id: P26367
gene_symbol: PAX6
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
existing_annotations:
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase
        II-specific
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Furthermore, we demonstrate that Pax6 directly binds and activates the
            promoter region of the three genes through specific binding sites
        - reference_id: file:human/PAX6/PAX6-deep-research-falcon.md
          supporting_text: 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
  - term:
      id: GO:0003309
      label: type B pancreatic cell differentiation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: homozygous mutant mice for Pax6 are characterized by markedly decreased
            β and δ cells and absent α cells
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      reason: Directly supported by experimental promoter binding/regulation studies and is the
        general process underlying PAX6's function; appropriate IBA-level annotation.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 controls the transcription of the Proglucagon and processing enzyme
            PC2 genes
  - term:
      id: GO:0007420
      label: brain development
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PAX6 is required for normal brain development; homozygous loss causes gross brain
        malformations and heterozygous human variants are associated with cerebral anomalies.
      action: KEEP_AS_NON_CORE
      reason: Strongly supported pleiotropic developmental process, downstream of the core TF
        activity; appropriate to retain as a non-core biological role.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: 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
  - term:
      id: GO:0007423
      label: sensory organ development
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:11756345
          supporting_text: PAX6, is a well-known regulator of eye development
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA
        binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      reason: This is the precise DNA-binding activity of PAX6, supported by direct binding studies
        and phylogenetic inference; ideal level of specificity.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: we identified PAX6 binding sites and active enhancers genome-wide in an
            in vitro model of human NE development
  - term:
      id: GO:0030900
      label: forebrain development
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PAX6 patterns the developing forebrain and cerebral cortex, with gradients important
        for cortical arealisation. Pleiotropic developmental process.
      action: KEEP_AS_NON_CORE
      reason: Well-supported downstream developmental role; retained as non-core relative to PAX6's
        core TF molecular function.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: common themes are now emerging concerning the role of PAX6 in neural
            tissues
  - term:
      id: GO:0060041
      label: retina development in camera-type eye
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PAX6 is essential for retinal progenitor competence and retinal development in the
        camera-type eye. Pleiotropic developmental process.
      action: KEEP_AS_NON_CORE
      reason: Strongly supported eye-development role downstream of the core TF function; retained as
        non-core.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: Gradients of Pax6 expression are important for determining positional
            characteristics in the retina
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase
        II-specific
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Electronic annotation duplicating the core RNA Pol II DNA-binding transcription factor
        activity, consistent with IBA and experimental evidence.
      action: ACCEPT
      reason: Correct and concordant with manually supported annotations; duplicate of the core MF.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
            through specific binding sites
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:10747901
          supporting_text: Modulation of PAX6 homeodomain function by the paired domain
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: PAX6 is a nuclear transcription factor; nuclear localization is documented by
        immunofluorescence and inferred from its function.
      action: ACCEPT
      reason: Correct subcellular localization consistent with UniProt and experimental IDA data.
      supported_by:
        - reference_id: PMID:17291498
          supporting_text: Pax-6 immunoreactivity was detectable in the nucleus and the cytoplasm of
            SVZ cells
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Broad transcriptional-regulation process inferred from paired/homeodomain InterPro
        records; subsumed by the more specific RNA Pol II regulation annotations.
      action: ACCEPT
      reason: Correct parent-level process term; concordant with experimental data, acceptable as a
        broad electronic annotation.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 controls the transcription of the Proglucagon and processing enzyme
            PC2 genes
  - term:
      id: GO:0007417
      label: central nervous system development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: PAX6 is required for CNS development including cortex and spinal cord patterning.
        Pleiotropic developmental process.
      action: KEEP_AS_NON_CORE
      reason: Well-supported but broad developmental role downstream of the core TF function.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: The PAX6 protein is a member of the PAX (paired-box) family of
            transcriptional regulators and is essential for normal ocular and neural development
  - term:
      id: GO:0009653
      label: anatomical structure morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:7550230
          supporting_text: Three novel aniridia mutations in the human PAX6 gene
  - term:
      id: GO:0030154
      label: cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Generic cell-differentiation term from a Swiss-Prot keyword mapping. PAX6 drives
        differentiation of multiple lineages but this term is non-specific.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 is critical for α cell function and differentiation
  - term:
      id: GO:0043010
      label: camera-type eye development
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: PAX6 is the master regulator of camera-type eye development, a hallmark function
        established across vertebrates and by human aniridia genetics.
      action: KEEP_AS_NON_CORE
      reason: Strongly supported, signature developmental process; retained as non-core relative to
        the molecular DNA-binding TF function.
      supported_by:
        - reference_id: PMID:11756345
          supporting_text: PAX6, is a well-known regulator of eye development
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: PAX6 acts as a transcriptional activator at RNA Pol II promoters/enhancers, directly
        demonstrated for pancreatic alpha-cell genes and miR-135b.
      action: ACCEPT
      reason: Concordant with experimental IMP/IDA/ISS annotations; correct activator activity.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
            through specific binding sites
  - term:
      id: GO:0050877
      label: nervous system process
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      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.
