Affinage

PAX6

Paired box protein Pax-6 · UniProt P26367

Length
422 aa
Mass
46.7 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAX6 is a dosage-sensitive paired-domain/homeodomain transcription factor that serves as a master regulator of eye, brain, and pancreas development, acting cell-autonomously to specify and maintain tissue identity, control cell adhesion and migration, and govern lineage commitment (PMID:8600027, PMID:20621053, PMID:27941241). It binds DNA through both its paired domain and homeodomain — each required for full activity, since the C-terminal Q422R mutation abolishes homeodomain binding and P375Q disrupts paired-domain binding (PMID:14744876, PMID:11309364) — to directly activate tissue-specific target genes such as Optimedin in the eye and beta-cell genes in the pancreas, while concurrently repressing alternative-lineage programs (PMID:16115881, PMID:27941241, PMID:27462442). In the developing eye PAX6 sits within mutually reinforcing regulatory loops with Six3, and dosage is tightly controlled: a critical protein threshold is required for lens placode formation, and haploinsufficiency produces lens, corneal, and migration defects (PMID:11076764, PMID:12072567, PMID:17066077). PAX6 enforces neuroectodermal fate in human cells in an isoform-specific manner, with PAX6a—but not PAX6b—binding neuroectoderm gene promoters and co-occupying targets with Sox2 to drive unidirectional neuronal commitment while repressing mesodermal and endodermal genes (PMID:20621053, PMID:27462442). It maintains epithelial identity in the cornea, where it specifies limbal stem cells and where its loss converts corneal to skin-like epithelium (PMID:25030175, PMID:27818314), and it maintains adult pancreatic beta-cell identity, repressing alpha/delta-cell genes such that beta-cell deletion causes lethal hyperglycemia (PMID:27941241). PAX6 transcriptional output is tuned by post-translational and cofactor mechanisms: HIPK2 phosphorylates it at T281/T304/T373 to promote p300 interaction and transactivation, and it recruits the histone methyltransferase NSD1 (in concert with the lncRNA PAUPAR) through its C-terminal PST domain to deposit H3K36 methylation at neural targets (PMID:16407227, PMID:33544864). Loss-of-function mutations in PAX6 cause human aniridia, which maps to a single locus at 11p13 (PMID:1345175, PMID:1505982).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1992 High

    Establishing the genetic basis of aniridia: linkage and mutation analysis resolved that all autosomal dominant aniridia maps to a single 11p13 locus and that loss-of-function mutations in PAX6 are causative, defining PAX6 as a haploinsufficient disease gene.

    Evidence Interspecific backcross mapping of mouse Sey, expanded-kindred linkage analysis, and cDNA cloning with direct sequencing of aniridia patient DNA

    PMID:1345175 PMID:1505982 PMID:2347591

    Open questions at the time
    • Did not define the molecular DNA-binding mechanism
    • Did not establish the downstream target genes affected
  2. 1996 High

    Resolving whether PAX6 acts within cells or on their environment: chimera analysis showed Pax6 functions cell-autonomously to control surface ectoderm fate and intermixing, framing it as an intrinsic determinant of lens, nasal, and retinal lineages.

    Evidence Chimeric mouse embryos combining wild-type and Sey mutant cells

    PMID:8600027

    Open questions at the time
    • Did not identify direct transcriptional targets mediating cell-autonomy
    • Non-autonomous roles in other tissues not excluded
  3. 1999 High

    Defining PAX6 as a regulator of neuronal migration and cytoskeletal organization: loss-of-function in hindbrain, telencephalon, and cerebellar granule cells revealed roles in cell migration, polarity, and neurite extension, with Unc5h3 identified as a downstream target.

    Evidence Pax6-null and Small Eye mouse/rat analysis, focal GFP cell tracking, granule cell culture with rescue, and in situ hybridization for Unc5h3

    PMID:10409504 PMID:10572034 PMID:11688562

    Open questions at the time
    • Mechanistic link between PAX6 transcription and cytoskeletal change incomplete
    • Direct vs indirect regulation of Unc5h3 not resolved
  4. 1999 Medium

    Mapping how PAX6 expression itself is controlled and how PAX6 contacts the transcription machinery: dual promoters (P0/P1) with intron-4 elements were shown to drive tissue-specific expression, and the homeodomain was shown to bind TBP and Rb.

    Evidence Transgenic promoter-deletion reporter assays; GST pull-downs and immunoprecipitation from lens nuclear extracts

    PMID:10359315 PMID:9847251

    Open questions at the time
    • Functional consequence of the Rb interaction not established
    • TBP interaction not validated in vivo
  5. 2000 High

    Explaining dosage sensitivity mechanistically: a critical PAX6 protein threshold was shown necessary for lens placode formation, with heterozygosity causing delayed placode formation, N-cadherin failure, and apoptosis—shown not to result from monoallelic expression.

