PAX6 is a paired-box/homeobox sequence-specific DNA-binding transcription factor that acts as a master regulator of development of the eye, central nervous system (forebrain, cerebral cortex, spinal cord), olfactory structures, and pancreatic endocrine cells. The protein contains two DNA-binding modules, an N-terminal bipartite paired domain (with PAI and RED subdomains) and a C-terminal paired-type homeodomain, together with a proline/serine/threonine-rich (PST) C-terminal transactivation domain. PAX6 binds promoter and enhancer cis-regulatory elements of numerous developmental target genes and can act as either a transcriptional activator or repressor in a context-dependent manner. It operates in the nucleus on chromatin and cooperates with partners such as SOX2, MAF/MAFB and the TGF-beta/SMAD pathway. In the endocrine pancreas it controls genes for alpha-cell (glucagon) and beta-cell differentiation and function, contributing to glucose homeostasis. Heterozygous loss-of-function variants cause aniridia and a broad spectrum of anterior and posterior eye malformations, and can be accompanied by glucose intolerance, reflecting the gene's dosage sensitivity and pleiotropy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. PAX6 is a paired-box/homeodomain sequence-specific RNA polymerase II transcription factor, supported by phylogenetic inference across Pax6 orthologs and by direct experimental data in human cells. Reason: This IBA annotation captures the central, well-supported molecular function of PAX6 at the appropriate level of specificity. PAX6 directly binds cis-regulatory elements and regulates RNA Pol II transcription of developmental and endocrine genes. Supporting Evidence: PMID:20592023 Furthermore, we demonstrate that Pax6 directly binds and activates the promoter region of the three genes through specific binding sites file:human/PAX6/PAX6-deep-research-falcon.md Sequence-specific DNA-binding transcription factor with dual PD and homeobox domains; binds and regulates promoters/enhancers of developmental and endocrine effector genes, acting as activator/repressor in a context-dependent manner |
| GO:0003309 type B pancreatic cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAX6 contributes to pancreatic beta (type B) cell differentiation; mouse Pax6 nulls have markedly decreased beta and delta cells. This is a developmental process downstream of PAX6's core DNA-binding transcription factor activity. Reason: Well-supported developmental role but one of many pleiotropic downstream processes for this master regulator; the core function is sequence-specific DNA-binding TF activity. Supporting Evidence: PMID:20592023 homozygous mutant mice for Pax6 are characterized by markedly decreased Ξ² and Ξ΄ cells and absent Ξ± cells |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: PAX6 regulates RNA polymerase II transcription of target genes, acting as both activator and repressor. This is a core biological-process correlate of its TF activity. Reason: Directly supported by experimental promoter binding/regulation studies and is the general process underlying PAX6's function; appropriate IBA-level annotation. Supporting Evidence: PMID:20592023 Pax6 controls the transcription of the Proglucagon and processing enzyme PC2 genes |
| GO:0007420 brain development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAX6 is required for normal brain development; homozygous loss causes gross brain malformations and heterozygous human variants are associated with cerebral anomalies. Reason: Strongly supported pleiotropic developmental process, downstream of the core TF activity; appropriate to retain as a non-core biological role. Supporting Evidence: PMID:16098226 Homozygous mutations in man and mouse are lethal and result in severe developmental abnormalities including anophthalmia, severe reduction of the olfactory structures and gross brain malformations |
| GO:0007423 sensory organ development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAX6 is central to development of sensory organs, most prominently the eye and olfactory structures. A broad developmental-process term downstream of its TF function. Reason: Correct but general developmental role; retained as non-core given PAX6's pleiotropy and its primary molecular function being DNA-binding transcription factor activity. Supporting Evidence: PMID:11756345 PAX6, is a well-known regulator of eye development |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: PAX6 binds RNA Pol II cis-regulatory (promoter/enhancer) elements in a sequence-specific manner via its paired and homeodomain modules. Core molecular function. Reason: This is the precise DNA-binding activity of PAX6, supported by direct binding studies and phylogenetic inference; ideal level of specificity. Supporting Evidence: PMID:24802670 we identified PAX6 binding sites and active enhancers genome-wide in an in vitro model of human NE development |
| GO:0030900 forebrain development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAX6 patterns the developing forebrain and cerebral cortex, with gradients important for cortical arealisation. Pleiotropic developmental process. Reason: Well-supported downstream developmental role; retained as non-core relative to PAX6's core TF molecular function. Supporting Evidence: PMID:16098226 common themes are now emerging concerning the role of PAX6 in neural tissues |