      action: REMOVE
      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.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: essential for normal ocular and neural development
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16098226
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: Three novel PAX6-interacting proteins were identified the post-synaptic
            density (PSD) protein HOMER3, the dynein subunit DNCL1, and the tripartite motif protein
            TRIM11
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: High-throughput binary interactome (HuRI) interactions. Bare "protein binding" with
        many partners from a single large-scale screen provides little functional insight.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: A reference map of the human binary protein interactome
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: ACCEPT
      reason: Concordant with the ISS annotation and UniProt functional notes; PAX6 has documented
        repressor activity at Pol II promoters.
      supported_by:
        - reference_id: PMID:17251190
          supporting_text: the MH1 domain of Smad3 binds to the paired domain of Pax6 releasing it
            from its own promoter-binding site
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      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.
      action: ACCEPT
      reason: Correct cellular component for a sequence-specific TF, concordant with the IDA and ISA
        chromatin annotations.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region
  - term:
      id: GO:0000976
      label: transcription cis-regulatory region binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: ACCEPT
      reason: Correct and concordant with ISS and experimental binding data.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: PAX6 binding to active enhancers was found in the proximity of several
            microRNAs, including hsa-miR-135b
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA
        binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Electronic duplicate of the core sequence-specific Pol II cis-regulatory DNA-binding
        activity, supported by IBA and experimental IDA.
      action: ACCEPT
      reason: Correct core molecular function; duplicates manually supported annotations.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: we identified PAX6 binding sites and active enhancers genome-wide
  - term:
      id: GO:0000979
      label: RNA polymerase II core promoter sequence-specific DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
            through specific binding sites
  - term:
      id: GO:0001221
      label: transcription coregulator binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 binds transcriptional coregulators/cofactors (e.g. histone acetyltransferases,
        SMADs, MAF proteins) to modulate target-gene transcription.
      action: ACCEPT
      reason: Concordant with the ISS annotation and with documented interactions with coactivators
        and SMAD/MAF partners.
      supported_by:
        - reference_id: PMID:17251190
          supporting_text: Pax6 co-immunoprecipitated with Smad3 following TGFbeta receptor activation
  - term:
      id: GO:0001227
      label: DNA-binding transcription repressor activity, RNA polymerase
        II-specific
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 has context-dependent repressor activity at RNA Pol II genes, consistent with its
        dual activator/repressor behavior.
      action: ACCEPT
      reason: Supported by UniProt note (represses NFATC1-mediated expression) and the negative
        regulation annotations; correct specific repressor MF.
      supported_by:
        - reference_id: PMID:17251190
          supporting_text: represses autoregulation of the Pax6 P1 promoter
  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase
        II-specific
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 acts as a sequence-specific transcriptional activator at RNA Pol II genes,
        directly demonstrated for miR-135b and alpha-cell genes.
      action: ACCEPT
      reason: Concordant with experimental IDA annotations; a core activator molecular function.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: MiR-135b is a direct PAX6 target
  - term:
      id: GO:0003322
      label: pancreatic A cell development
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: PAX6 is required for pancreatic alpha (A) cell development and glucagon-gene control;
        Pax6 nulls lack alpha cells.
      action: KEEP_AS_NON_CORE
      reason: Well-supported developmental process (also captured by experimental IMP) but downstream
        of the core TF function for this pleiotropic gene.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: homozygous mutant mice for Pax6 are characterized by markedly decreased β
            and δ cells and absent α cells
  - term:
      id: GO:0003682
      label: chromatin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 binds chromatin to regulate transcription, consistent with its chromatin
        localization and genome-wide binding profiles.
      action: ACCEPT
      reason: Correct molecular function for a chromatin-acting TF; concordant with chromatin CC and
        binding data.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: PAX6 binding to active enhancers
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: General DNA-binding transcription factor activity, the parent of the RNA Pol
        II-specific term; the core function of PAX6.
      action: ACCEPT
      reason: Correct, concordant with TAS and IBA annotations; an acceptable parent-level statement
        of the core molecular function.
      supported_by:
        - reference_id: PMID:10441571
          supporting_text: Missense mutation in the alternative splice region of the PAX6 gene in eye
            anomalies
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: REMOVE
      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.
      supported_by:
        - reference_id: PMID:10747901
          supporting_text: Modulation of PAX6 homeodomain function by the paired domain
  - term:
      id: GO:0006338
      label: chromatin remodeling
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Ensembl-projected "chromatin remodeling". PAX6 binds chromatin and recruits cofactors
        but is not itself an ATP-dependent chromatin-remodeling enzyme.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: we identified PAX6 binding sites and active enhancers genome-wide
  - term:
      id: GO:0007399
      label: nervous system development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 is essential for nervous system development, supported by experimental IMP and
        broad genetics. Pleiotropic developmental process.
      action: KEEP_AS_NON_CORE
      reason: Well-supported developmental role downstream of the core TF function; duplicate of the
        experimentally supported IMP annotation.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: PAX6 was shown to be critical for human NE specification
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: PAX6 positively regulates expression of target genes; broad process term concordant
        with its activator activity.
      action: ACCEPT
      reason: Correct and concordant with the experimental IMP annotation; acceptable broad process.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: A reference map of the human binary protein interactome
  - term:
      id: GO:0021517
      label: ventral spinal cord development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 specifies ventral neuron subtypes by establishing progenitor domains in the
        spinal cord. Pleiotropic developmental process.
      action: KEEP_AS_NON_CORE
      reason: Supported by ISS and UniProt functional note; downstream developmental role retained as
        non-core.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: The Pax6 gene has a spatially and temporally complex expression pattern in
            the eye, brain, nasal structures, spinal cord and pancreas
  - term:
      id: GO:0021987
      label: cerebral cortex development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 controls cortical neurogenesis and arealisation of the cerebral cortex.