    Evidence Histology, cell counting, apoptosis assays, and allele-specific expression analysis in heterozygous Sey mouse embryos

    PMID:11076764

    Open questions at the time
    • Direct PAX6 regulation of N-cadherin not demonstrated
    • Threshold mechanism at the molecular level unresolved
  6. 2001 High

    Dissecting the contribution of each DNA-binding module: missense mutations showed that Q422R selectively abolishes homeodomain DNA binding and P375Q disrupts paired-domain binding, establishing that both domains and the C-terminal residue are required for full function.

    Evidence Site-directed mutagenesis, EMSA, and transfection reporter assays in multiple cell lines

    PMID:11309364 PMID:14744876

    Open questions at the time
    • Did not map full target-gene repertoire dependent on each domain
    • In vivo consequences of isolated domain loss not tested
  7. 2002 High

    Placing PAX6 in cross-regulatory networks: mutual activation with Six3 in the lens (and mutual repression with Emx2 in cortex) revealed feedback loops, and Six3-driven rescue of haploinsufficiency activated the PDGF-alpha-R/cyclin D1 proliferative pathway.

    Evidence EMSA, transgenic reporter assays, Pax6+/- rescue transgenics, and loss-of-function marker analysis

    PMID:11739261 PMID:12072567

    Open questions at the time
    • Direct binding sites in Six3/Emx2 regulatory regions only partially defined
    • Hierarchy among feedback loops in vivo unclear
  8. 2005 High

    Demonstrating direct target gene activation: PAX6 was shown to bind the Optimedin promoter through its paired domain in vivo and activate transcription, providing a defined direct target with binding-site validation.

    Evidence EMSA, site-directed mutagenesis, luciferase reporter, and ChIP

    PMID:16115881

    Open questions at the time
    • Functional role of Optimedin downstream of PAX6 not established
    • Generalizability of paired-domain binding to other targets not shown here
  9. 2006 High

    Identifying post-translational and upstream control of activity: HIPK2 phosphorylation at T281/T304/T373 promotes p300 interaction and transactivation, Six3 directly activates Pax6 at the top of the lens pathway, and a Meis-Pbx enhancer controls pancreatic Pax6 expression.

    Evidence Mass spectrometry, mutagenesis, shRNA, co-IP, ChIP/EMSA, conditional and knockout mouse models, and transgenic enhancer assays

    PMID:16407227 PMID:17049510 PMID:17066077

    Open questions at the time
    • Whether phosphorylation occurs in all PAX6-expressing tissues unknown
    • Integration of upstream activators with phosphorylation not addressed
  10. 2009 Medium

    Establishing roles in differentiation, proliferation, and tissue homeostasis: conditional knockout showed PAX6 is required for lens fiber differentiation and cell-cycle exit (via Sfrp2), morpholino knockdown showed it drives proliferation in lens regeneration, and heterozygosity produced a chronic-wound-like corneal phenotype.

    Evidence Cre/loxP conditional knockout, newt morpholino knockdown with BrdU assays, and corneal histology/MAPK analysis in Pax6+/- mice

    PMID:17003134 PMID:19570848 PMID:19933176

    Open questions at the time
    • Direct vs indirect regulation of Sfrp2 incompletely resolved
    • Single-lab observations for regeneration and corneal phenotypes
  11. 2010 High

    Resolving isoform-specific function in human cell-fate decisions: PAX6a (not PAX6b or PAX6deltaPD) was shown sufficient to convert hESCs to neuroectoderm, with PAX6a binding NE gene promoters while PAX6b binds pluripotency genes.

    Evidence hESC differentiation, isoform overexpression and knockdown, and ChIP-based promoter binding analysis

    PMID:20621053

    Open questions at the time
    • Structural basis for isoform-specific target selection not defined
    • Cofactors distinguishing isoform binding not identified
  12. 2016 High

    Defining genome-wide target logic and adult identity maintenance: ChIP-seq revealed PAX6 co-occupies promoters with Sox2 to activate neural and repress non-neural genes (including direct activation of Ift74), and conditional deletion showed PAX6 maintains adult beta-cell identity by repressing alternative islet genes.

    Evidence ChIP-seq, transcriptome analysis, in utero knockdown, conditional beta-cell deletion with lineage tracing, and human islet shRNA

    PMID:27462442 PMID:27818314 PMID:27941241

    Open questions at the time
    • Mechanism of repression vs activation at co-occupied loci unresolved
    • How cofactor context switches PAX6 between activation and repression unknown
  13. 2021 Medium

    Adding chromatin-modifying and disease-context mechanisms: PAX6 recruits NSD1 via its C-terminal PST domain (with lncRNA PAUPAR) to deposit H3K36 methylation at neural targets, and in Alzheimer's brains PAX6 directly drives GSK-3beta transcription to promote tau hyperphosphorylation.