| GO:0060041 retina development in camera-type eye | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAX6 is essential for retinal progenitor competence and retinal development in the camera-type eye. Pleiotropic developmental process. Reason: Strongly supported eye-development role downstream of the core TF function; retained as non-core. Supporting Evidence: PMID:16098226 Gradients of Pax6 expression are important for determining positional characteristics in the retina |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation duplicating the core RNA Pol II DNA-binding transcription factor activity, consistent with IBA and experimental evidence. Reason: Correct and concordant with manually supported annotations; duplicate of the core MF. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes through specific binding sites |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Generic DNA binding inferred from the paired and homeodomain InterPro signatures. Correct but less informative than the sequence-specific Pol II DNA-binding terms. Reason: Accurate parent term but superseded by more specific sequence-specific DNA-binding annotations; keep as a non-core, broad annotation rather than a representative core function. Supporting Evidence: PMID:10747901 Modulation of PAX6 homeodomain function by the paired domain |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: PAX6 is a nuclear transcription factor; nuclear localization is documented by immunofluorescence and inferred from its function. Reason: Correct subcellular localization consistent with UniProt and experimental IDA data. Supporting Evidence: PMID:17291498 Pax-6 immunoreactivity was detectable in the nucleus and the cytoplasm of SVZ cells |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: Broad transcriptional-regulation process inferred from paired/homeodomain InterPro records; subsumed by the more specific RNA Pol II regulation annotations. Reason: Correct parent-level process term; concordant with experimental data, acceptable as a broad electronic annotation. Supporting Evidence: PMID:20592023 Pax6 controls the transcription of the Proglucagon and processing enzyme PC2 genes |
| GO:0007417 central nervous system development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: PAX6 is required for CNS development including cortex and spinal cord patterning. Pleiotropic developmental process. Reason: Well-supported but broad developmental role downstream of the core TF function. Supporting Evidence: PMID:16098226 The PAX6 protein is a member of the PAX (paired-box) family of transcriptional regulators and is essential for normal ocular and neural development |
| GO:0009653 anatomical structure morphogenesis | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Very general morphogenesis term from an ARBA machine-learning model; PAX6 does underlie morphogenesis of eye and brain structures but this term is uninformatively broad. Reason: The essence (PAX6 drives morphogenesis) is correct, but this high-level term adds little beyond the more specific eye/brain/iris/cornea morphogenesis annotations already present. Supporting Evidence: PMID:7550230 Three novel aniridia mutations in the human PAX6 gene |
| GO:0030154 cell differentiation | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: Generic cell-differentiation term from a Swiss-Prot keyword mapping. PAX6 drives differentiation of multiple lineages but this term is non-specific. Reason: True at a high level but uninformative; more specific differentiation terms (neuron, pancreatic A cell, type B pancreatic cell) already capture the relevant biology. Supporting Evidence: PMID:20592023 Pax6 is critical for Ξ± cell function and differentiation |
| GO:0043010 camera-type eye development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: PAX6 is the master regulator of camera-type eye development, a hallmark function established across vertebrates and by human aniridia genetics. Reason: Strongly supported, signature developmental process; retained as non-core relative to the molecular DNA-binding TF function. Supporting Evidence: PMID:11756345 PAX6, is a well-known regulator of eye development |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000117 | ACCEPT | Summary: PAX6 acts as a transcriptional activator at RNA Pol II promoters/enhancers, directly demonstrated for pancreatic alpha-cell genes and miR-135b. Reason: Concordant with experimental IMP/IDA/ISS annotations; correct activator activity. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes through specific binding sites |
| GO:0050877 nervous system process | IEA GO_REF:0000117 | REMOVE | Summary: ARBA machine-learning prediction of "nervous system process" (a physiological process term, e.g. neurotransmission). PAX6 is a developmental TF, not a mediator of nervous system physiological processes per se. Reason: This term denotes ongoing physiological functioning of the nervous system rather than development. PAX6's nervous-system roles are developmental (already captured by CNS/forebrain development terms). No evidence supports a direct nervous system process function; likely an over-broad electronic mis-mapping. Supporting Evidence: PMID:16098226 essential for normal ocular and neural development |