        Pleiotropic developmental process.
      action: KEEP_AS_NON_CORE
      reason: Well-supported cortical-development role downstream of the core TF function.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: roles of PAX6 in brain development ... include arealisation of the cerebral
            cortex
  - term:
      id: GO:0030182
      label: neuron differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 promotes differentiation of neurons from multipotent precursors via activation of
        proneural bHLH genes (e.g. Ngn2). Pleiotropic developmental process.
      action: KEEP_AS_NON_CORE
      reason: Well-supported neuronal differentiation role downstream of the core TF function.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: It is also involved in the differentiation of neural cell types from
            multipotent precursors
  - term:
      id: GO:0031490
      label: chromatin DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 binds chromatinized DNA at regulatory regions; consistent with its
        chromatin/cis-regulatory binding profile.
      action: ACCEPT
      reason: Correct molecular function concordant with chromatin binding and genome-wide
        occupancy data.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: PAX6 binding to active enhancers
  - term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 interacts with the E3 ubiquitin ligase TRIM11, which ubiquitinates PAX6 and
        targets it for proteasomal degradation.
      action: ACCEPT
      reason: Supported by the experimental interaction screen (TRIM11) and UniProt PTM note; correct
        specific binding function.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: the tripartite motif protein TRIM11
  - term:
      id: GO:0035035
      label: histone acetyltransferase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 binds histone acetyltransferase coactivators to activate transcription;
        concordant with the ISS annotation.
      action: ACCEPT
      reason: Supported by ISS transfer and by PAX6's documented recruitment of coactivators;
        plausible specific binding function.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: ACCEPT
      reason: Correct core molecular function concordant with structural and binding studies.
      supported_by:
        - reference_id: PMID:28473536
          supporting_text: Impact of cytosine methylation on DNA binding specificities of human
            transcription factors
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 positively regulates DNA-templated transcription of target genes; concordant with
        experimental IDA/IMP.
      action: ACCEPT
      reason: Correct process term, duplicate of experimentally supported annotations.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
  - term:
      id: GO:0070410
      label: co-SMAD binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: ACCEPT
      reason: Supported by direct interaction data (Pax6 interacts with Smad4); correct specific
        binding function.
      supported_by:
        - reference_id: PMID:17251190
          supporting_text: Pax6 interacts with Smad 1, 3, 4 and 5, but not Smad2
  - term:
      id: GO:0070412
      label: R-SMAD binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 binds receptor-regulated SMADs (R-SMADs); the MH1 domain of Smad3 binds the PAX6
        paired domain.
      action: ACCEPT
      reason: Supported by direct GST pull-down/co-IP evidence and duplicates the experimental IPI
        annotation; correct specific binding function.
      supported_by:
        - reference_id: PMID:17251190
          supporting_text: the MH1 domain of Smad3 was observed binding the RED sub-domain of the Pax6
            paired domain
  - term:
      id: GO:0071837
      label: HMG box domain binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: PAX6 cooperates with the HMG-box transcription factor SOX2 on lens-specific enhancers,
        consistent with HMG box domain binding.
      action: ACCEPT
      reason: Supported by the well-established PAX6-SOX2 partnership (SOX2 contains an HMG box) and by
        ISS transfer; plausible specific binding function.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: with SOX2 on the lens-specific enhancer element of the δ-crystallin gene
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: HPA immunofluorescence localizes PAX6 to the nucleoplasm, consistent with its role as a
        nuclear transcription factor.
      action: ACCEPT
      reason: Correct subcellular localization supported by IDA immunofluorescence data.
      supported_by:
        - reference_id: PMID:17291498
          supporting_text: Pax-6 immunoreactivity was detectable in the nucleus and the cytoplasm of
            SVZ cells
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA
        binding
    evidence_type: IDA
    original_reference_id: PMID:24802670
    review:
      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.
      action: ACCEPT
      reason: Strong experimental (IDA) support for the core DNA-binding molecular function in a human
        system.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: we identified PAX6 binding sites and active enhancers genome-wide in an in
            vitro model of human NE development
  - term:
      id: GO:0001228
      label: DNA-binding transcription activator activity, RNA polymerase
        II-specific
    evidence_type: IDA
    original_reference_id: PMID:24802670
    review:
      summary: PAX6 directly activates miR-135b transcription through enhancer binding in human
        neuroectoderm, demonstrating activator activity.