    Evidence hESC/organoid differentiation with PAUPAR knockdown, co-IP and ChIP; AD brain and APP transgenic analysis with ChIP and tau phosphorylation assays

    PMID:33544864 PMID:34428276

    Open questions at the time
    • NSD1/PAUPAR mechanism resolved by single-lab co-IP and ChIP
    • Causality of PAX6 in human AD pathology not established beyond correlation and knockdown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PAX6 context-dependently switches between gene activation and repression at co-occupied loci, and how its dosage, isoform usage, phosphorylation, and chromatin-cofactor recruitment are integrated across distinct tissues, remains unresolved.
  • No unified model linking domain-specific binding to activation vs repression outcomes
  • Tissue-specific cofactor maps incomplete
  • Structural basis of isoform-selective targeting not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 6 GO:0140110 transcription regulator activity 6
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 1
Partners
EP300HIPK2NSD1PAUPARRB1SIX3SOX2TBP

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 PAX6 spans 22 kilobases and is divided into 14 exons; intragenic mutations (including nonsense and frameshift) in PAX6 cause human aniridia, establishing that aniridia results from loss-of-function of the PAX6 gene. cDNA cloning, intron-exon mapping, direct sequencing of aniridia patient DNA Nature genetics High 1345175
1990 Chromosomal mapping placed the mouse Small eye (Sey) gene on chromosome 2 in a region syntenic with human chromosome 11p13, where the aniridia locus AN2 resides, establishing that Sey is the mouse homolog of human PAX6/AN2. Interspecific backcross linkage mapping Genomics Medium 2347591
1992 The originally proposed AN1 locus on chromosome 2p for autosomal dominant aniridia was shown by linkage analysis to be misassigned; all aniridia maps to a single locus at 11p13 corresponding to PAX6/AN2. Linkage analysis with chromosome 2p and 11p13 markers in expanded aniridia kindred Genomics High 1505982
1996 Pax6 acts cell-autonomously in the optic cup and controls the fate of surface ectoderm giving rise to lens and nasal epithelium; Pax6-mutant cells were excluded from the lens, nasal epithelium, and retinal pigmented epithelium in chimeric embryos, and did not intermix normally in other retinal regions. Chimeric mouse embryo analysis (wild-type + Sey mutant cells) Genes & development High 8600027
1999 Pax6 is required for cell migration and neurite extension of rhombic lip-derived neurons; Pax6-null embryos show disruption of three of five precerebellar nuclei and absence of granule cell pre-migratory sub-layer, associated with complete loss of Unc5h3 (netrin receptor) expression, placing Pax6 upstream of Unc5h3 in hindbrain migration. Analysis of Pax6(Sey/Sey) null mouse embryos; in situ hybridization for Unc5h3 Development (Cambridge, England) High 10409504
1999 Pax6 restricts ventro-dorsal cell migration in the developing telencephalon; loss of Pax6 strongly enhances invasion of cortex by cells from the ganglionic eminence, demonstrating Pax6 functions to maintain the cortico-striatal boundary. Adenoviral GFP focal injection to track cell migration in wild-type vs. Pax6 mutant (Small Eye) mouse telencephalon Development (Cambridge, England) High 10572034
1999 Pax6 is regulated by two distinct promoters (P0 and P1) that direct differential expression in the developing eye; P0-initiated transcripts predominate in lens placode and corneal/conjunctival epithelia, while P1-initiated transcripts are expressed in lens placode, optic vesicle, and CNS. Multiple cis-acting elements (including one in intron 4) combinatorially control tissue-specific expression. Transgenic mouse reporter assays with promoter-deletion constructs Development (Cambridge, England) High 9847251
1999 Pax6 homeodomain (HD) physically interacts with TATA-box-binding protein (TBP), mediated by the N-terminal arm and first two alpha-helices of the HD plus the C-terminal activation domain; Pax6 HD also interacts with retinoblastoma protein (Rb), and Pax6/Rb complexes were detected in lens nuclear extracts. Affinity chromatography, GST pull-down assays, immunoprecipitation from lens nuclear extracts Investigative ophthalmology & visual science Medium 10359315
2000 A critical threshold of PAX6 protein is required for lens placode formation; heterozygous Pax6 mutation causes a delay in lens placode formation, failure of N-cadherin expression at the lens cup edge, and apoptosis, not due to monoallelic expression (shown to be biallelic by allelic expression analysis). Analysis of Pax6(Sey-1Neu)/+ heterozygous embryos; cell counting, mitotic index, apoptosis assays, allele-specific expression analysis Development (Cambridge, England) High 11076764
2001 Pax6 controls cytoskeletal organization and polarity of cerebellar granule cells; Pax6 mutant rat granule cells fail to form parallel fiber axons and migrate tangentially, sprouting multiple neurites with enlarged growth cones. This effect is cell-autonomous and rescuable by ectopic Pax6 expression, and is independent of ROCK-mediated Rho GTPase signaling. Analysis of Pax6 mutant rats (rSey2/rSey2); granule cell culture; rescue by ectopic Pax6 expression; ROCK pathway inhibition Development (Cambridge, England) High 11688562
2002 Pax6 and Emx2 mutually down-regulate each other's expression in the developing cortex; loss of Emx2 or Pax6 reduces their respective cortical regions and impairs WNT signaling center at the medial-caudal cortical edge. Analysis of Emx2 and Pax6 loss-of-function mouse mutants; molecular marker expression Cerebral cortex (New York, N.Y. : 1991) Medium 11739261
