterior-segment disorders, including Peters anomaly and aphakia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: Human FOXE3 chromatin occupancy corroborates the TFClass location assignment. Reason: The 27218149 Methods describe anti-FOXE3 ChIP from human lens epithelial cells without stated FOXE3 overexpression for that experiment; the assayed DNAJB1 regulatory regions are enriched. This supports chromatin association beyond the TFClass inference. Formaldehyde-crosslinked nucleoprotein occupancy does not identify purified DNA affinity, the exact contacted motif or a stable stoichiometric transcription complex. Supporting Evidence: |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Inherited cis-regulatory DNA recognition fits the verified FOXE3 lineage and experiments. Reason: The authentic PTHR11829 tree places human Q13461 below the positive PTN000930906 IBD, and its MSA sequence exactly matches the official 319-aa protein. Mouse Foxe3 forkhead-fragment binding in 11980846 and human FOXE3 occupancy of DNAJB1 regulatory chromatin with reporter activation in 27218149 are complementary target-family evidence. The ChIP experiment is not purified DNA binding, and the mouse probe is a FOXC1 consensus rather than a determined optimal human FOXE3 motif. These limitations do not contradict the supported ancestral placement. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: Pol II DNA-binding transcription-factor activity is the defining inherited activity. Reason: The positive PTN000930906 IBD is on the actual Q13461 path, with exact target sequence grounding. Human WT FOXE3 stimulates DNAJB1 promoter reporters and endogenous RNA in 27218149, while the conserved forkhead domain has experimentally supported DNA recognition. Current and retained historical WITH/FROM differences remain unchanged; neither donor count nor the presence of target evidence is a reason to reject the phylogenetic judgment. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: The TFClass assignment agrees with demonstrated human promoter regulation. Reason: The original TFClass 3.3.1 classification is consistent with human FOXE3 being a forkhead Pol II transcription factor. Human chromatin occupancy and reporter/RNA responses in 27218149 corroborate this activity independently of the classification. The ISA record is retained as a classification assertion rather than relabeled as an additional experimental assay. Supporting Evidence: |
| GO:0001654 eye development | IMP PMID:27218149 FOXE3 contributes to Peters anomaly through transcriptional ... | KEEP AS NON CORE | Summary: Human FOXE3 variants connect transcriptional dysfunction with anterior-eye developmental disease. Reason: The 27218149 study reports segregating human FOXE3 alleles in families with Peters anomaly or congenital cataract and tests the encoded proteins in human cells. That combination supports eye-development involvement, with the lens being a central affected tissue. DNAJB1 knockdown and zebrafish dnajb1 morpholino/rescue experiments are separate downstream-gene tests, not direct FOXE3 developmental rescue. The broad eye outcome is retained contextually without assigning an autonomous role in every ocular tissue. Supporting Evidence: |
| GO:0002088 lens development in camera-type eye | IEA GO_REF:0000107 | ACCEPT | Summary: Conserved lens development is supported by mouse genetics and independent human evidence. Reason: The original Q9QY14/Ensembl transfer is consistent with source-matched mouse Foxe3 developmental annotations and the inspected mouse knockout/dyl studies. Foxe3 regulates lens epithelial proliferation and differentiation, and human FOXE3 variants with impaired promoter activity are associated with lens abnormalities. Retain the original IEA provenance; mouse genetics and human functional assays remain distinct, complementary evidence, and the complete developmental target program is not established. |
| GO:0002088 lens development in camera-type eye | IMP PMID:27218149 FOXE3 contributes to Peters anomaly through transcriptional ... | ACCEPT | Summary: Human familial variants and their functional defects support the central lens developmental role. Reason: The 27218149 study combines human segregating FOXE3 variants associated with congenital cataract or Peters anomaly with impaired reporter/RNA regulation by the encoded proteins. Together with direct FOXE3 chromatin occupancy, this supports a transcriptional contribution to lens development. Downstream DNAJB1 perturbations provide a proposed mechanistic connection but do not constitute FOXE3 perturbation or rescue in zebrafish, and the exact in vivo human lens targets remain incompletely resolved. Supporting Evidence: |