      action: ACCEPT
      reason: Direct experimental support for the core activator molecular function.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: MiR-135b was activated during NE development, and ectopic expression of
            miR-135b in hESC promoted differentiation toward NE
  - term:
      id: GO:0007399
      label: nervous system development
    evidence_type: IMP
    original_reference_id: PMID:24802670
    review:
      summary: PAX6 is critical for human neuroectoderm specification; perturbation alters neural fate
        commitment via the PAX6-miR-135b module.
      action: KEEP_AS_NON_CORE
      reason: Experimentally supported developmental role downstream of the core TF function; retained
        as non-core for this pleiotropic gene.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: the TF PAX6 was shown to be critical for human NE specification
  - term:
      id: GO:1902895
      label: positive regulation of miRNA transcription
    evidence_type: IDA
    original_reference_id: PMID:24802670
    review:
      summary: PAX6 directly binds an active enhancer near miR-135b and activates its transcription
        during neuroectoderm development.
      action: ACCEPT
      reason: Specific, experimentally supported process; a precise instance of PAX6 transcriptional
        activation acting on a miRNA gene.
      supported_by:
        - reference_id: PMID:24802670
          supporting_text: MiR-135b is a direct PAX6 target and specifies human neuroectoderm by
            inhibiting TGF-β/BMP signaling
  - term:
      id: GO:0001221
      label: transcription coregulator binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS transfer (from mouse Pax6) of coregulator binding; PAX6 binds coactivators/SMADs to
        modulate transcription.
      action: ACCEPT
      reason: Concordant with the IEA annotation and supported by documented cofactor interactions;
        correct molecular function.
      supported_by:
        - reference_id: PMID:17251190
          supporting_text: Pax6 co-immunoprecipitated with Smad3 following TGFbeta receptor activation
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS transfer of repressor activity from mouse Pax6; PAX6 represses transcription in some
        contexts (e.g. NFATC1-mediated expression, P1 autoregulation).
      action: ACCEPT
      reason: Concordant with the IEA negative-regulation annotation and UniProt note; correct.
      supported_by:
        - reference_id: PMID:17251190
          supporting_text: represses autoregulation of the Pax6 P1 promoter
  - term:
      id: GO:0000976
      label: transcription cis-regulatory region binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS transfer of cis-regulatory region binding; PAX6 binds promoter/enhancer elements of
        target genes. Core DNA-binding function.
      action: ACCEPT
      reason: Concordant with experimental binding data and the IEA annotation.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
            through specific binding sites
  - term:
      id: GO:1990837
      label: sequence-specific double-stranded DNA binding
    evidence_type: IDA
    original_reference_id: PMID:28473536
    review:
      summary: High-throughput SELEX/methyl-SELEX measured PAX6 sequence-specific double-stranded DNA
        binding and the impact of cytosine methylation on its specificity.
      action: ACCEPT
      reason: Direct biochemical demonstration of the core sequence-specific dsDNA binding activity.
      supported_by:
        - reference_id: PMID:28473536
          supporting_text: Impact of cytosine methylation on DNA binding specificities of human
            transcription factors
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:20592023
    review:
      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.
      action: ACCEPT
      reason: Experimentally supported (IMP) activator process; core to PAX6's function in endocrine
        cells.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: constitutive expression of a dominant-negative form of Pax6 in
            glucagon-producing cells (InR1G9) inhibits the activities of the promoters
  - term:
      id: GO:0021517
      label: ventral spinal cord development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS transfer of ventral spinal cord development; PAX6 establishes progenitor domains
        specifying ventral neuron subtypes. Pleiotropic developmental process.
      action: KEEP_AS_NON_CORE
      reason: Supported developmental role downstream of the core TF function; retained as non-core.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: The Pax6 gene has a spatially and temporally complex expression pattern in
            the eye, brain, nasal structures, spinal cord and pancreas
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: ISA
    original_reference_id: GO_REF:0000113
    review:
      summary: TFClass-based DbTF annotation placing PAX6 on chromatin, consistent with its
        sequence-specific TF role.
      action: ACCEPT
      reason: Correct cellular component concordant with IDA and IEA chromatin annotations.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase
        II-specific
    evidence_type: ISA
    original_reference_id: GO_REF:0000113
    review:
      summary: TFClass DbTF classification of PAX6 as an RNA Pol II sequence-specific transcription
        factor; the core molecular function.
      action: ACCEPT
      reason: Correct core function concordant with IBA, IEA and experimental annotations.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
            through specific binding sites
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:20725088
    review:
      summary: PAX6 directly induces transcription of its primate-specific target gene RFPL1; PAX6
        gain of function elicits endogenous RFPL1 expression.
      action: ACCEPT
      reason: Direct experimental support for PAX6 positively regulating transcription of a specific
        target gene.
      supported_by:
        - reference_id: PMID:20725088
          supporting_text: Pax6-elicited expression of the human (h)RFPL1 gene in HeLa cells
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA
        binding
    evidence_type: IDA
    original_reference_id: PMID:20592023
    review:
      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.