2002 Six3 and Pax6 mutually activate each other's expression in the developing lens: Six3 binds regulatory sequences of Pax6 and Pax6 binds regulatory sequences of Six3 (in vitro and transgenic approaches). Rescue of the Pax6 haploinsufficient lens phenotype by lens-specific Six3 overexpression activates the PDGF-alpha-R/cyclin D1 proliferative pathway. In vitro binding assays (EMSA), transgenic mouse reporter assays, Pax6+/- rescue transgenic mice Proceedings of the National Academy of Sciences of the United States of America High 12072567
2003 Pax6 regulates cell adhesion in the developing cerebral cortex in a cell-autonomous manner; Pax6-deficient cortical cells segregate from wild-type cells and form dense clusters after transplantation into wild-type cortex, and show enhanced clustering in explant migration assays. Cell transplants into wild-type embryonic cortex; explant migration assays with Pax6(Sey/Sey) cells Cerebral cortex (New York, N.Y. : 1991) Medium 12764036
2003 Pax6 regulates radial migration of neuronal precursors, specifically affecting movement at the subventricular zone/intermediate zone boundary; chimera analysis shows Pax6-deficient cells are specifically reduced in the mediocaudal cortical domain, indicating a role in regionalization alongside migration. Mouse chimera analysis (wild-type + Pax6-deficient cells); BrdU labeling and cell distribution analysis Developmental biology Medium 12618140
2004 Pax6 is genetically upstream of En1 (Engrailed 1) in Renshaw cell development; Pax6 is required for an early step in Renshaw cell specification, while En1 (downstream of Pax6) regulates inhibitory synapse formation between Renshaw cells and motor neurons. Analysis of Pax6 and En1 mutant mice; genetic epistasis; immunohistochemistry The Journal of neuroscience Medium 14762144
2004 Sustained ectopic Pax6 expression in lens fiber cells disrupts differentiation: it reduces cMaf protein levels and dramatically decreases betaB1-crystallin expression, demonstrating that downregulation of Pax6 is required for normal fiber cell differentiation and that Pax6 negatively regulates cMaf. Transgenic mice with alphaA-crystallin promoter-driven Pax6; 2D gel electrophoresis, immunohistochemistry, RT-PCR, in situ hybridization Investigative ophthalmology & visual science High 15452066
2004 PAX6 and PAX6(5a) transactivation is modulated by specific cellular environments and the location/type of missense mutation; DNA binding by PAX6 homeodomain is required for full function, and a C-terminal missense mutation (Q422R) abolishes homeodomain DNA binding. Site-directed mutagenesis, transfection reporter assays in four cell lines, EMSA Investigative ophthalmology & visual science High 14744876
2001 Missense mutation Q422R at the C-terminus of PAX6 specifically abolishes homeodomain DNA binding of intact PAX6, demonstrating that the C-terminal amino acid modulates homeodomain function; paired domain DNA binding is separately disrupted by the P375Q mutation. Site-directed mutagenesis of PAX6; electrophoretic mobility shift assays; transfection reporter assays Human molecular genetics High 11309364
2005 Pax6 directly binds the proximal promoter of Optimedin (Olfactomedin 3) through its paired domain at position -86/-70, activates Optimedin transcription, and occupies this site in vivo; mutations abolishing the binding site eliminate both Pax6 binding and promoter activation. EMSA, site-directed mutagenesis, transfection luciferase reporter assay, chromatin immunoprecipitation (ChIP) The Journal of biological chemistry High 16115881
2006 HIPK2 phosphorylates PAX6 at threonines 281, 304, and 373 in the C-terminal activation domain, enhancing Pax6 transactivation by promoting its interaction with p300; HIPK2 knockdown inhibits Pax6 phosphorylation and its transactivating function on the proglucagon promoter. Mass spectrometry identification of phosphorylation sites; site-directed mutagenesis (T→A, T→E); HIPK2 shRNA knockdown; co-immunoprecipitation; transactivation assays The Journal of biological chemistry High 16407227
2006 Six3 directly activates Pax6 (and Sox2) expression in the presumptive lens ectoderm, placing Six3 upstream of Pax6 at the top of the lens formation regulatory pathway; confirmed by ChIP, EMSA, luciferase reporter assay, and Six3 conditional deletion causing Pax6 downregulation. Conditional deletion of Six3 in presumptive lens ectoderm; ChIP; EMSA; luciferase reporter assay; chick misexpression The EMBO journal High 17066077
2006 Pax6 pancreatic expression is controlled by a minimal enhancer containing a composite Meis-Pbx binding site; Meis and Pbx proteins form a synergistic complex on this enhancer, and both sites are required for enhancer activity in transgenic mice; Pax6 pancreatic expression becomes dependent on Pbx1/Pbx2 during islet formation. Enhancer deletion analysis; EMSA; transgenic mouse reporter assays; Pbx1/Pbx2 knockout analysis Developmental biology High 17049510
2009 Pax6 is essential for lens fiber cell differentiation and cell cycle exit; conditional Pax6 inactivation in developing mouse lens leads to failure of secondary fiber differentiation, apoptosis of lens epithelial cells, and upregulation of Wnt antagonist Sfrp2 (a Pax6 target); the differentiation failure is independent of beta-catenin signaling or Sox2 activity. Cre/loxP conditional knockout in mouse lens; histology; gene expression analysis; pathway rescue experiments Development (Cambridge, England) High 19570848
2009 Pax6 controls cell proliferation during newt lens regeneration; Pax6 morpholino knockdown dramatically reduces proliferation of iris pigment epithelial cells both in vitro and in vivo, retarding lens regeneration and inhibiting early crystallin expression and lens fiber induction. Morpholino knockdown in newt; BrdU proliferation assays in vitro and in vivo; crystallin immunohistochemistry Proceedings of the National Academy of Sciences of the United States of America Medium 17003134