| GO:0002088 lens development in camera-type eye | ISS PMID:17064680 Foxe3 is required for morphogenesis and differentiation of t... | ACCEPT | Summary: The original mouse-null comparison establishes a conserved lens developmental role. Reason: In 17064680, targeted Foxe3 disruption and dyl are compared on a largely congenic Balb/c background, with histology and molecular markers demonstrating severely abnormal lens morphogenesis and differentiation. This supports the human ISS transfer from Q9QY14 alongside independent human FOXE3 disease and transcriptional evidence. The five-generation backcross comparison is kept distinct from the earlier mixed-background study; no human rescue or complete direct-target program is claimed. |
| GO:0002930 trabecular meshwork development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Trabecular-meshwork development is retained as a mouse-supported anterior-segment consequence. Reason: The current Q9QY14 donor carries the matching experimental 17064680 context. Mouse Foxe3 loss disrupts lens and filtration-angle development, supporting the transferred developmental assertion. The inspected work cannot separate every lens-dependent signaling or mechanical effect from autonomous action in trabecular cells. Preserve the human IEA and alternative Ensembl source without upgrading it to a direct human trabecular assay. Supporting Evidence: |
| GO:0002930 trabecular meshwork development | ISS PMID:17064680 Foxe3 is required for morphogenesis and differentiation of t... | KEEP AS NON CORE | Summary: The mouse study supports trabecular developmental involvement with tissue-autonomy limits. Reason: The selected 17064680 Results and anterior-segment histology describe impaired filtration-angle/trabecular organization accompanying severe lens defects. The original human ISS source remains Q9QY14. Positive anatomical evidence warrants contextual retention, while proposed secreted lens factors and endothelial-polarization mechanisms remain hypotheses rather than demonstrated human FOXE3 actions in trabecular cells. Supporting Evidence: |
| GO:0003677 DNA binding | IDA PMID:25504734 Functional analysis of FOXE3 mutations causing dominant and ... | TOO GENERAL | Summary: Broad DNA binding is subsumed by the retained Pol II cis-regulatory recognition activity. Reason: Retained GO:0000978 is an is_a descendant of GO:0003677, supported by the target-specific PAINT placement and complementary mouse fragment binding and human chromatin/promoter experiments. The broad unrestricted term therefore adds no distinct binding specificity. The authentic 25504734 abstract reports differing band-shift activities among FOXE3 variants, but its probe, protein preparation, constructs and controls were not recovered. The supplement listing is not experimental data. Independent evidence does not authenticate that original IDA assay, and its source citation and access caveat remain unchanged in scope. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:10652278 A forkhead gene, FoxE3, is essential for lens epithelial pro... | TOO GENERAL | Summary: General transcription-factor activity is represented by the independently supported Pol II-specific activity. Reason: Retained GO:0000981 is an is_a descendant of GO:0003700 and specifies the human promoter-regulatory activity independently supported in 27218149. The broad unrestricted term adds no separate molecular function. Selected original 10652278 text establishes mouse lens phenotypes and predicts reduced DNA binding from conserved forkhead substitutions; it does not measure that binding or a human reporter response in the inspected text. Human cloning-probe use does not turn the mouse experiments into human assays. The original human IDA source-to-assay link remains unresolved; this term-level judgment is not a categorical wrong-reference finding. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:25504734 Functional analysis of FOXE3 mutations causing dominant and ... | TOO GENERAL | Summary: The broad TF term is subsumed by retained Pol II-specific activity, while the original variant assays remain access-limited. Reason: Retained GO:0000981 is an is_a descendant of GO:0003700, with independent human FOXE3 promoter/RNA evidence in 27218149. This supports a consistent TOO_GENERAL judgment for the unrestricted broad term. The 25504734 abstract reports altered transactivation among variants and intermediate activity in a modeled heterozygote without a dominant-negative effect in that experiment. Its original Methods, reporter design, host, exact constructs and abundance controls remain inaccessible. No such details are inferred or substituted from the independent paper, and the original IDA citation is preserved. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: The domain-derived TF term is represented by the retained Pol II-specific activity. Reason: The three original InterPro assignments agree with FOXE3 being a forkhead transcription factor. GO:0000981 is an is_a descendant of GO:0003700 and specifies the demonstrated human Pol II promoter-regulatory activity. This electronic row is sound but adds no distinct molecular activity beyond the retained specific term. Supporting Evidence: |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:8825632 Chromosomal localization of six human forkhead genes, freac-... | TOO GENERAL | Summary: The general TF assertion is represented more specifically by retained Pol II transcription-factor activity. Reason: Retained GO:0000981 is an is_a descendant of GO:0003700 and describes the independently demonstrated human promoter-regulatory activity in 27218149. The original TAS term is therefore broader than the retained activity. Authentic metadata and the 8825632 abstract establish human FREAC8/FKHL12 cloning and mapping among forkhead genes, but its original body and precise target-specific TF assay remain unavailable. The independent activity evidence does not replace that citation or make its original assay verified; the family-focused abstract is not evidence of misattribution. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: The verified nuclear IBA agrees with human FOXE3 localization and chromatin activity. Reason: The positive nucleus IBD is on the actual Q13461 target path, with the official 319-aa sequence reproduced by the MSA. Human WT and C240* GFP fusions are reported nuclear in HeLa/HLE cells in 27218149, and anti-FOXE3 ChIP independently supports nuclear chromatin access. Q13461 appearing among descendant sources is valid target evidence, not circularity. The original is_active_in qualifier is retained, and exclusive localization is not claimed. Supporting Evidence: |
| GO:0005634 nucleus | IDA PMID:25504734 Functional analysis of FOXE3 mutations causing dominant and ... | ACCEPT | Summary: Human nuclear localization is independently supported, while this original localization assay remains unverified. Reason: Human FOXE3 nuclear localization is independently supported by the WT/GFP localization experiments in HeLa and HLE cells reported in 27218149 and agrees with the other retained nucleus annotations. Accept the unrestricted located_in nucleus assertion at gene level. The publisher listing for 25504734 describes FLAG-tagged FOXE3 localization, but its actual supplement, images, host and construct details were not recovered. Those original IDA assay details remain unverified; no negative result, exact product identity or recovery of the inaccessible experiment is inferred. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic nuclear location agrees with independent human and mouse observations. Reason: The original Q9QY14/Ensembl/SL-0191 source groups are consistent with mouse lens nuclear immunostaining in 17064680 and human GFP-fusion localization plus chromatin occupancy in 27218149. Retain located_in nucleus as a defining functional location. The current donor objects remain separate, and neither the inference nor the overexpression assay proves that FOXE3 is exclusively nuclear in every physiological state. |
| GO:0005667 transcription regulator complex | IDA PMID:10652278 A forkhead gene, FoxE3, is essential for lens epithelial pro... | UNDECIDED | Summary: The exact transcription-regulator-complex assertion is not established by the inspected source. Reason: GO:0005667 describes a protein complex capable of associating with DNA and regulating transcription. The selected 10652278 Methods/Results describe mouse genetics, cloning and lens phenotypes, without an inspected complex-isolation or equivalent complex-membership experiment. A transcription-factor identity or later chromatin occupancy alone does not establish this exact part_of complex claim. Preserve the original human IDA source and qualifier as unresolved rather than label the curator’s attribution incorrect. Supporting Evidence: |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | TOO GENERAL | Summary: The domain-inferred transcription process is covered by Pol II-specific regulation. Reason: The InterPro-based assertion is consistent with FOXE3 function. Proposed GO:0045944 is an is_a descendant of GO:0006357 and, through it, GO:0006355. The