      action: ACCEPT
      reason: Direct experimental (IDA) support for the core DNA-binding molecular function.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
            through specific binding sites
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS transfer of protein kinase binding from mouse Pax6. Plausible given PAX6
        phosphorylation and kinase interactome data, but peripheral.
      action: KEEP_AS_NON_CORE
      reason: Supported by ISS and interactome evidence but not a central characterized function;
        retained as non-core.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: A reference map of the human binary protein interactome
  - term:
      id: GO:0035035
      label: histone acetyltransferase binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS transfer of histone acetyltransferase binding; PAX6 recruits acetyltransferase
        coactivators for target-gene activation.
      action: ACCEPT
      reason: Concordant with the IEA annotation and with PAX6's coactivator recruitment; correct
        specific binding function.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS transfer of activator process; PAX6 positively regulates Pol II transcription of
        target genes, concordant with experimental IMP data.
      action: ACCEPT
      reason: Correct, concordant with the IMP annotation; core activator process.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
  - term:
      id: GO:0042593
      label: glucose homeostasis
    evidence_type: IMP
    original_reference_id: PMID:11756345
    review:
      summary: Human PAX6 mutation carriers with aniridia show glucose intolerance with impaired
        insulin secretion, linking PAX6 to glucose homeostasis via islet-cell function.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:11756345
          supporting_text: all of the patients with a PAX6 gene mutation had glucose intolerance
            characterized by impaired insulin secretion
  - term:
      id: GO:0001568
      label: blood vessel development
    evidence_type: IMP
    original_reference_id: PMID:7550230
    review:
      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.
      action: REMOVE
      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.
      supported_by:
        - reference_id: PMID:7550230
          supporting_text: Three novel aniridia mutations in the human PAX6 gene
  - term:
      id: GO:0061072
      label: iris morphogenesis
    evidence_type: IMP
    original_reference_id: PMID:7550230
    review:
      summary: Heterozygous PAX6 loss-of-function mutations cause aniridia (absence/hypoplasia of the
        iris), directly implicating PAX6 in iris morphogenesis.
      action: KEEP_AS_NON_CORE
      reason: Strongly supported by human aniridia genetics; a specific eye-morphogenesis process
        downstream of PAX6's TF function, retained as non-core.
      supported_by:
        - reference_id: PMID:7550230
          supporting_text: Three novel aniridia mutations in the human PAX6 gene
  - term:
      id: GO:0061303
      label: cornea development in camera-type eye
    evidence_type: IMP
    original_reference_id: PMID:7550230
    review:
      summary: PAX6 mutations cause corneal changes (opacity, keratitis, vascularization) within the
        aniridia/anterior-segment spectrum, implicating PAX6 in corneal development.
      action: KEEP_AS_NON_CORE
      reason: Supported by human ocular genetics (PAX6 variants cause corneal/anterior-segment
        defects); specific developmental process retained as non-core.
      supported_by:
        - reference_id: PMID:7550230
          supporting_text: Three novel aniridia mutations in the human PAX6 gene
  - term:
      id: GO:0070412
      label: R-SMAD binding
    evidence_type: IPI
    original_reference_id: PMID:17251190
    review:
      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.
      action: ACCEPT
      reason: Strong experimental (IPI) support for a specific, functionally meaningful R-SMAD binding
        activity linking PAX6 to TGF-beta signaling.
      supported_by:
        - reference_id: PMID:17251190
          supporting_text: the MH1 domain of Smad3 was observed binding the RED sub-domain of the Pax6
            paired domain
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: IDA
    original_reference_id: PMID:20592023
    review:
      summary: ChIP/binding assays place PAX6 on chromatin at target-gene promoters in alpha cells,
        supporting chromatin localization.
      action: ACCEPT
      reason: Direct experimental support for chromatin localization of PAX6.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase
        II-specific
    evidence_type: IDA
    original_reference_id: PMID:20592023
    review:
      summary: PAX6 directly binds and activates promoters of MafB, cMaf and NeuroD1 in primary alpha
        cells, demonstrating sequence-specific Pol II transcription factor activity.
      action: ACCEPT
      reason: Direct experimental (IDA) support for the core molecular function.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
            through specific binding sites
  - term:
      id: GO:0003322
      label: pancreatic A cell development
    evidence_type: IMP
    original_reference_id: PMID:20592023
    review:
      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.
      action: KEEP_AS_NON_CORE
      reason: Experimentally supported developmental process downstream of the core TF function;
        retained as non-core for this pleiotropic gene.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 is critical for α cell function and differentiation through the
            transcriptional control of key genes
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:20592023
    review:
      summary: PAX6 loss reduces, and PAX6 activity increases, expression of alpha-cell target genes,
        demonstrating positive regulation of gene expression.
      action: ACCEPT
      reason: Experimentally supported broad process, concordant with the activator molecular function.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: Pax6 directly binds and activates the promoter region of the three genes
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IMP
    original_reference_id: PMID:20592023
    review:
      summary: PAX6 positively regulates transcription of glucagon-pathway and alpha-cell
        differentiation genes; dominant-negative PAX6 reduces promoter activity.