2009 PAX6 heterozygosity causes cytoskeletal and cell adhesion defects in corneal epithelium resembling a chronic wound state: Pax6+/- corneas show altered desmoplakin and actin localization, protein oxidation, and ERK1/2 and p38 MAPK phosphorylation similar to wounded wild-type corneas. Immunohistochemistry and electron microscopy of Pax6+/- mouse corneas and wounded wild-type corneas; protein oxidation assays; MAPK phosphorylation analysis Investigative ophthalmology & visual science Medium 19933176
2009 Pax6 regulates the proglucagon processing enzyme PC2 and its chaperone 7B2 in pancreatic alpha cells: Pax6 indirectly regulates PC2 transcription through cMaf and Beta2/NeuroD1, while it activates 7B2 both directly and indirectly through these same transcription factors. Pax6 siRNA knockdown and dominant-negative Pax6 in InR1G9 alpha cells; binding and transactivation studies; promoter analysis Molecular and cellular biology Medium 19223471
2010 PAX6 is a transcriptional determinant of human neuroectoderm: PAX6 knockdown blocks NE specification from hESCs; only PAX6a (not PAX6b or PAX6deltaPD) converts hESCs to NE; PAX6a binds to NE gene promoters during human NE specification while PAX6b only binds pluripotency gene promoters. hESC differentiation; Pax6 knockdown; overexpression of isoforms; chromatin immunoprecipitation; promoter binding analysis Cell stem cell High 20621053
2013 Pax6 regulates hindbrain segmentation by repressing Krox20 expression domains; Pax6 and Krox20 engage in mutual negative cross-talk through Pax6-mediated regulation of the Krox20 repressor Nab1; FGF signaling acts upstream of the Pax6-Krox20 network. Gain- and loss-of-function approaches in chick and mice; in situ hybridization; boundary analysis Development (Cambridge, England) Medium 23578930
2014 WNT7A controls corneal epithelium differentiation through PAX6; PAX6 together with p63 specifies limbal stem cells; loss of WNT7A or PAX6 converts limbal stem cells to a skin-like epithelium; transduction of PAX6 into skin epithelial stem cells is sufficient to convert them to LSC-like cells capable of repairing corneal surface after transplantation. In vitro feeder-free LSC expansion; 3D corneal differentiation; PAX6 lentiviral transduction; rabbit corneal injury transplantation model Nature High 25030175
2015 Onecut1 and Onecut2 transcription factors operate downstream of Pax6 in retinal horizontal cell development; Pax6 inactivation in retinal progenitors leads to loss of Onecut1/2 expression, and Onecut-deficient retinae completely lack horizontal cells, placing Pax6 → Onecut1/2 → horizontal cell maintenance. Pax6 conditional knockout; Onecut1/Onecut2 single and compound mutants; immunohistochemistry for horizontal cell markers (Foxn4, Ptf1a, Prox1, Lim1) Developmental biology Medium 25794677
2016 PAX6 maintains adult beta cell identity by directly activating beta cell genes and repressing alternative islet cell genes (ghrelin, glucagon, somatostatin); beta-cell-specific Pax6 deletion causes lethal hyperglycemia and expansion of alpha cells; lineage tracing and chromatin analysis confirm direct PAX6 binding at promoters and enhancers of repressed genes. Conditional Pax6 deletion in adult beta cells; lineage tracing; transcriptome analysis; chromatin immunoprecipitation; shRNA in human islets The Journal of clinical investigation High 27941241
2016 Pax6 targets a large number of promoters in neural progenitor cells, many co-occupied with Sox2; Pax6 activates neuronal/ectodermal genes while concurrently repressing mesodermal and endodermal genes, ensuring unidirectional neuronal lineage commitment; Pax6 directly binds and activates Ift74, whose knockdown impairs polarity and migration of newborn neurons. ChIP-seq; transcriptome analysis in Pax6-deficient neural progenitors; in utero knockdown of Ift74 Cell discovery High 27462442
2016 PAX6 knockout in human corneal epithelial cells (CRISPR/Cas9) leads to downregulation of cornea-specific genes (KRT12, KRT3, CLU, ALDH3A1, ANGPTL7, TKT) and upregulation of epidermis-related genes (KRT10, KRT1, IVL, FLG), demonstrating PAX6 maintains corneal epithelial cell identity. CRISPR/Cas9 PAX6 knockout in human corneal epithelial cells; microarray transcriptome analysis Experimental eye research Medium 27818314
2021 PAX6 is upregulated in Alzheimer's disease brains downstream of amyloid-β/E2F1/c-Myb signaling and directly regulates GSK-3β transcription, promoting tau hyperphosphorylation at Ser356, Ser396, and Ser404; PAX6 downregulation protects against amyloid-β-induced neuronal death. Analysis of AD brains and APP transgenic mice; PAX6 knockdown; ChIP for E2F1, c-Myb, and PAX6 binding to GSK-3β promoter; tau phosphorylation assays Brain : a journal of neurology Medium 34428276
2021 The lncRNA PAUPAR interacts with PAX6 to confer proper binding sites on target neural genes; PAX6 recruits histone methyltransferase NSD1 through its C-terminal PST domain to regulate H3K36 methylation and expression of neural target genes during cortical differentiation. hESC neural differentiation; PAUPAR knockdown; ChIP; co-immunoprecipitation; 3D cerebral organoid system Nucleic acids research Medium 33544864
2018 Drosophila Eyeless/Pax6 acts non-autonomously from the peripodial epithelium to control eye pattern formation by regulating decapentaplegic (dpp) expression, which is required for morphogenetic furrow initiation in the eye disc; loss of Ey in peripodial cells abolishes dpp expression and retinal development. Clonal analysis and targeted Ey knockdown/knockout in Drosophila peripodial epithelium; in situ hybridization for dpp Development (Cambridge, England) Medium 29980566

