pax6a

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA GO_REF:0000033	ACCEPT	Summary: Sequence-specific binding of RNA polymerase II cis-regulatory DNA by the paired domain and homeodomain. Reason: Both zebrafish Pax6 co-orthologues retain complete paired domains and homeodomains and activate paired-domain (CD19) and homeodomain (P3) reporter targets at indistinguishable levels in the same assay (PMID:18282108); both act as transcriptional activators and both induce ectopic eyes in Drosophila (PMID:9831649). The molecular function is therefore conserved in both copies and is correctly shared across the pair. Pax6a activates reporters through a homeodomain target (P3) and a paired-domain target (CD19), which requires sequence-specific binding of these sites. Supporting Evidence: PMID:18282108 Activation by the two wild type co-orthologues through the P3 homeodomain target [45] (Figure 1D), or the CD19 paired domain target [46] (Figure 1E), was not significantly different, in contrast to the original observations by Nornes et al [43]. PMID:9831649 The coding sequences of the two genes show 82% identity whereas the deduced amino acid sequences are 95% identical with complete conservation of the paired- and homeodomains.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IBA GO_REF:0000033	ACCEPT	Summary: pax6a encodes a paired/homeodomain sequence-specific DNA-binding transcription factor; transcriptional activation by Pax6a has been directly measured in reporter assays. Reason: Both zebrafish Pax6 co-orthologues retain complete paired domains and homeodomains and activate paired-domain (CD19) and homeodomain (P3) reporter targets at indistinguishable levels in the same assay (PMID:18282108); both act as transcriptional activators and both induce ectopic eyes in Drosophila (PMID:9831649). The molecular function is therefore conserved in both copies and is correctly shared across the pair. Supporting Evidence: PMID:18282108 Activation by the two wild type co-orthologues through the P3 homeodomain target [45] (Figure 1D), or the CD19 paired domain target [46] (Figure 1E), was not significantly different, in contrast to the original observations by Nornes et al [43]. PMID:9831649 Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. PMID:9831649 The coding sequences of the two genes show 82% identity whereas the deduced amino acid sequences are 95% identical with complete conservation of the paired- and homeodomains.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IEA GO_REF:0000002	ACCEPT	Summary: pax6a encodes a paired/homeodomain sequence-specific DNA-binding transcription factor; transcriptional activation by Pax6a has been directly measured in reporter assays. Reason: Both zebrafish Pax6 co-orthologues retain complete paired domains and homeodomains and activate paired-domain (CD19) and homeodomain (P3) reporter targets at indistinguishable levels in the same assay (PMID:18282108); both act as transcriptional activators and both induce ectopic eyes in Drosophila (PMID:9831649). The molecular function is therefore conserved in both copies and is correctly shared across the pair. Supporting Evidence: PMID:18282108 Activation by the two wild type co-orthologues through the P3 homeodomain target [45] (Figure 1D), or the CD19 paired domain target [46] (Figure 1E), was not significantly different, in contrast to the original observations by Nornes et al [43]. PMID:9831649 Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. PMID:9831649 The coding sequences of the two genes show 82% identity whereas the deduced amino acid sequences are 95% identical with complete conservation of the paired- and homeodomains.
GO:0003309 type B pancreatic cell differentiation	IBA GO_REF:0000033	REMOVE	Summary: IBA transfer of pancreatic beta-cell differentiation to pax6a. pax6a is not expressed in the developing or adult zebrafish pancreas; this ancestral PAX6 role has been partitioned entirely to pax6b. Reason: The PAINT node correctly places endocrine-pancreas function in the vertebrate Pax6 clade, and pax6a retains the molecular function. But there is target-specific evidence that pax6a lost this role at the expression level after the teleost genome duplication: pax6a is not expressed in the embryonic or adult pancreas, is not induced there even when pax6b is mutant (PMID:18282108), and its upstream enhancers A and C are inactive in the pancreas because of divergence in PDX1-binding cis-elements (PMID:18485195). The pancreatic endocrine phenotypes are produced by pax6b loss alone (PMID:20177065). A gene not expressed in the tissue does not take part in the differentiation of its cells, so this IBA is a propagation that the expression partition of the duplicate pair does not support. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN002900580 SUPPORTS SOURCE BUT NOT TARGET Node placement is sound for vertebrate Pax6; after the TGD only the pax6b copy kept pancreatic expression. ZFIN:ZDB-GENE-001031-1 · pax6b SUPPORTS SOURCE BUT NOT TARGET Experimental seed from the paralogue pax6b; pancreas-specific, does not transfer to pax6a. Supporting Evidence: PMID:18282108 only pax6b is expressed in the pancreas isolated from 6 month old wild type and sri/sri fish, while eyes from the same individuals express both pax6a and pax6b PMID:18282108 We also showed that pax6a expression is not induced in the pancreas of the sunrise mutant. PMID:18485195 While both zebrafish pax6 genes are expressed in the developing eye and nervous system, only pax6b is expressed in the endocrine cells of the pancreas. PMID:18485195 In constrast, regions A and C of the zebrafish pax6a gene are not active in the pancreas, this difference being attributable to sequence divergences within two cis-elements binding the pancreatic homeoprotein PDX1.
GO:0003677 DNA binding	IEA GO_REF:0000120	ACCEPT	Summary: DNA binding is correct but general; pax6a binds specific paired-domain and homeodomain sites in cis-regulatory regions. Reason: Broad electronic term, consistent with the more specific IBA term GO:0000978 on this entry. It is not wrong, and IEA terms broader than the IBA/experimental set are acceptable. Supporting Evidence: PMID:9831649 The coding sequences of the two genes show 82% identity whereas the deduced amino acid sequences are 95% identical with complete conservation of the paired- and homeodomains.
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Nuclear localization is expected for a sequence-specific transcription factor. Reason: PAX6 family transcription factors act in the nucleus; the IBA and the UniProt subcellular-location mapping agree. pax6a activates target reporters, which requires nuclear activity (PMID:18282108). Supporting Evidence: PMID:18282108 Activation by the two wild type co-orthologues through the P3 homeodomain target [45] (Figure 1D), or the CD19 paired domain target [46] (Figure 1E), was not significantly different, in contrast to the original observations by Nornes et al [43].
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Nuclear localization is expected for a sequence-specific transcription factor. Reason: PAX6 family transcription factors act in the nucleus; the IBA and the UniProt subcellular-location mapping agree. pax6a activates target reporters, which requires nuclear activity (PMID:18282108). Supporting Evidence: PMID:18282108 Activation by the two wild type co-orthologues through the P3 homeodomain target [45] (Figure 1D), or the CD19 paired domain target [46] (Figure 1E), was not significantly different, in contrast to the original observations by Nornes et al [43].
GO:0006355 regulation of DNA-templated transcription	IEA GO_REF:0000002	ACCEPT	Summary: pax6a regulates transcription as a DNA-binding transcription factor. Reason: Correct process for a sequence-specific transcription factor with demonstrated activator activity (PMID:9831649, PMID:18282108). Supporting Evidence: PMID:9831649 Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. PMID:18282108 Activation by the two wild type co-orthologues through the P3 homeodomain target [45] (Figure 1D), or the CD19 paired domain target [46] (Figure 1E), was not significantly different, in contrast to the original observations by Nornes et al [43].
GO:0006357 regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	Summary: pax6a regulates transcription as a DNA-binding transcription factor. Reason: Correct process for a sequence-specific transcription factor with demonstrated activator activity (PMID:9831649, PMID:18282108). Supporting Evidence: PMID:9831649 Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. PMID:18282108 Activation by the two wild type co-orthologues through the P3 homeodomain target [45] (Figure 1D), or the CD19 paired domain target [46] (Figure 1E), was not significantly different, in contrast to the original observations by Nornes et al [43].
GO:0007420 brain development	IBA GO_REF:0000033	ACCEPT	Summary: pax6a is the major brain-expressed pax6 co-orthologue (telencephalon, diencephalon, hindbrain, spinal cord) and is required for habenular neurogenesis. Reason: The PAINT node places the vertebrate Pax6 role in brain development at an ancestral node; pax6a is inside that clade and, if anything, retains most of the ancestral brain expression and cis-regulatory elements (PMID:18282108). Loss-of-function evidence specific to pax6a exists for the habenula (PMID:27387288). Supporting Evidence: PMID:18282108 pax6a is expressed in the lens and retina, as well as more widely in the developing telencephalon, diencephalon, hind brain, and spinal cord, although not in developing pancreas [49]. PMID:18282108 This may be the situation where several brain-specific elements, with spatiotemporal overlap in expression pattern, have been lost from pax6b. PMID:27387288 Here, we show that habenular neurogenesis requires the homeobox transcription factor Pax6a and the redundant action of two proneural bHLH factors, Neurog1 and Neurod4.