      action: ACCEPT
      reason: Experimentally supported positive transcriptional regulation; concordant with related
        annotations.
      supported_by:
        - reference_id: PMID:20592023
          supporting_text: constitutive expression of a dominant-negative form of Pax6 in
            glucagon-producing cells (InR1G9) inhibits the activities of the promoters
  - term:
      id: GO:0050768
      label: negative regulation of neurogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ISS transfer (from mouse Pax6, UniProt Q99PQ2). PAX6 has context-dependent effects on
        neurogenesis, including negative regulation of neuroblast proliferation in some domains.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:16098226
          supporting_text: differentiation of neural cell types from multipotent precursors
  - term:
      id: GO:0009611
      label: response to wounding
    evidence_type: IEP
    original_reference_id: PMID:17982423
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:17982423
          supporting_text: after wounding ... the differentiation markers Pax-6 and Sox-2 were seen
  - term:
      id: GO:0048663
      label: neuron fate commitment
    evidence_type: NAS
    original_reference_id: PMID:17291498
    review:
      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).
      action: KEEP_AS_NON_CORE
      reason: NAS-level support for a developmental neuronal fate-specification role downstream of the
        core TF function; retained as non-core.
      supported_by:
        - reference_id: PMID:17291498
          supporting_text: Sox-2 and Pax-6 specify a glial and neuronal fate, respectively
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17291498
    review:
      summary: Immunostaining detects Pax-6 in the nucleus of human SVZ cells, consistent with its TF
        function.
      action: ACCEPT
      reason: Direct experimental support for nuclear localization.
      supported_by:
        - reference_id: PMID:17291498
          supporting_text: Pax-6 immunoreactivity was detectable in the nucleus and the cytoplasm of
            SVZ cells
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:17291498
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:17291498
          supporting_text: Pax-6 immunoreactivity was detectable in the nucleus and the cytoplasm of
            SVZ cells
  - term:
      id: GO:0001654
      label: eye development
    evidence_type: TAS
    original_reference_id: PMID:10747901
    review:
      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.
      action: KEEP_AS_NON_CORE
      reason: Signature, well-supported developmental process downstream of the core TF function;
        retained as non-core relative to the molecular DNA-binding TF activity.
      supported_by:
        - reference_id: PMID:10747901
          supporting_text: Modulation of PAX6 homeodomain function by the paired domain
  - term:
      id: GO:0009887
      label: animal organ morphogenesis
    evidence_type: TAS
    original_reference_id: PMID:10441571
    review:
      summary: Broad organ-morphogenesis term; PAX6 drives morphogenesis of the eye and other organs,
        but this term is uninformatively general.
      action: MARK_AS_OVER_ANNOTATED
      reason: Correct at a high level but superseded by specific eye/iris/cornea morphogenesis
        annotations; adds little functional specificity.
      supported_by:
        - reference_id: PMID:10441571
          supporting_text: Missense mutation in the alternative splice region of the PAX6 gene in eye
            anomalies
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: TAS
    original_reference_id: PMID:10441571
    review:
      summary: PAX6 binds DNA via its paired and homeodomain modules; alternative splicing of the
        paired domain modulates DNA-binding specificity.
      action: KEEP_AS_NON_CORE
      reason: Correct but general; superseded by the sequence-specific Pol II DNA-binding terms that
        better represent the core function.
      supported_by:
        - reference_id: PMID:10441571
          supporting_text: Missense mutation in the alternative splice region of the PAX6 gene in eye
            anomalies
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: TAS
    original_reference_id: PMID:10441571
    review:
      summary: PAX6 is a DNA-binding transcription factor; mutations affecting the splice region alter
        paired-domain function and cause eye anomalies.
      action: ACCEPT
      reason: Correct core molecular function supported by author statement; concordant with all other
        TF-activity annotations.
      supported_by:
        - reference_id: PMID:10441571
          supporting_text: Missense mutation in the alternative splice region of the PAX6 gene in eye
            anomalies
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: TAS
    original_reference_id: PMID:10747901
    review:
      summary: PAX6 is a DNA-binding transcription factor whose homeodomain function is modulated by
        the paired domain.
      action: ACCEPT
      reason: Correct core molecular function; duplicate TAS annotation from an independent reference.
      supported_by:
        - reference_id: PMID:10747901
          supporting_text: Modulation of PAX6 homeodomain function by the paired domain
  - term:
      id: GO:0007417
      label: central nervous system development
    evidence_type: TAS
    original_reference_id: PMID:10747901
    review:
      summary: PAX6 is required for central nervous system development; the paired domain and
        homeodomain cooperate in regulating CNS target genes.
      action: KEEP_AS_NON_CORE
      reason: Well-supported developmental process downstream of the core TF function; retained as
        non-core.
      supported_by:
        - reference_id: PMID:10747901
          supporting_text: Modulation of PAX6 homeodomain function by the paired domain
  - term:
      id: GO:0007601
      label: visual perception
    evidence_type: TAS
    original_reference_id: PMID:10441571
    review:
      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.
      action: KEEP_AS_NON_CORE
      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).
      supported_by:
        - reference_id: PMID:10441571
          supporting_text: Missense mutation in the alternative splice region of the PAX6 gene in eye
            anomalies
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword
      mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000113
    title: Gene Ontology annotation of human sequence-specific DNA binding
      transcription factors (DbTFs) based on the TFClass database
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10441571
    title: Missense mutation in the alternative splice region of the PAX6 gene
      in eye anomalies.
    findings:
      - statement: PAX6 is a DNA-binding transcription factor whose paired-domain function and DNA
          binding are altered by mutations in the alternative splice region, causing eye anomalies.
        supporting_text: Missense mutation in the alternative splice region of the PAX6 gene in eye
          anomalies.