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nature genetics 574 1345175
2010 Pax6 is a human neuroectoderm cell fate determinant. Cell stem cell 377 20621053
1997 PAX-6 in development and evolution. Annual review of neuroscience 368 9056723
1995 Cloning and characterization of the maize An1 gene. The Plant cell 332 7696880
2002 Pax6; a pleiotropic player in development. BioEssays : news and reviews in molecular, cellular and developmental biology 257 12386935
1999 Role of Pax6 in development of the cerebellar system. Development (Cambridge, England) 250 10409504
2004 Regionalization and fate specification in neurospheres: the role of Olig2 and Pax6. Molecular and cellular neurosciences 226 15080895
2014 WNT7A and PAX6 define corneal epithelium homeostasis and pathogenesis. Nature 201 25030175
1998 PAX6 mutations reviewed. Human mutation 200 9482572
1996 Multiple functions for Pax6 in mouse eye and nasal development. Genes & development 197 8600027
2012 Pax6: a multi-level regulator of ocular development. Progress in retinal and eye research 192 22561546
2001 Pax6 lights-up the way for eye development. Current opinion in cell biology 185 11698186
2002 PAX6 in sensory development. Human molecular genetics 184 12015275
2005 PAX6 mutations: genotype-phenotype correlations. BMC genetics 174 15918896
2010 Two R2R3-MYB genes, homologs of Petunia AN2, regulate anthocyanin biosyntheses in flower Tepals, tepal spots and leaves of asiatic hybrid lily. Plant & cell physiology 158 20118109
1993 PAX6 mutations in aniridia. Human molecular genetics 154 8364574
1999 Regulation of Pax6 expression is conserved between mice and flies. Development (Cambridge, England) 152 9847251
2004 Pax6 and engrailed 1 regulate two distinct aspects of renshaw cell development. The Journal of neuroscience : the official journal of the Society for Neuroscience 148 14762144
2011 The role of Pax6 in forebrain development. Developmental neurobiology 147 21538923
2019 The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye. Genes 140 31861090
2006 Six3 activation of Pax6 expression is essential for mammalian lens induction and specification. The EMBO journal 139 17066077
2002 Emx2 and Pax6 control regionalization of the pre-neuronogenic cortical primordium. Cerebral cortex (New York, N.Y. : 1991) 136 11739261
2016 PAX6 maintains β cell identity by repressing genes of alternative islet cell types. The Journal of clinical investigation 129 27941241
2002 PAX6 mutation as a genetic factor common to aniridia and glucose intolerance. Diabetes 121 11756345
1995 Mutation of the PAX6 gene in patients with autosomal dominant keratitis. American journal of human genetics 118 7668281
2001 AN2/NG2 protein-expressing glial progenitor cells in the murine CNS: isolation, differentiation, and association with radial glia. Glia 111 11329183
1999 The role of Pax6 in restricting cell migration between developing cortex and basal ganglia. Development (Cambridge, England) 110 10572034
2016 PAX6: 25th anniversary and more to learn. Experimental eye research 108 27126352
2009 Pax6 is essential for lens fiber cell differentiation. Development (Cambridge, England) 107 19570848
2005 The maize An2 gene is induced by Fusarium attack and encodes an ent-copalyl diphosphate synthase. Plant molecular biology 107 16307364
1990 Targeted degradation of mRNA in Xenopus oocytes and embryos directed by modified oligonucleotides: studies of An2 and cyclin in embryogenesis. Nucleic acids research 107 1697675
2010 Expression of pax6 and sox2 in adult olfactory epithelium. The Journal of comparative neurology 104 20852734
2000 Dosage requirement and allelic expression of PAX6 during lens placode formation. Development (Cambridge, England) 95 11076764
2001 Pax6 regulates granule cell polarization during parallel fiber formation in the developing cerebellum. Development (Cambridge, England) 93 11688562
2016 Mapping gene regulatory circuitry of Pax6 during neurogenesis. Cell discovery 92 27462442
2005 PAX6 expression identifies progenitor cells for corneal keratocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 88 15901670