positive DNAJB1 promoter response in PMID:27218149 therefore supplies more informative regulatory coverage than this broad electronic term. Preserve the imported source object; the observed positive effect does not establish the sign of every FOXE3 target. Supporting Evidence: |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | TOO GENERAL | Summary: Inherited Pol II regulation is represented more specifically by the independently demonstrated positive target response. Reason: The authentic FOXE3 lineage retains the positive PTN000930906 IBD for GO:0006357. That inherited general regulatory assertion remains biologically supported. Proposed GO:0045944 is an is_a child of GO:0006357 and captures the positive DNAJB1 promoter/RNA response independently observed for human FOXE3 in PMID:27218149. The more informative gene-level term supports TOO_GENERAL for this unrestricted broad annotation. Positive regulatory direction is established by the human experiments, not inferred at the ancestral IBD node or from donor counts. Preserve the complete original IBA sources and their current-versus-historical provenance differences; activation of every FOXE3 target is not implied. Supporting Evidence: |
| GO:0006366 transcription by RNA polymerase II | IDA PMID:10652278 A forkhead gene, FoxE3, is essential for lens epithelial pro... | MODIFY | Summary: Positive Pol II regulation better describes the demonstrated human FOXE3 transcriptional contribution. Reason: The original broad acts_upstream_of_or_within transcription assertion is compatible with a regulatory contribution. Independent human evidence in PMID:27218149 shows FOXE3-associated DNAJB1 chromatin in HLE cells and increased DNAJB1 promoter activity and RNA expression in transfected HEK293FT cells, supporting the more informative GO:0045944 replacement. This is a role-specific refinement, not a claim that only catalytic polymerase subunits can participate in transcription. GO:0045944 positively_regulates GO:0006366; that relation is not is_a subsumption and does not justify TOO_GENERAL here. The original PMID:10652278 citation, IDA code and broader qualifier remain unchanged. Its inspected mouse experiments, human cloning probe and unpublished cDNA comparison still do not authenticate the original human transcription assay; independent support does not erase that source-specific uncertainty. Proposed replacements: positive regulation of transcription by RNA polymerase II |
| GO:0009653 anatomical structure morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Morphogenetic involvement is consistent with the grounded IBA and ocular phenotypes. Reason: The positive ancestral node lies on the verified Q13461 lineage, with no target-specific loss of inherited morphogenetic function established. Mouse Foxe3 disruption and human FOXE3-associated anterior-segment abnormalities support the general process. Its broad anatomical scope is retained contextually; neither the phylogeny nor the phenotypes specify autonomous activity in every affected tissue. |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: FOXE3 regulates lens-cell differentiation within the verified inherited clade. Reason: The exact target path supports the cell-differentiation IBD. Mouse Foxe3 loss causes premature epithelial-to-fiber transitions together with incomplete later fiber maturation, showing that its role is not a universal positive differentiation switch. Retain the broad inherited process while preserving this stage dependence and distinguishing altered differentiation markers from direct occupancy of their genes. |
| GO:0042789 mRNA transcription by RNA polymerase II | IDA PMID:27218149 FOXE3 contributes to Peters anomaly through transcriptional ... | MODIFY | Summary: FOXE3 positively regulates the tested human DNAJB1 promoter and target RNA. Reason: In PMID:27218149, anti-FOXE3 ChIP in human lens epithelial cells detects DNAJB1 regulatory chromatin. Ectopic human FOXE3 increases DNAJB1 promoter-reporter activity and target RNA in HEK293FT cells, with promoter-only, promoter-less and empty-expression-vector controls described in the selected Results and Methods. GO:0045944 captures this demonstrated positive regulatory work more informatively than the broad mRNA-transcription process. The refinement does not exclude transcription factors from participation in transcription. Reporter and qPCR observations govern the positive direction despite contradictory discovery-screen prose; steady-state RNA is not a nascent-transcription assay, and this result does not establish activation of every target or allele. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:22527307 Growth inhibition of human lens epithelial cells by short ha... | UNDECIDED | Summary: The original human apoptosis endpoint is not accessible for verification. Reason: The authentic 22527307 abstract describes FOXE3 shRNA, reduced growth and G1 arrest in HLEB-3 cells. It does not expose the exact apoptotic measurements or controls behind this IMP row, and the full original Methods/Results were not recovered. Preserve the curator’s assertion as undecided; absence of an apoptosis description in the abstract is not evidence that the experiment was absent or the annotation false. Supporting Evidence: |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000120 | TOO GENERAL | Summary: The electronic sequence-binding row adds no specificity beyond retained regulatory DNA recognition. Reason: The original mouse, Ensembl and InterPro source groups are compatible with sequence-specific DNA binding. GO:0000978 is an is_a descendant of GO:0043565 and captures the relevant regulatory recognition, while the source-specific experimental transfer in 11980846 is retained separately. This redundancy judgment does not deny the positive mouse binding result or rewrite the electronic source groups. |
| GO:0043565 sequence-specific DNA binding | ISS PMID:11980846 Foxe3 haploinsufficiency in mice: a model for Peters' anomal... | TOO GENERAL | Summary: Positive mouse-fragment recognition evidence supports the human transfer, while the broad binding term is subsumed. Reason: In 11980846, reticulocyte-lysate translated mouse WT Foxe3 residues 60–175 shift a FOXC1 consensus probe, whereas the dyl fragment does not. The corresponding human R90L region is reported to retain binding in a data-not-shown experiment. This supports the original human ISS transfer from Q9QY14, with the matching mouse IDA source preserved. GO:0000978 is an is_a descendant of GO:0043565, so the broader term adds no distinct specificity, consistently with the electronic row. The assay is not a purified full-length human affinity measurement, an optimal human motif determination or proof that R90L causes disease. Supporting Evidence: |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | TOO GENERAL | Summary: The broad electronic organ-development assertion adds no resolved organ beyond the ocular contexts. Reason: FOXE3 developmental evidence is specifically concentrated on the lens and anterior eye. The official path from lens development to animal organ development begins with part_of camera-type eye development, followed by is_a eye/sensory-organ development; it is not an all-is_a subclass path. This broad ARBA row is retained in provenance but marked too general because the source-specific ocular contexts convey the supported developmental scope. |
| GO:0048731 system development | IEA GO_REF:0000117 | TOO GENERAL | Summary: System development is broader than the experimentally resolved ocular developmental scope. Reason: The official lens-to-system path contains part_of edges into camera-type eye and visual-system development and is_a edges into sensory-system/system development. It must not be described as pure subclass generality. The ARBA row adds no separately demonstrated system beyond the retained ocular contexts and is therefore too general, without asserting that FOXE3 has no wider developmental consequences. |
| GO:0051726 regulation of cell cycle | IMP PMID:22527307 Growth inhibition of human lens epithelial cells by short ha... | KEEP AS NON CORE | Summary: The reported human lens-cell G1-arrest response supports a non-core cell-cycle regulatory context. Reason: The authentic PMID:22527307 abstract reports reduced FOXE3 RNA/protein and G1-phase arrest after FOXE3 shRNA in human HLEB-3 cells, alongside reduced growth by cell counting and MTT. This directly reported phase-distribution response supports retaining the curator’s IMP cell-cycle-regulation assertion as non-core. Independent mouse Foxe3 loss reduces lens epithelial BrdU incorporation and epithelial maintenance in PMID:16199865, providing compatible proliferation evidence without substituting for the human experiment. Full original PMID:22527307 Methods/Results and specificity/rescue controls remain inaccessible and are not marked verified. The observations do not resolve direct cell-cycle targets, all intermediate mechanisms or the contribution of differentiation and survival; an exclusively downstream mechanism cannot be assumed to justify over-annotation. |