| GO:0005515 protein binding | IPI PMID:16098226 A screen for proteins that interact with PAX6: C-terminal mu... | ACCEPT | Summary: Yeast two-hybrid identification of PAX6 interactions with HOMER3, DNCL1 and TRIM11 via the C-terminal PST domain; C-terminal aniridia mutations disrupt the HOMER3/DNCL1 interactions. Reason: This specific IPI is supported by experimental data; per curation guidance bare "protein binding" is uninformative, but the annotation correctly records real interactions with named partners (the WITH field captures DNCL1/HOMER3). Retained but not treated as a core function. Supporting Evidence: PMID:16098226 Three novel PAX6-interacting proteins were identified the post-synaptic density (PSD) protein HOMER3, the dynein subunit DNCL1, and the tripartite motif protein TRIM11 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: High-throughput binary interactome (HuRI) interactions. Bare "protein binding" with many partners from a single large-scale screen provides little functional insight. Reason: Per curation guidelines, uninformative "protein binding" from a high-throughput map; the many listed partners are not individually validated for PAX6 biology. Not removed because the interactions are real data, but it should not be regarded as a core function. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 can act as a transcriptional repressor as well as an activator; e.g. it represses NFATC1-mediated expression (UniProt) and competes with PAX4 at endocrine promoters. Reason: Concordant with the ISS annotation and UniProt functional notes; PAX6 has documented repressor activity at Pol II promoters. Supporting Evidence: PMID:17251190 the MH1 domain of Smad3 binds to the paired domain of Pax6 releasing it from its own promoter-binding site |
| GO:0000785 chromatin | IEA GO_REF:0000120 | ACCEPT | Summary: As a DNA-binding TF acting at promoters/enhancers, PAX6 localizes to chromatin; this is supported by ChIP/genome-wide binding and IDA evidence. Reason: Correct cellular component for a sequence-specific TF, concordant with the IDA and ISA chromatin annotations. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region |
| GO:0000976 transcription cis-regulatory region binding | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 binds cis-regulatory regions (promoters/enhancers) of target genes. Core DNA-binding function, here at a slightly more general level than GO:0000978. Reason: Correct and concordant with ISS and experimental binding data. Supporting Evidence: PMID:24802670 PAX6 binding to active enhancers was found in the proximity of several microRNAs, including hsa-miR-135b |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic duplicate of the core sequence-specific Pol II cis-regulatory DNA-binding activity, supported by IBA and experimental IDA. Reason: Correct core molecular function; duplicates manually supported annotations. Supporting Evidence: PMID:24802670 we identified PAX6 binding sites and active enhancers genome-wide |
| GO:0000979 RNA polymerase II core promoter sequence-specific DNA binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-projected binding to RNA Pol II core promoter sequence. PAX6 binding is best characterized at cis-regulatory/enhancer and proximal-promoter elements rather than the core promoter specifically. Reason: Plausible but the more accurate and supported term is cis-regulatory region binding (GO:0000978/GO:0000976); this core-promoter specialization is electronic and not directly evidenced, so retained as non-core rather than treated as a representative function. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes through specific binding sites |
| GO:0001221 transcription coregulator binding | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 binds transcriptional coregulators/cofactors (e.g. histone acetyltransferases, SMADs, MAF proteins) to modulate target-gene transcription. Reason: Concordant with the ISS annotation and with documented interactions with coactivators and SMAD/MAF partners. Supporting Evidence: PMID:17251190 Pax6 co-immunoprecipitated with Smad3 following TGFbeta receptor activation |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 has context-dependent repressor activity at RNA Pol II genes, consistent with its dual activator/repressor behavior. Reason: Supported by UniProt note (represses NFATC1-mediated expression) and the negative regulation annotations; correct specific repressor MF. Supporting Evidence: PMID:17251190 represses autoregulation of the Pax6 P1 promoter |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 acts as a sequence-specific transcriptional activator at RNA Pol II genes, directly demonstrated for miR-135b and alpha-cell genes. Reason: Concordant with experimental IDA annotations; a core activator molecular function. Supporting Evidence: PMID:24802670 MiR-135b is a direct PAX6 target |
| GO:0003322 pancreatic A cell development | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: PAX6 is required for pancreatic alpha (A) cell development and glucagon-gene control; Pax6 nulls lack alpha cells. Reason: Well-supported developmental process (also captured by experimental IMP) but downstream of the core TF function for this pleiotropic gene. Supporting Evidence: PMID:20592023 homozygous mutant mice for Pax6 are characterized by markedly decreased Ξ² and Ξ΄ cells and absent Ξ± cells |
| GO:0003682 chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 binds chromatin to regulate transcription, consistent with its chromatin localization and genome-wide binding profiles. Reason: Correct molecular function for a chromatin-acting TF; concordant with chromatin CC and binding data. Supporting Evidence: PMID:24802670 PAX6 binding to active enhancers |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000107 | ACCEPT | Summary: General DNA-binding transcription factor activity, the parent of the RNA Pol II-specific term; the core function of PAX6. Reason: Correct, concordant with TAS and IBA annotations; an acceptable parent-level statement of the core molecular function. Supporting Evidence: PMID:10441571 Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies |
| GO:0003723 RNA binding | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl-projected "RNA binding". There is no compelling evidence that PAX6 functions as an RNA-binding protein; PAX6 is a DNA-binding transcription factor. Reason: This appears to be an electronic over-annotation likely arising from generic nucleic-acid-binding inference. No experimental or literature support for a bona fide RNA binding molecular function for PAX6; risks confusing the core DNA-binding role. Supporting Evidence: PMID:10747901 Modulation of PAX6 homeodomain function by the paired domain |
| GO:0006338 chromatin remodeling | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-projected "chromatin remodeling". PAX6 binds chromatin and recruits cofactors but is not itself an ATP-dependent chromatin-remodeling enzyme. Reason: PAX6 is a sequence-specific TF, not a remodeler; while it may help recruit chromatin-modifying machinery, annotating it directly to chromatin remodeling overstates its activity. Better captured by transcription regulation and HAT-binding annotations. Supporting Evidence: PMID:24802670 we identified PAX6 binding sites and active enhancers genome-wide |
| GO:0007399 nervous system development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PAX6 is essential for nervous system development, supported by experimental IMP and broad genetics. Pleiotropic developmental process. Reason: Well-supported developmental role downstream of the core TF function; duplicate of the experimentally supported IMP annotation. Supporting Evidence: PMID:24802670 PAX6 was shown to be critical for human NE specification |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000120 | ACCEPT | Summary: PAX6 positively regulates expression of target genes; broad process term concordant with its activator activity. Reason: Correct and concordant with the experimental IMP annotation; acceptable broad process. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes |
| GO:0019901 protein kinase binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl/ISS-projected protein kinase binding. PAX6 is phosphorylated and appears in kinase interactome data (e.g. HIPK, CSNK2A1), so kinase binding is plausible but is not a central characterized function. Reason: Supported by ISS transfer from mouse and by interactome data, but represents a peripheral binding activity rather than a core function; retained as non-core. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0021517 ventral spinal cord development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PAX6 specifies ventral neuron subtypes by establishing progenitor domains in the spinal cord. Pleiotropic developmental process. Reason: Supported by ISS and UniProt functional note; downstream developmental role retained as non-core. Supporting Evidence: PMID:16098226 The Pax6 gene has a spatially and temporally complex expression pattern in the eye, brain, nasal structures, spinal cord and pancreas |
| GO:0021987 cerebral cortex development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PAX6 controls cortical neurogenesis and arealisation of the cerebral cortex. Pleiotropic developmental process. Reason: Well-supported cortical-development role downstream of the core TF function. Supporting Evidence: PMID:16098226 roles of PAX6 in brain development ... include arealisation of the cerebral cortex |
| GO:0030182 neuron differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PAX6 promotes differentiation of neurons from multipotent precursors via activation of proneural bHLH genes (e.g. Ngn2). Pleiotropic developmental process. Reason: Well-supported neuronal differentiation role downstream of the core TF function. Supporting Evidence: PMID:16098226 It is also involved in the differentiation of neural cell types from multipotent precursors |
| GO:0031490 chromatin DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 binds chromatinized DNA at regulatory regions; consistent with its chromatin/cis-regulatory binding profile. Reason: Correct molecular function concordant with chromatin binding and genome-wide occupancy data. Supporting Evidence: PMID:24802670 PAX6 binding to active enhancers |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 interacts with the E3 ubiquitin ligase TRIM11, which ubiquitinates PAX6 and targets it for proteasomal degradation. Reason: Supported by the experimental interaction screen (TRIM11) and UniProt PTM note; correct specific binding function. Supporting Evidence: PMID:16098226 the tripartite motif protein TRIM11 |
| GO:0035035 histone acetyltransferase binding | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 binds histone acetyltransferase coactivators to activate transcription; concordant with the ISS annotation. Reason: Supported by ISS transfer and by PAX6's documented recruitment of coactivators; plausible specific binding function. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 binds DNA in a sequence-specific manner via its paired and homeodomain modules; a parent of the Pol II-specific binding terms and a core function. Reason: Correct core molecular function concordant with structural and binding studies. Supporting Evidence: PMID:28473536 Impact of cytosine methylation on DNA binding specificities of human transcription factors |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 positively regulates DNA-templated transcription of target genes; concordant with experimental IDA/IMP. Reason: Correct process term, duplicate of experimentally supported annotations. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes |
| GO:0070410 co-SMAD binding | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 interacts with co-SMAD (SMAD4) and R-SMADs in the TGF-beta pathway; GST pull-downs show PAX6 binds Smad1, 3, 4 and 5. Reason: Supported by direct interaction data (Pax6 interacts with Smad4); correct specific binding function. Supporting Evidence: PMID:17251190 Pax6 interacts with Smad 1, 3, 4 and 5, but not Smad2 |
| GO:0070412 R-SMAD binding | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 binds receptor-regulated SMADs (R-SMADs); the MH1 domain of Smad3 binds the PAX6 paired domain. Reason: Supported by direct GST pull-down/co-IP evidence and duplicates the experimental IPI annotation; correct specific binding function. Supporting Evidence: PMID:17251190 the MH1 domain of Smad3 was observed binding the RED sub-domain of the Pax6 paired domain |
| GO:0071837 HMG box domain binding | IEA GO_REF:0000107 | ACCEPT | Summary: PAX6 cooperates with the HMG-box transcription factor SOX2 on lens-specific enhancers, consistent with HMG box domain binding. Reason: Supported by the well-established PAX6-SOX2 partnership (SOX2 contains an HMG box) and by ISS transfer; plausible specific binding function. Supporting Evidence: PMID:16098226 with SOX2 on the lens-specific enhancer element of the Ξ΄-crystallin gene |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence localizes PAX6 to the nucleoplasm, consistent with its role as a nuclear transcription factor. Reason: Correct subcellular localization supported by IDA immunofluorescence data. Supporting Evidence: PMID:17291498 Pax-6 immunoreactivity was detectable in the nucleus and the cytoplasm of SVZ cells |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:24802670 MiR-135b is a direct PAX6 target and specifies human neuroec... | ACCEPT | Summary: Genome-wide identification of PAX6 binding sites at active enhancers in human neuroectoderm, including the miR-135b locus; direct demonstration of sequence-specific cis-regulatory DNA binding. Reason: Strong experimental (IDA) support for the core DNA-binding molecular function in a human system. Supporting Evidence: PMID:24802670 we identified PAX6 binding sites and active enhancers genome-wide in an in vitro model of human NE development |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:24802670 MiR-135b is a direct PAX6 target and specifies human neuroec... | ACCEPT | Summary: PAX6 directly activates miR-135b transcription through enhancer binding in human neuroectoderm, demonstrating activator activity. Reason: Direct experimental support for the core activator molecular function. Supporting Evidence: PMID:24802670 MiR-135b was activated during NE development, and ectopic expression of miR-135b in hESC promoted differentiation toward NE |
| GO:0007399 nervous system development | IMP PMID:24802670 MiR-135b is a direct PAX6 target and specifies human neuroec... | KEEP AS NON CORE | Summary: PAX6 is critical for human neuroectoderm specification; perturbation alters neural fate commitment via the PAX6-miR-135b module. Reason: Experimentally supported developmental role downstream of the core TF function; retained as non-core for this pleiotropic gene. Supporting Evidence: PMID:24802670 the TF PAX6 was shown to be critical for human NE specification |
| GO:1902895 positive regulation of miRNA transcription | IDA PMID:24802670 MiR-135b is a direct PAX6 target and specifies human neuroec... | ACCEPT | Summary: PAX6 directly binds an active enhancer near miR-135b and activates its transcription during neuroectoderm development. Reason: Specific, experimentally supported process; a precise instance of PAX6 transcriptional activation acting on a miRNA gene. Supporting Evidence: PMID:24802670 MiR-135b is a direct PAX6 target and specifies human neuroectoderm by inhibiting TGF-Ξ²/BMP signaling |
| GO:0001221 transcription coregulator binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer (from mouse Pax6) of coregulator binding; PAX6 binds coactivators/SMADs to modulate transcription. Reason: Concordant with the IEA annotation and supported by documented cofactor interactions; correct molecular function. Supporting Evidence: PMID:17251190 Pax6 co-immunoprecipitated with Smad3 following TGFbeta receptor activation |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of repressor activity from mouse Pax6; PAX6 represses transcription in some contexts (e.g. NFATC1-mediated expression, P1 autoregulation). Reason: Concordant with the IEA negative-regulation annotation and UniProt note; correct. Supporting Evidence: PMID:17251190 represses autoregulation of the Pax6 P1 promoter |
| GO:0000976 transcription cis-regulatory region binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of cis-regulatory region binding; PAX6 binds promoter/enhancer elements of target genes. Core DNA-binding function. Reason: Concordant with experimental binding data and the IEA annotation. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes through specific binding sites |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: High-throughput SELEX/methyl-SELEX measured PAX6 sequence-specific double-stranded DNA binding and the impact of cytosine methylation on its specificity. Reason: Direct biochemical demonstration of the core sequence-specific dsDNA binding activity. Supporting Evidence: PMID:28473536 Impact of cytosine methylation on DNA binding specificities of human transcription factors |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:20592023 Pax6 controls the expression of critical genes involved in p... | ACCEPT | Summary: Loss of PAX6 function (siRNA/dominant-negative) in primary rat alpha cells reduces transcription of glucagon and other target genes, demonstrating positive regulation of Pol II transcription. Reason: Experimentally supported (IMP) activator process; core to PAX6's function in endocrine cells. Supporting Evidence: PMID:20592023 constitutive expression of a dominant-negative form of Pax6 in glucagon-producing cells (InR1G9) inhibits the activities of the promoters |