1999 PAX6 expression in the developing human eye. The British journal of ophthalmology 87 10340984
2000 Regulation of eye formation by the Rx and pax6 homeobox genes. Cellular and molecular life sciences : CMLS 83 10766016
1999 Pax2/5 and Pax6 subdivide the early neural tube into three domains. Mechanisms of development 83 10354469
2003 Emx1, emx2 and pax6 in specification, regionalization and arealization of the cerebral cortex. Cerebral cortex (New York, N.Y. : 1991) 81 12764040
1998 The Human PAX6 Mutation Database. Nucleic acids research 74 9399848
2002 Mutually regulated expression of Pax6 and Six3 and its implications for the Pax6 haploinsufficient lens phenotype. Proceedings of the National Academy of Sciences of the United States of America 73 12072567
2006 Phosphorylation and transactivation of Pax6 by homeodomain-interacting protein kinase 2. The Journal of biological chemistry 68 16407227
2000 PAX6 methylation and ectopic expression in human tumor cells. International journal of cancer 68 10861471
2001 Early and late changes in Pax6 expression accompany eye degeneration during cavefish development. Development genes and evolution 64 11455425
2014 High AN1 variability and interaction with basic helix-loop-helix co-factors related to anthocyanin biosynthesis in potato leaves. The Plant journal : for cell and molecular biology 58 25159050
2003 PAX6 and congenital eye malformations. Pediatric research 58 14561779
2016 Genotype-phenotype correlation of PAX6 gene mutations in aniridia. Human genome variation 57 27081561
2016 PAX6 regulates human corneal epithelium cell identity. Experimental eye research 57 27818314
2006 Pax6 is regulated by Meis and Pbx homeoproteins during pancreatic development. Developmental biology 57 17049510
2016 Genetic Analysis of 'PAX6-Negative' Individuals with Aniridia or Gillespie Syndrome. PloS one 55 27124303
2007 Phylogenetic and expression analysis of ZnF-AN1 genes in plants. Genomics 54 17524611
2001 The AN2 protein is a novel marker for the Schwann cell lineage expressed by immature and nonmyelinating Schwann cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 54 11157078
2008 Spatio-temporal expression of Pax6 in Xenopus forebrain. Brain research 53 18786519
2003 Pax6 regulates regional development and neuronal migration in the cerebral cortex. Developmental biology 53 12618140
2006 The role of Pax-6 in lens regeneration. Proceedings of the National Academy of Sciences of the United States of America 52 17003134
1999 Expression pattern of PAX3 and PAX6 genes during human embryogenesis. The International journal of developmental biology 52 10610023
2009 PAX6 aniridia and interhemispheric brain anomalies. Molecular vision 51 19862335
2005 Pax6-dependence of Six3, Eya1 and Dach1 expression during lens and nasal placode induction. Gene expression patterns : GEP 51 16024294
2011 OsDOG, a gibberellin-induced A20/AN1 zinc-finger protein, negatively regulates gibberellin-mediated cell elongation in rice. Journal of plant physiology 50 21316795
2004 Functional properties of natural human PAX6 and PAX6(5a) mutants. Investigative ophthalmology & visual science 50 14744876
2001 Missense mutation at the C-terminus of PAX6 negatively modulates homeodomain function. Human molecular genetics 49 11309364
1999 Pax-6 interactions with TATA-box-binding protein and retinoblastoma protein. Investigative ophthalmology & visual science 49 10359315
2007 Mechanisms controlling Pax6 isoform expression in the retina have been conserved between teleosts and mammals. Developmental biology 47 17509554
2016 A Novel and Multivalent Role of Pax6 in Cerebellar Development. The Journal of neuroscience : the official journal of the Society for Neuroscience 46 27581449
2004 Ectopic Pax6 expression disturbs lens fiber cell differentiation. Investigative ophthalmology & visual science 45 15452066
1990 Location of the gene involving the small eye mutation on mouse chromosome 2 suggests homology with human aniridia 2 (AN2). Genomics 45 2347591
2002 AN2, the mouse homologue of NG2, is a surface antigen on glial precursor cells implicated in control of cell migration. Journal of neurocytology 44 14501219