GO:0007423 sensory organ development	IBA GO_REF:0000033	ACCEPT	Summary: pax6a contributes to eye development (retina, lens, anterior segment), a sensory organ. Reason: pax6a is expressed in lens and retina (PMID:18282108) and, together with pax6b, is required for lens and anterior eye segment formation; double mutants lack lens, iris and corneal endothelium (PMID:32555736). General but correct. Supporting Evidence: PMID:18282108 pax6a is expressed in the lens and retina, as well as more widely in the developing telencephalon, diencephalon, hind brain, and spinal cord, although not in developing pancreas [49]. PMID:32555736 In concordance with mouse homozygous pax6 mutant phenotypes, zebrafish pax6a-/-;pax6b-/- double homozygous mutants showed severe defects in distal eye structures, lacking the lens, iris, corneal endothelium and ganglion cell layer of the retina.
GO:0008284 positive regulation of cell population proliferation	IMP PMID:20152834 Pax6a and Pax6b are required at different points in neuronal...	MODIFY	Summary: Morpholino knockdown of pax6a in the light-damaged adult retina reduced later divisions of Muller glia-derived neuronal progenitors. Reason: The IMP is sound, but the proliferating cells are specifically Muller glia-derived neuronal progenitors during photoreceptor regeneration (PMID:20152834); Muller glia and rod precursor proliferation were not Pax6-dependent. A term naming neural precursor proliferation is more accurate than generic cell population proliferation. This is a regeneration context, so non-core. Proposed replacements: positive regulation of neural precursor cell proliferation Supporting Evidence: PMID:20152834 In contrast, the paralogous Pax6a protein was required for later neuronal progenitor cell divisions, which maximized the number of neuronal progenitors. PMID:20152834 This work also defines distinct roles for Pax6a and Pax6b in regulating neuronal progenitor cell proliferation in the adult zebrafish retina
GO:0009952 anterior/posterior pattern specification	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA-predicted role in anterior/posterior pattern specification; supported by reduced pax6a/pax6b activity anteriorizing the hoxd4a expression border. Reason: Knockdown of pax6a and/or pax6b malformed rhombomere boundaries and shifted the hoxd4a border (PMID:17010333), consistent with a conserved Pax6 input to Hoxd4 enhancer activity. A peripheral patterning role, not the core function. Supporting Evidence: PMID:17010333 Additionally, stage-matched zebrafish embryos having decreased pax6a and/or pax6b activity display malformed rhombomere boundaries and an anteriorized hoxd4a expression border.
GO:0030154 cell differentiation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Very general term; pax6a acts in differentiation of several neural and ocular cell types. Reason: Not wrong, but uninformative; the specific developmental processes (habenula, retina, lens/anterior segment) are captured by other annotations. Supporting Evidence: PMID:27387288 Here, we show that habenular neurogenesis requires the homeobox transcription factor Pax6a and the redundant action of two proneural bHLH factors, Neurog1 and Neurod4.
GO:0030900 forebrain development	IBA GO_REF:0000033	ACCEPT	Summary: pax6a is broadly expressed in the telencephalon and diencephalon and is required for habenular (dorsal diencephalon) neurogenesis. Reason: Supported by the forebrain expression of pax6a (PMID:18282108) and by pax6a-specific loss of habenular neurogenesis markers (PMID:27387288); double knockdown of pax6a and pax6b expands MDO shh expression and disrupts epithalamus formation (PMID:24528677). Supporting Evidence: PMID:18282108 pax6a is expressed in the lens and retina, as well as more widely in the developing telencephalon, diencephalon, hind brain, and spinal cord, although not in developing pancreas [49]. PMID:27387288 Somewhat surprisingly, on the other hand, morpholino knock-down of pax6a alone abrogated the expression of both markers (Fig 2C and 2G); pax6a morphant/pax6bsa86 mutant embryos behaved the same as pax6a morphants alone with respect to these markers (Fig 2D and 2H). PMID:24528677 we show that pax6 controls the formation of the epithalamus mostly via the regulation of MDO shh expression in zebrafish.