| GO:0061072 iris morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The mouse-derived iris context is supported with lens-dependent effects unresolved. Reason: The current Q9QY14 donor contains matching 17064680 experimental evidence, and the original study reports abnormal iris/anterior-segment morphology after Foxe3 disruption. This supports a contextual developmental transfer. The study does not establish a direct human iris target program or separate lens-derived effects from iris-cell autonomy; the human IEA and alternative Ensembl source remain unchanged. Supporting Evidence: |
| GO:0061072 iris morphogenesis | ISS PMID:17064680 Foxe3 is required for morphogenesis and differentiation of t... | KEEP AS NON CORE | Summary: Iris morphogenesis is retained from the inspected mouse developmental study. Reason: The original 17064680 Results and Figure 4 caption describe iris/ciliary abnormalities in the mouse-null comparison. This supports the human ISS context with Q9QY14, while the severity of accompanying lens defects limits mechanistic interpretation. The proposed extracellular lens signals remain hypotheses, not measured human FOXE3 signaling activities. Supporting Evidence: |
| GO:0061073 ciliary body morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse ciliary-body morphology supports the transferred developmental assertion. Reason: The exact donor includes the corresponding experimental 17064680 annotation. Altered ciliary-body organization accompanies Foxe3-dependent anterior-segment defects, supporting contextual retention of the human IEA. Donor and Ensembl groups are preserved; no autonomous human ciliary-cell transcriptional mechanism is inferred from the mouse phenotype. Supporting Evidence: |
| GO:0061073 ciliary body morphogenesis | ISS PMID:17064680 Foxe3 is required for morphogenesis and differentiation of t... | KEEP AS NON CORE | Summary: The original mouse study supports ciliary-body morphogenesis without resolving the causal tissue. Reason: The inspected 17064680 anterior-segment Results and captions document ciliary-body abnormalities in the Foxe3-null/dyl comparison. Retain the human ISS transfer as a developmental role, with the simultaneous loss or malformation of the lens explicitly limiting cell-autonomy claims. A direct FOXE3 target program in ciliary tissue is not established. Supporting Evidence: |
| GO:0061303 cornea development in camera-type eye | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The electronic corneal-development transfer is consistent with mouse and human ocular evidence. Reason: The Q9QY14 donor includes experimental corneal developmental evidence from 17064680. Mouse anterior-segment defects and human FOXE3-associated Peters anomaly independently support the broader context. This does not establish that human FOXE3 directly controls a corneal-cell gene program; lens separation, tissue interactions and the original IEA provenance remain distinct. |
| GO:0061303 cornea development in camera-type eye | ISS PMID:17064680 Foxe3 is required for morphogenesis and differentiation of t... | KEEP AS NON CORE | Summary: The mouse source supports corneal development with anterior-segment interaction limits. Reason: In 17064680, histology and ultrastructure demonstrate abnormal corneal organization alongside severely disrupted lens development. That positive phenotype supports the human ISS transfer, but does not distinguish all secondary mechanical/signaling consequences from direct corneal action. The paper’s proposed lens-derived signals are not treated as experimentally identified effectors. Supporting Evidence: |
| GO:1902747 negative regulation of lens fiber cell differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: Foxe3 delays premature lens-fiber differentiation in a stage-dependent developmental program. Reason: The current mouse donor carries the matching 16199865 experiment. Mouse-null epithelial cells prematurely express fiber-associated markers while later fiber maturation remains incomplete. This supports negative regulation of the early differentiation transition, not suppression of every maturation step. Retain the original human IEA and donor/Ensembl alternatives without claiming direct human target occupancy or an invariant differentiation sign. This stage-specific lens epithelial maintenance role is part of the core developmental program. Supporting Evidence: |