2000 Mutation in the PAX6 gene in twenty patients with aniridia. Human mutation 43 10737978
2021 Amyloid-β toxicity modulates tau phosphorylation through the PAX6 signalling pathway. Brain : a journal of neurology 41 34428276
2011 Discovery and assessment of conserved Pax6 target genes and enhancers. Genome research 40 21617155
2016 MiR-433 inhibits retinoblastoma malignancy by suppressing Notch1 and PAX6 expression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 39 27470361
2003 Pax6 regulates cell adhesion during cortical development. Cerebral cortex (New York, N.Y. : 1991) 38 12764036
2015 Onecut1 and Onecut2 transcription factors operate downstream of Pax6 to regulate horizontal cell development. Developmental biology 36 25794677
2018 Implication of non-coding PAX6 mutations in aniridia. Human genetics 35 30291432
2016 Sox2 and Pax6 Play Counteracting Roles in Regulating Neurogenesis within the Murine Olfactory Epithelium. PloS one 35 27171428
2020 PAX6 Genotypic and Retinal Phenotypic Characterization in Congenital Aniridia. Investigative ophthalmology & visual science 34 32396632
1992 Resolution of the two loci for autosomal dominant aniridia, AN1 and AN2, to a single locus on chromosome 11p13. Genomics 34 1505982
2014 PAX6 gene associated with high myopia: a meta-analysis. Optometry and vision science : official publication of the American Academy of Optometry 33 24637479
2009 Cytoskeletal and cell adhesion defects in wounded and Pax6+/- corneal epithelia. Investigative ophthalmology & visual science 32 19933176
2021 Longitudinal genotype-phenotype analysis in 86 patients with PAX6-related aniridia. JCI insight 29 34101622
2020 AN1-type zinc finger protein 3 (ZFAND3) is a transcriptional regulator that drives Glioblastoma invasion. Nature communications 29 33311477
2004 Differential expression of Pax6 and Ngn2 between pair-generated cortical neurons. Journal of neuroscience research 29 15523634
2019 Functional MYB transcription factor encoding gene AN2 is associated with anthocyanin biosynthesis in Lycium ruthenicum Murray. BMC plant biology 28 31035916
2009 Pax6 regulates the proglucagon processing enzyme PC2 and its chaperone 7B2. Molecular and cellular biology 28 19223471
2005 The Optimedin gene is a downstream target of Pax6. The Journal of biological chemistry 28 16115881
2002 Differential Pax6 promoter activity and transcript expression during forebrain development. Mechanisms of development 28 12175506
2014 Regulation of Human PAX6 Expression by miR-7. Evolutionary bioinformatics online 27 25089088
2013 A novel role for Pax6 in the segmental organization of the hindbrain. Development (Cambridge, England) 27 23578930
2009 Shh and Pax6 have unconventional expression patterns in embryonic morphogenesis in Sepia officinalis (Cephalopoda). Gene expression patterns : GEP 27 19683074
2020 Gene dosage manipulation alleviates manifestations of hereditary PAX6 haploinsufficiency in mice. Science translational medicine 26 33298563
2011 Pax6 regulates proliferation and apoptosis of human retinoblastoma cells. Investigative ophthalmology & visual science 26 21169528
2020 Analysis of genotype-phenotype correlations in PAX6-associated aniridia. Journal of medical genetics 25 32467297
2018 Plant A20/AN1 protein serves as the important hub to mediate antiviral immunity. PLoS pathogens 25 30212572
2021 PAUPAR and PAX6 sequentially regulate human embryonic stem cell cortical differentiation. Nucleic acids research 24 33544864
2018 Eyeless/Pax6 initiates eye formation non-autonomously from the peripodial epithelium. Development (Cambridge, England) 24 29980566
2011 A common variant upstream of the PAX6 gene influences islet function in man. Diabetologia 24 21922321
2018 Association of the PAX6 gene with extreme myopia rather than lower grade myopias. The British journal of ophthalmology 23 29436400
2015 Pax6 influences expression patterns of genes involved in neuro- degeneration. Annals of neurosciences 23 26525840
2011 A stress-associated protein containing A20/AN1 zing-finger domains expressed in Medicago truncatula seeds. Plant physiology and biochemistry : PPB 23 21296585

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