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 | TOO GENERAL | Summary: ARBA machine-learning prediction of nervous system process, a physiological process term. PAX6 is a developmental transcription factor, and the broad term is entailed only through the visual perception annotation kept in this review. Reason: Nervous system process is entailed by the visual perception annotation kept in this review, so the broad machine-generated term is consistent with a kept row and cannot be removed while that row stands. It adds nothing to it; the roles of PAX6 in the nervous system are developmental and are captured by specific terms. It is recorded as too general. 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... | REMOVE | 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: Bare "protein binding" is uninformative. The yeast two-hybrid interactions with HOMER3, DNCL1 and TRIM11 are not shown to define a PAX6 molecular activity (the paper proposes possible roles in transport/turnover but does not establish an adaptor or coregulator function), so no more informative MF term is supported. Removal does not mean the interactions are false. 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. | REMOVE | 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 binary interactome map; the partners are not individually validated for PAX6 biology and no more informative molecular function is supported. Removal does not mean the interactions are false. 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 | KEEP AS NON CORE | Summary: Ensembl-projected "RNA binding", transferred from the mouse Pax6 IDA annotation (PMID:24488179), in which the lncRNA Paupar physically associates with PAX6 protein in neural cells. PAX6 is primarily a DNA-binding transcription factor. Reason: Revised from REMOVE for consistency with the mouse Pax6 review (ortholog audit 2026-10-12). The source of this projection is an experimental mouse annotation (RNA immunoprecipitation of the Paupar lncRNA with PAX6), so the earlier statement that there is no experimental support was incorrect. The PAX6-Paupar association is a peripheral property rather than a core RNA-binding molecular function, so it is kept as non-core rather than accepted. Supporting Evidence: PMID:24488179 in part through physical association with PAX6 protein |
| 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 | KEEP AS NON CORE | Summary: PAX6 interacts with the E3 ubiquitin ligase TRIM11, which ubiquitinates PAX6 and targets it for proteasomal degradation. Reason: Revised from ACCEPT for consistency with the mouse Pax6 review (ortholog audit 2026-10-12). The interaction with TRIM11 is experimentally supported (interaction screen and the mouse Trim11 study from which this Ensembl projection derives), but PAX6 is the ubiquitination substrate; binding an E3 ligase is not part of its core transcription-factor function, so it is kept as non-core. Supporting Evidence: PMID:16098226 the tripartite motif protein TRIM11 PMID:18628401 Trim11, a member of the TRIM/RBCC protein family of E3 ubiquitin ligases, interacts with Pax6 |
| 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 | MARK AS OVER ANNOTATED | Summary: Co-SMAD binding (IEA), transferred from the rodent ortholog, where binding of Pax6 to Smad4 was seen in vitro but not confirmed in cells (PMID:17251190). Reason: The row is transferred from the rodent ortholog, annotated by direct assay in a study that detected binding of Pax6 to the co-SMAD Smad4 in vitro (PMID:17251190), so an experimental observation lies behind it. As this review records, that interaction was seen only in vitro and was not confirmed in cells, whereas the interaction with Smad3 was validated and is captured by the R-SMAD binding annotation. An in vitro interaction of unconfirmed relevance is an over-annotation rather than a false statement, and is marked rather than removed. Supporting Evidence: PMID:17251190 These data serve to validate the interaction of Smad3, and non-interaction of Smad2 with Pax6, while invalidating the Smad4 interaction that was observed only in vitro |
| 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. | MARK AS OVER ANNOTATED | Summary: Blood vessel development (IMP) from a study of PAX6 mutations in aniridia patients (PMID:7550230; abstract only); vascular involvement in PAX6 deficiency is an indirect consequence of defective eye development. Reason: The row is a mutant-phenotype annotation from a study of PAX6 mutations in aniridia patients, of which only the abstract is available, so the phenotype on which the curator relied could not be examined. Vascular abnormalities in PAX6 haploinsufficiency, such as loss of corneal avascularity, are indirect consequences of defective eye development rather than evidence that the transcription factor acts in blood vessel development. The term over-reads a disease phenotype; it is not contradicted, so it is marked as an over-annotation rather than removed. 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 |
Loading supporting contentβ¦
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
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)