| GO:0021517 ventral spinal cord development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer of ventral spinal cord development; PAX6 establishes progenitor domains specifying ventral neuron subtypes. Pleiotropic developmental process. Reason: Supported developmental role downstream of the core TF function; retained as non-core. Supporting Evidence: PMID:16098226 The Pax6 gene has a spatially and temporally complex expression pattern in the eye, brain, nasal structures, spinal cord and pancreas |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based DbTF annotation placing PAX6 on chromatin, consistent with its sequence-specific TF role. Reason: Correct cellular component concordant with IDA and IEA chromatin annotations. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass DbTF classification of PAX6 as an RNA Pol II sequence-specific transcription factor; the core molecular function. Reason: Correct core function concordant with IBA, IEA and experimental annotations. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes through specific binding sites |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:20725088 Primate-specific RFPL1 gene controls cell-cycle progression ... | ACCEPT | Summary: PAX6 directly induces transcription of its primate-specific target gene RFPL1; PAX6 gain of function elicits endogenous RFPL1 expression. Reason: Direct experimental support for PAX6 positively regulating transcription of a specific target gene. Supporting Evidence: PMID:20725088 Pax6-elicited expression of the human (h)RFPL1 gene in HeLa cells |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:20592023 Pax6 controls the expression of critical genes involved in p... | ACCEPT | Summary: PAX6 directly binds specific cis-regulatory sites in the promoters of MafB, cMaf and NeuroD1 in primary alpha cells, demonstrating sequence-specific cis-regulatory DNA binding. Reason: Direct experimental (IDA) support for the core DNA-binding molecular function. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes through specific binding sites |
| GO:0019901 protein kinase binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer of protein kinase binding from mouse Pax6. Plausible given PAX6 phosphorylation and kinase interactome data, but peripheral. Reason: Supported by ISS and interactome evidence but not a central characterized function; retained as non-core. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0035035 histone acetyltransferase binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of histone acetyltransferase binding; PAX6 recruits acetyltransferase coactivators for target-gene activation. Reason: Concordant with the IEA annotation and with PAX6's coactivator recruitment; correct specific binding function. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of activator process; PAX6 positively regulates Pol II transcription of target genes, concordant with experimental IMP data. Reason: Correct, concordant with the IMP annotation; core activator process. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes |
| GO:0042593 glucose homeostasis | IMP PMID:11756345 PAX6 mutation as a genetic factor common to aniridia and glu... | KEEP AS NON CORE | Summary: Human PAX6 mutation carriers with aniridia show glucose intolerance with impaired insulin secretion, linking PAX6 to glucose homeostasis via islet-cell function. Reason: Experimentally/clinically supported physiological role downstream of PAX6's control of islet-cell gene expression; a non-core systemic phenotype rather than the core molecular function. Supporting Evidence: PMID:11756345 all of the patients with a PAX6 gene mutation had glucose intolerance characterized by impaired insulin secretion |
| GO:0001568 blood vessel development | IMP PMID:7550230 Three novel aniridia mutations in the human PAX6 gene. | REMOVE | Summary: This IMP cites a clinical aniridia mutation report (Hanson et al. 1995). The cited paper documents PAX6 coding mutations in aniridia/eye malformation; it does not provide evidence that PAX6 functions in blood vessel development. Reason: The supporting reference is an aniridia mutation screen and does not establish a role for PAX6 in blood vessel development. PAX6's vascular involvement is at best indirect (e.g. cornea avascularity defects); this annotation appears to be an inappropriate process assignment not supported by the cited evidence. Supporting Evidence: PMID:7550230 Three novel aniridia mutations in the human PAX6 gene |
| GO:0061072 iris morphogenesis | IMP PMID:7550230 Three novel aniridia mutations in the human PAX6 gene. | KEEP AS NON CORE | Summary: Heterozygous PAX6 loss-of-function mutations cause aniridia (absence/hypoplasia of the iris), directly implicating PAX6 in iris morphogenesis. Reason: Strongly supported by human aniridia genetics; a specific eye-morphogenesis process downstream of PAX6's TF function, retained as non-core. Supporting Evidence: PMID:7550230 Three novel aniridia mutations in the human PAX6 gene |
| GO:0061303 cornea development in camera-type eye | IMP PMID:7550230 Three novel aniridia mutations in the human PAX6 gene. | KEEP AS NON CORE | Summary: PAX6 mutations cause corneal changes (opacity, keratitis, vascularization) within the aniridia/anterior-segment spectrum, implicating PAX6 in corneal development. Reason: Supported by human ocular genetics (PAX6 variants cause corneal/anterior-segment defects); specific developmental process retained as non-core. Supporting Evidence: PMID:7550230 Three novel aniridia mutations in the human PAX6 gene |