  - id: PMID:10747901
    title: Modulation of PAX6 homeodomain function by the paired domain.
    findings:
      - statement: The PAX6 paired domain and homeodomain functionally interact to determine
          DNA-binding/transcription factor activity in eye and CNS development.
        supporting_text: Modulation of PAX6 homeodomain function by the paired domain.
  - id: PMID:11756345
    title: PAX6 mutation as a genetic factor common to aniridia and glucose
      intolerance.
    findings:
      - statement: Heterozygous PAX6 mutations cause both eye anomalies and glucose intolerance with
          impaired insulin secretion, linking PAX6 to glucose homeostasis via islet-cell function.
        supporting_text: all of the patients with a PAX6 gene mutation had glucose intolerance
          characterized by impaired insulin secretion
      - statement: Truncating PAX6 mutations lacking the C-terminal transactivation domain abolish
          transcriptional activity.
        supporting_text: in agreement with polypeptide truncation and a lack of the carboxyl-terminal
          transactivation domain in all of the mutated PAX6 proteins, no transcriptional activity was
          found in the reporter gene analyses
  - id: PMID:16098226
    title: 'A screen for proteins that interact with PAX6: C-terminal mutations disrupt
      interaction with HOMER3, DNCL1 and TRIM11.'
    findings:
      - statement: PAX6 interacts via its C-terminal PST domain with HOMER3, DNCL1 and the E3 ligase
          TRIM11; C-terminal aniridia mutations disrupt the HOMER3/DNCL1 interactions.
        supporting_text: Three novel PAX6-interacting proteins were identified the post-synaptic
          density (PSD) protein HOMER3, the dynein subunit DNCL1, and the tripartite motif protein
          TRIM11
      - statement: PAX6 is a paired-box transcription factor essential for ocular and neural
          development with a C-terminal PST transactivation domain.
        supporting_text: The PST domain, which encompasses the C-terminal 145 amino acids of PAX6,
          has been shown to act as a transcriptional activator
  - id: PMID:17251190
    title: The MH1 domain of Smad3 interacts with Pax6 and represses
      autoregulation of the Pax6 P1 promoter.
    findings:
      - statement: PAX6 binds R-SMADs and co-SMAD (Smad1, 3, 4, 5); the Smad3 MH1 domain binds the RED
          subdomain of the PAX6 paired domain and inhibits PAX6 DNA binding.
        supporting_text: the MH1 domain of Smad3 was observed binding the RED sub-domain of the Pax6
          paired domain
      - statement: PAX6 autoregulates its own P1 promoter and this is repressed by TGF-beta/Smad
          signaling.
        supporting_text: represses autoregulation of the Pax6 P1 promoter
  - id: PMID:17291498
    title: Sox-2 is expressed by glial and progenitor cells and Pax-6 is
      expressed by neuroblasts in the human subventricular zone.
    findings:
      - statement: PAX6 is expressed in nucleus and cytoplasm of human SVZ neuroblasts and is proposed
          to specify neuronal fate.
        supporting_text: Pax-6 immunoreactivity was detectable in the nucleus and the cytoplasm of SVZ
          cells and colocalised with PSA-NCAM-positive progenitor cells
  - id: PMID:17982423
    title: Stem cell markers in the human posterior limbus and corneal
      endothelium of unwounded and wounded corneas.
    findings:
      - statement: PAX6 protein is induced as a differentiation marker in the corneal endothelium and
          posterior limbus following corneal wounding.
        supporting_text: after wounding ... the differentiation markers Pax-6 and Sox-2 were seen
  - id: PMID:20592023
    title: Pax6 controls the expression of critical genes involved in pancreatic
      {alpha} cell differentiation and function.
    findings:
      - statement: PAX6 directly binds and activates promoters of MafB, cMaf and NeuroD1 (and
          proglucagon/PC2) to control alpha-cell differentiation and function.
        supporting_text: Pax6 directly binds and activates the promoter region of the three genes
          through specific binding sites
      - statement: Pax6-null mice lack alpha cells and have reduced beta and delta cells, showing PAX6
          is required for endocrine pancreas development.
        supporting_text: homozygous mutant mice for Pax6 are characterized by markedly decreased β and
          δ cells and absent α cells
  - id: PMID:20725088
    title: Primate-specific RFPL1 gene controls cell-cycle progression through
      cyclin B1/Cdc2 degradation.
    findings:
      - statement: PAX6 directly induces transcription of its primate-specific target gene RFPL1.