| GO:1902747 negative regulation of lens fiber cell differentiation | ISS PMID:16199865 Severe defects in proliferation and differentiation of lens ... | ACCEPT | Summary: The original mouse-null study supports restraint of premature fiber-cell differentiation. Reason: The selected 16199865 Results show premature but incomplete fiber differentiation following loss of Foxe3, with altered Prox1/p57/Pdgfra expression and persistent nuclei. These findings support the source-specific human ISS negative-regulation context. Reduced DLAD RNA is not a direct FOXE3–DLAD binding result, and the paper’s hypomorphic-dyl interpretation is kept separate from the later congenic comparison. This stage-specific lens epithelial maintenance role is part of the core developmental program. |
| GO:2001111 positive regulation of lens epithelial cell proliferation | IEA GO_REF:0000107 | ACCEPT | Summary: Mouse epithelial proliferation supports a conserved positive growth-regulatory context. Reason: The exact Q9QY14 donor includes the 16199865 IMP assertion and additional preserved donor provenance. BrdU and epithelial-cell depletion after mouse Foxe3 disruption support maintenance of lens epithelial proliferation. This retains the human IEA with its alternatives; it is not a direct assay of human FOXE3-controlled cell-cycle targets or proof of the mechanism of every donor record. This stage-specific lens epithelial maintenance role is part of the core developmental program. Supporting Evidence: |
| GO:2001111 positive regulation of lens epithelial cell proliferation | IMP PMID:22527307 Growth inhibition of human lens epithelial cells by short ha... | ACCEPT | Summary: Lens epithelial proliferation is supported at gene level, with the original human assay limitations retained. Reason: The original 22527307 abstract reports reduced HLEB-3 growth by counting and MTT after FOXE3 shRNA, together with reduced FOXE3 RNA/protein and G1 arrest. This is compatible with the positive lens-epithelial proliferation role independently supported by BrdU and epithelial maintenance in the mouse-null study 16199865, and with the other retained GO:2001111 contexts. Retain this shared lens epithelial maintenance function as part of the developmental core. The original human experimental design, specificity/rescue controls and separation of proliferation from survival remain uninspected; the mouse study neither replaces the human IMP citation nor verifies those controls. |
| GO:2001111 positive regulation of lens epithelial cell proliferation | ISS PMID:16199865 Severe defects in proliferation and differentiation of lens ... | ACCEPT | Summary: The original mouse-null study establishes a positive lens-epithelial proliferation role. Reason: In 16199865, targeted mouse Foxe3 loss reduces lens epithelial proliferation and epithelial maintenance, supported by BrdU, tissue morphology and expression markers. This warrants the original human ISS transfer while preserving species and developmental-stage limits. Altered Pdgfra or cell-cycle-marker expression does not establish a direct promoter target or exclude contributions from differentiation and survival. This stage-specific lens epithelial maintenance role is part of the core developmental program. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which endogenous FOXE3-bound genes directly maintain lens epithelial proliferation and the timing of fiber differentiation?
Q: How much of the iris, corneal and trabecular phenotype is mediated by lens-derived signals rather than FOXE3 action in the affected tissue?
Q: Which cofactor or DNA-recognition changes distinguish FOXE3 disease alleles at comparable endogenous abundance?
Q: To what extent does DNAJB1 mediate FOXE3-dependent lens epithelial survival and differentiation?
Experiment: Combine acute, dosage-controlled FOXE3 depletion with early nascent-RNA profiling and endogenous FOXE3 CUT&RUN in a lens epithelial or lens-organoid system; test candidate regulatory elements before late tissue collapse.
Hypothesis: Early, occupied targets distinguish direct FOXE3 regulatory work from secondary changes caused by altered proliferation or differentiation.
Experiment: Use temporally controlled, lens-restricted perturbation and tissue-specific rescue with matched developmental staging to compare lens and neighboring anterior-segment outcomes.
Hypothesis: Separating perturbation timing and tissue expression can distinguish lens-mediated developmental effects from autonomous requirements.
Experiment: Compare selected WT and disease-variant FOXE3 alleles at matched protein abundance using DNA binding, endogenous occupancy and target transcription as separate readouts; include controlled DNAJB1 restoration after FOXE3 depletion.
Hypothesis: The measurements can distinguish recognition, cofactor/reporter and downstream-target contributions without equating nuclear localization with preserved function.
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