| GO:0070412 R-SMAD binding | IPI PMID:17251190 The MH1 domain of Smad3 interacts with Pax6 and represses au... | ACCEPT | Summary: Direct interaction between PAX6 and the R-SMAD Smad3; the MH1 domain of Smad3 binds the RED subdomain of the PAX6 paired domain and inhibits PAX6 DNA binding. Reason: Strong experimental (IPI) support for a specific, functionally meaningful R-SMAD binding activity linking PAX6 to TGF-beta signaling. Supporting Evidence: PMID:17251190 the MH1 domain of Smad3 was observed binding the RED sub-domain of the Pax6 paired domain |
| GO:0000785 chromatin | IDA PMID:20592023 Pax6 controls the expression of critical genes involved in p... | ACCEPT | Summary: ChIP/binding assays place PAX6 on chromatin at target-gene promoters in alpha cells, supporting chromatin localization. Reason: Direct experimental support for chromatin localization of PAX6. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:20592023 Pax6 controls the expression of critical genes involved in p... | ACCEPT | Summary: PAX6 directly binds and activates promoters of MafB, cMaf and NeuroD1 in primary alpha cells, demonstrating sequence-specific Pol II transcription factor activity. Reason: Direct experimental (IDA) support for the core molecular function. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes through specific binding sites |
| GO:0003322 pancreatic A cell development | IMP PMID:20592023 Pax6 controls the expression of critical genes involved in p... | KEEP AS NON CORE | Summary: PAX6 loss-of-function in primary rat alpha cells disrupts the transcriptional program (MafB, cMaf, NeuroD1, proglucagon) required for alpha-cell differentiation and function. Reason: Experimentally supported developmental process downstream of the core TF function; retained as non-core for this pleiotropic gene. Supporting Evidence: PMID:20592023 Pax6 is critical for Ξ± cell function and differentiation through the transcriptional control of key genes |
| GO:0010628 positive regulation of gene expression | IMP PMID:20592023 Pax6 controls the expression of critical genes involved in p... | ACCEPT | Summary: PAX6 loss reduces, and PAX6 activity increases, expression of alpha-cell target genes, demonstrating positive regulation of gene expression. Reason: Experimentally supported broad process, concordant with the activator molecular function. Supporting Evidence: PMID:20592023 Pax6 directly binds and activates the promoter region of the three genes |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:20592023 Pax6 controls the expression of critical genes involved in p... | ACCEPT | Summary: PAX6 positively regulates transcription of glucagon-pathway and alpha-cell differentiation genes; dominant-negative PAX6 reduces promoter activity. Reason: Experimentally supported positive transcriptional regulation; concordant with related annotations. Supporting Evidence: PMID:20592023 constitutive expression of a dominant-negative form of Pax6 in glucagon-producing cells (InR1G9) inhibits the activities of the promoters |
| GO:0050768 negative regulation of neurogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer (from mouse Pax6, UniProt Q99PQ2). PAX6 has context-dependent effects on neurogenesis, including negative regulation of neuroblast proliferation in some domains. Reason: Supported by ISS transfer; a context-specific developmental regulatory role retained as non-core. PAX6 acts as both positive and negative regulator depending on context. Supporting Evidence: PMID:16098226 differentiation of neural cell types from multipotent precursors |
| GO:0009611 response to wounding | IEP PMID:17982423 Stem cell markers in the human posterior limbus and corneal ... | KEEP AS NON CORE | Summary: Pax-6 protein appears as a differentiation marker in the human corneal endothelium and posterior limbus after corneal wounding, an expression-pattern (IEP) correlation. Reason: IEP evidence shows PAX6 expression is induced upon corneal wounding, suggesting involvement in a wound/repair response, but this is correlative rather than a demonstrated mechanistic function; retained as non-core. Supporting Evidence: PMID:17982423 after wounding ... the differentiation markers Pax-6 and Sox-2 were seen |
| GO:0048663 neuron fate commitment | NAS PMID:17291498 Sox-2 is expressed by glial and progenitor cells and Pax-6 i... | KEEP AS NON CORE | Summary: In the adult human subventricular zone, Pax-6 marks neuroblasts and is proposed to specify a neuronal fate, supporting a role in neuron fate commitment (non-traceable author statement). Reason: NAS-level support for a developmental neuronal fate-specification role downstream of the core TF function; retained as non-core. Supporting Evidence: PMID:17291498 Sox-2 and Pax-6 specify a glial and neuronal fate, respectively |
| GO:0005634 nucleus | IDA PMID:17291498 Sox-2 is expressed by glial and progenitor cells and Pax-6 i... | ACCEPT | Summary: Immunostaining detects Pax-6 in the nucleus of human SVZ cells, consistent with its TF function. Reason: Direct experimental support for nuclear localization. Supporting Evidence: PMID:17291498 Pax-6 immunoreactivity was detectable in the nucleus and the cytoplasm of SVZ cells |