        supporting_text: Pax6-elicited expression of the human (h)RFPL1 gene in HeLa cells
  - id: PMID:24802670
    title: MiR-135b is a direct PAX6 target and specifies human neuroectoderm by
      inhibiting TGF-β/BMP signaling.
    findings:
      - statement: PAX6 binds active enhancers genome-wide in human neuroectoderm and directly
          activates miR-135b transcription, driving neural specification.
        supporting_text: MiR-135b is a direct PAX6 target and specifies human neuroectoderm by
          inhibiting TGF-β/BMP signaling
      - statement: PAX6 is critical for human neuroectoderm specification.
        supporting_text: the TF PAX6 was shown to be critical for human NE specification
  - id: PMID:28473536
    title: Impact of cytosine methylation on DNA binding specificities of human
      transcription factors.
    findings:
      - statement: PAX6 sequence-specific double-stranded DNA binding and its modulation by cytosine
          methylation were measured biochemically.
        supporting_text: Impact of cytosine methylation on DNA binding specificities of human
          transcription factors
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings:
      - statement: PAX6 protein-protein interactions were captured in a large-scale binary interactome
          map (HuRI); individual interactions are not separately validated for PAX6 biology.
        supporting_text: A reference map of the human binary protein interactome
  - id: PMID:7550230
    title: Three novel aniridia mutations in the human PAX6 gene.
    findings:
      - statement: Heterozygous loss-of-function PAX6 mutations cause aniridia and anterior-segment
          (iris/cornea) eye malformations.
        supporting_text: Three novel aniridia mutations in the human PAX6 gene.
  - id: file:human/PAX6/PAX6-deep-research-falcon.md
    title: Deep research report on PAX6
    findings:
      - statement: PAX6 is a paired-box transcription factor with paired domain (PAI/RED subdomains)
          and homeodomain that binds promoters/enhancers and acts as activator or repressor; master
          regulator of eye, brain and pancreatic endocrine development; haploinsufficiency causes
          aniridia and predisposes to diabetes.
        supporting_text: 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
core_functions:
  - description: PAX6 is a sequence-specific RNA polymerase II DNA-binding transcription factor that
      binds cis-regulatory (promoter/enhancer) elements of developmental and endocrine target genes via
      its bipartite paired domain and paired-type homeodomain, acting as a context-dependent activator
      or repressor.
    molecular_function:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
    directly_involved_in:
      - id: GO:0006357
        label: regulation of transcription by RNA polymerase II
    locations:
      - id: GO:0000785
        label: chromatin
      - id: GO:0005654
        label: nucleoplasm
    supported_by:
      - reference_id: PMID:20592023
        supporting_text: Pax6 directly binds and activates the promoter region of the three genes
          through specific binding sites
      - reference_id: PMID:24802670
        supporting_text: we identified PAX6 binding sites and active enhancers genome-wide in an in
          vitro model of human NE development
  - description: PAX6 binds RNA polymerase II cis-regulatory regions in a sequence-specific manner and
      activates target genes (e.g. miR-135b, glucagon-pathway genes), positively regulating
      transcription during neural and pancreatic-endocrine programs.
    molecular_function:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
    directly_involved_in:
      - id: GO:0045944
        label: positive regulation of transcription by RNA polymerase II
    locations:
      - id: GO:0000785
        label: chromatin
    supported_by:
      - reference_id: PMID:24802670
        supporting_text: MiR-135b is a direct PAX6 target
      - reference_id: PMID:20592023
        supporting_text: constitutive expression of a dominant-negative form of Pax6 in
          glucagon-producing cells (InR1G9) inhibits the activities of the promoters
  - description: As part of its transcriptional mechanism, PAX6 binds transcriptional cofactors and
      signaling partners, including R-SMAD/co-SMAD proteins (linking it to TGF-beta signaling) and
      histone acetyltransferase coactivators, to modulate target-gene output.
    molecular_function:
      id: GO:0001221
      label: transcription coregulator binding
    directly_involved_in:
      - id: GO:0006357
        label: regulation of transcription by RNA polymerase II
    locations:
      - id: GO:0005634
        label: nucleus
    supported_by:
      - reference_id: PMID:17251190
        supporting_text: the MH1 domain of Smad3 was observed binding the RED sub-domain of the Pax6
          paired domain
proposed_new_terms: []
suggested_questions:
  - question: 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?
    experts:
      - van Heyningen V
      - Kleinjan DA
  - question: 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?
    experts:
      - Cooper ST
      - Hanson IM
suggested_experiments:
  - hypothesis: PAX6 binds distinct enhancer repertoires in eye, forebrain and pancreatic-islet
      lineages, explaining its pleiotropic developmental functions through context-specific
      cis-regulatory targeting.
    description: 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.
    experiment_type: genome-wide DNA-binding and transcriptomic profiling
  - hypothesis: The PAX6-SMAD interaction sets a quantitative threshold on PAX6 target-gene activation
      that is dosage-sensitive and relevant to aniridia haploinsufficiency.
    description: 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.
    experiment_type: quantitative gene-regulation/dosage assay