GO:0030902 hindbrain development	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA-predicted role in hindbrain development; pax6a is expressed in hindbrain and knockdown malformed rhombomere boundaries. Reason: pax6a is expressed in the hindbrain (PMID:18282108) and reduced pax6a and/or pax6b activity malformed rhombomere boundaries (PMID:17010333). Supported but peripheral. Supporting Evidence: PMID:18282108 pax6a is expressed in the lens and retina, as well as more widely in the developing telencephalon, diencephalon, hind brain, and spinal cord, although not in developing pancreas [49]. PMID:17010333 Additionally, stage-matched zebrafish embryos having decreased pax6a and/or pax6b activity display malformed rhombomere boundaries and an anteriorized hoxd4a expression border.
GO:0042670 retinal cone cell differentiation	IMP PMID:20152834 Pax6a and Pax6b are required at different points in neuronal...	MARK AS OVER ANNOTATED	Summary: Cone photoreceptor regeneration after light damage was reduced after pax6a knockdown, but the reduction was not statistically significant and is secondary to reduced progenitor amplification. Reason: The paper (full text read) reports that the pax6a morphant retina had cone regeneration intermediate between controls and pax6b morphants and that the difference from controls was not statistically significant (PMID:20152834). The effect of Pax6a is on the number of Muller glia-derived neuronal progenitors; fewer cones follow from fewer progenitors. Pax6a function is better captured by the progenitor-proliferation term. Supporting Evidence: PMID:20152834 the pax6a morphant retina exhibited a level of cone cell regeneration intermediate to the controls and the pax6b morphant and pax6a/pax6b double morphants PMID:20152834 although this value was not statistically significant relative to the controls PMID:20152834 The reduced number of INL neuronal progenitor cells in both Pax6 knockdown retinas resulted in a corresponding loss of regenerated cones, but not rods.
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000117	ACCEPT	Summary: pax6a activates transcription from Pax6 target sites. Reason: Pax6a (Pax6.1) acts as a transcriptional activator in reporter assays (PMID:9831649, PMID:18282108). Supporting Evidence: PMID:9831649 Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. PMID:18282108 Activation by the two wild type co-orthologues through the P3 homeodomain target [45] (Figure 1D), or the CD19 paired domain target [46] (Figure 1E), was not significantly different, in contrast to the original observations by Nornes et al [43].
GO:0048593 camera-type eye morphogenesis	IEA GO_REF:0000117	ACCEPT	Summary: pax6a takes part in camera-type eye morphogenesis together with pax6b. Reason: pax6a is expressed in lens epithelium and retina (PMID:32555736, PMID:18282108); pax6a;pax6b double mutants lack lens, iris and corneal endothelium, and anterior segment defects scale with the number of mutant pax6a/b copies (PMID:32555736). Supporting Evidence: PMID:32555736 In the WT, the lens epithelium located on the distal end expresses pax6a (E, black arrow) and pax6b (F, black arrow). PMID:32555736 In concordance with mouse homozygous pax6 mutant phenotypes, zebrafish pax6a-/-;pax6b-/- double homozygous mutants showed severe defects in distal eye structures, lacking the lens, iris, corneal endothelium and ganglion cell layer of the retina. PMID:32555736 Largely, AS phenotypes of pax6a/b single and double mutants supported an overall correlation between the degree of reduced pax6a/b gene copy number and the severity of ASD (Fig 6B–6I), as observed in mouse studies [11][33].
GO:0060041 retina development in camera-type eye	IBA GO_REF:0000033	ACCEPT	Summary: pax6a is expressed in the developing retina and acts in retinal development, shared with pax6b. Reason: Retinal expression of pax6a is established (PMID:18282108) and double mutants lack the retinal ganglion cell layer (PMID:32555736). The IBA is consistent with the conserved ancestral role. Supporting Evidence: PMID:18282108 pax6a is expressed in the lens and retina, as well as more widely in the developing telencephalon, diencephalon, hind brain, and spinal cord, although not in developing pancreas [49]. PMID:32555736 In concordance with mouse homozygous pax6 mutant phenotypes, zebrafish pax6a-/-;pax6b-/- double homozygous mutants showed severe defects in distal eye structures, lacking the lens, iris, corneal endothelium and ganglion cell layer of the retina.