| GO:0005737 cytoplasm | IDA PMID:17291498 Sox-2 is expressed by glial and progenitor cells and Pax-6 i... | KEEP AS NON CORE | Summary: Immunostaining detects Pax-6 in both nucleus and cytoplasm of human SVZ cells. Cytoplasmic PAX6 may reflect a paired-less isoform and/or shuttling, but PAX6 functions in the nucleus. Reason: Cytoplasmic localization is observed (IDA) and may correspond to specific isoforms or a regulatory pool, but it is not the site of PAX6's core transcriptional function; retained as non-core localization. Supporting Evidence: PMID:17291498 Pax-6 immunoreactivity was detectable in the nucleus and the cytoplasm of SVZ cells |
| GO:0001654 eye development | TAS PMID:10747901 Modulation of PAX6 homeodomain function by the paired domain... | KEEP AS NON CORE | Summary: PAX6 is the master regulator of eye development, established by human aniridia genetics and cross-species studies; the homeodomain and paired domain cooperate in DNA binding. Reason: Signature, well-supported developmental process downstream of the core TF function; retained as non-core relative to the molecular DNA-binding TF activity. Supporting Evidence: PMID:10747901 Modulation of PAX6 homeodomain function by the paired domain |
| GO:0009887 animal organ morphogenesis | TAS PMID:10441571 Missense mutation in the alternative splice region of the PA... | MARK AS OVER ANNOTATED | Summary: Broad organ-morphogenesis term; PAX6 drives morphogenesis of the eye and other organs, but this term is uninformatively general. Reason: Correct at a high level but superseded by specific eye/iris/cornea morphogenesis annotations; adds little functional specificity. Supporting Evidence: PMID:10441571 Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies |
| GO:0003677 DNA binding | TAS PMID:10441571 Missense mutation in the alternative splice region of the PA... | KEEP AS NON CORE | Summary: PAX6 binds DNA via its paired and homeodomain modules; alternative splicing of the paired domain modulates DNA-binding specificity. Reason: Correct but general; superseded by the sequence-specific Pol II DNA-binding terms that better represent the core function. Supporting Evidence: PMID:10441571 Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:10441571 Missense mutation in the alternative splice region of the PA... | ACCEPT | Summary: PAX6 is a DNA-binding transcription factor; mutations affecting the splice region alter paired-domain function and cause eye anomalies. Reason: Correct core molecular function supported by author statement; concordant with all other TF-activity annotations. Supporting Evidence: PMID:10441571 Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies |
| GO:0003700 DNA-binding transcription factor activity | TAS PMID:10747901 Modulation of PAX6 homeodomain function by the paired domain... | ACCEPT | Summary: PAX6 is a DNA-binding transcription factor whose homeodomain function is modulated by the paired domain. Reason: Correct core molecular function; duplicate TAS annotation from an independent reference. Supporting Evidence: PMID:10747901 Modulation of PAX6 homeodomain function by the paired domain |
| GO:0007417 central nervous system development | TAS PMID:10747901 Modulation of PAX6 homeodomain function by the paired domain... | KEEP AS NON CORE | Summary: PAX6 is required for central nervous system development; the paired domain and homeodomain cooperate in regulating CNS target genes. Reason: Well-supported developmental process downstream of the core TF function; retained as non-core. Supporting Evidence: PMID:10747901 Modulation of PAX6 homeodomain function by the paired domain |
| GO:0007601 visual perception | TAS PMID:10441571 Missense mutation in the alternative splice region of the PA... | KEEP AS NON CORE | Summary: PAX6 variants cause eye anomalies with reduced visual acuity; the link to visual perception is via PAX6's developmental role in building the visual apparatus rather than a direct role in perception physiology. Reason: Defects in visual perception in PAX6 patients are a downstream consequence of abnormal eye development. Retained as a non-core phenotype-associated process rather than a core function (PAX6 is not a phototransduction component). Supporting Evidence: PMID:10441571 Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies |
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Download this section (compressed HTML)Q: Should PAX6 be considered a pioneer transcription factor, and if so, would a pioneer activity term better capture its ability to access closed chromatin at developmental enhancers?
Suggested experts: van Heyningen V, Kleinjan DA
Q: Are the cytoplasmic PAX6 pools observed in some tissues attributable to specific isoforms (e.g. paired-less forms) and do they have a distinct, non-transcriptional function warranting separate annotation?
Suggested experts: Cooper ST, Hanson IM
Experiment: Perform comparative ChIP-seq/CUT&RUN for PAX6 across isogenic human eye, cortical and pancreatic-endocrine cell models differentiated from the same iPSC line, integrated with chromatin accessibility and transcriptomics.
Hypothesis: PAX6 binds distinct enhancer repertoires in eye, forebrain and pancreatic-islet lineages, explaining its pleiotropic developmental functions through context-specific cis-regulatory targeting.
Type: genome-wide DNA-binding and transcriptomic profiling
Experiment: Use degron-controlled titration of PAX6 levels combined with TGF-beta pathway modulation in human lens/neuroectoderm models, measuring target-gene activation as a function of PAX6 dose and SMAD activity.
Hypothesis: The PAX6-SMAD interaction sets a quantitative threshold on PAX6 target-gene activation that is dosage-sensitive and relevant to aniridia haploinsufficiency.
Type: quantitative gene-regulation/dosage assay
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