GO:0060221 retinal rod cell differentiation	IMP PMID:20152834 Pax6a and Pax6b are required at different points in neuronal...	REMOVE	Summary: Rod photoreceptor regeneration after light damage did not depend on Pax6a. Reason: The cited paper itself shows that reduction of neuronal progenitors after pax6 knockdown reduced regenerated cones but not rods, and that rods regenerate from resident ONL rod precursors whose proliferation is not directly dependent on Pax6 (PMID:20152834). The rod differentiation annotation is contradicted by the full text of its own source. Supporting Evidence: PMID:20152834 The reduced number of INL neuronal progenitor cells in both Pax6 knockdown retinas resulted in a corresponding loss of regenerated cones, but not rods. PMID:20152834 Furthermore, the increased number of PCNA-positive rod precursor cells in both the pax6b and the pax6a morphant retinas clearly shows that rod precursor proliferation is not directly dependent of Pax6.
GO:0021986 habenula development	IMP PMID:27387288 Habenular Neurogenesis in Zebrafish Is Regulated by a Hedgeh...	NEW	Summary: pax6a is required for habenular neurogenesis; pax6b is not. Reason: Morpholino knockdown of pax6a abolished expression of the habenular neuron markers cxcr4b and brn3a, whereas pax6b null mutants had normal habenular markers (PMID:27387288). pax6a acts upstream of neurog1/neurod4 in habenular progenitors, so the transcription factor does the regulatory work of this developmental process. ZFIN has made this IMP annotation to pax6a, but on RefSeq-derived UniProt accessions (e.g. A0A8M3AP00), not on the Swiss-Prot entry P26630 reviewed here. Supporting Evidence: PMID:27387288 Here, we show that habenular neurogenesis requires the homeobox transcription factor Pax6a and the redundant action of two proneural bHLH factors, Neurog1 and Neurod4. PMID:27387288 Homozygous pax6bsa86 mutant embryos display cxcr4b and brn3a expression in the habenulae largely indistinguishable from that of wild type siblings (Fig 2A, 2B, 2E and 2F). PMID:27387288 Somewhat surprisingly, on the other hand, morpholino knock-down of pax6a alone abrogated the expression of both markers (Fig 2C and 2G); pax6a morphant/pax6bsa86 mutant embryos behaved the same as pax6a morphants alone with respect to these markers (Fig 2D and 2H).
GO:0021538 epithalamus development	IGI PMID:24528677 Pax6 regulates the formation of the habenular nuclei by cont...	NEW	Summary: Combined pax6a/pax6b knockdown expands MDO shh expression and disrupts epithalamus formation. Reason: Double knockdown of pax6a and pax6b expanded the MDO shh domain and pax6 controls epithalamus formation via shh (PMID:24528677). The same IGI is on pax6b in GOA and is made by ZFIN to pax6a on RefSeq-derived accessions only; it should be shared across the pair. Consistent with the pax6a-specific habenula result (PMID:27387288). Supporting Evidence: PMID:24528677 Similar to the loss of Pax6 in mice, blockage of the function of both zebrafish homologues pax6a and pax6b by morpholino oligomers led to an expansion of the MDO shh expression domain PMID:24528677 we show that pax6 controls the formation of the epithalamus mostly via the regulation of MDO shh expression in zebrafish. PMID:27387288 Somewhat surprisingly, on the other hand, morpholino knock-down of pax6a alone abrogated the expression of both markers (Fig 2C and 2G); pax6a morphant/pax6bsa86 mutant embryos behaved the same as pax6a morphants alone with respect to these markers (Fig 2D and 2H).
GO:0001755 neural crest cell migration	IGI PMID:32555736 Pax6 organizes the anterior eye segment by guiding two disti...	NEW	Summary: pax6a and pax6b together guide two periocular neural crest waves into the anterior eye segment. Reason: Compound pax6a/pax6b mutants misroute neural crest cells in a gene-dose-dependent way (PMID:32555736). The IGI is present on pax6b in GOA and is made by ZFIN to pax6a on RefSeq-derived accessions only; the genetic evidence involves both copies. The effect is partly non-cell-autonomous (lens and guidance cues), so this is a non-core annotation. Supporting Evidence: PMID:32555736 By analysing zebrafish pax6a/b compound mutants presenting anterior segment dysgenesis, we demonstrate that Pax6a/b guide the two NC populations to distinct proximodistal locations. PMID:32555736 Taken together, our data are consistent with a gene number dependent effect of pax6a/b on the migration of the two distinct waves of NC cells. PMID:32555736 In double heterozygous mutants, pax6a+/-;pax6b+/-, the 2°NC entry into the distal eye compartment was affected in nearly half of the embryos (39%, Table 1), suggesting that this pax6 gene number provides a borderline dose of Pax6 protein.

Gene Description

Existing Annotations Review

Core Functions

Sequence-specific DNA-binding transcription factor (paired domain plus homeodomain) that activates RNA polymerase II target genes; activity equivalent to that of pax6b.

Transcriptional regulator of forebrain development; required (without pax6b) for habenular neurogenesis in the dorsal diencephalon.

Shared with pax6b in a dose-dependent manner: development of the retina, lens and anterior eye segment.

References

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