id: A0A0R4IQL7 gene_symbol: pax6b product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:7955 label: Danio rerio description: >- pax6b is one of two zebrafish co-orthologues of vertebrate PAX6, retained from the teleost-specific genome duplication. It encodes a transcription factor with a paired domain and a paired-type homeodomain that binds cis-regulatory DNA and activates target genes with the same efficiency as its paralogue pax6a. pax6b is expressed in the developing retina and lens placode, in restricted domains of the dorsal diencephalon, midbrain-hindbrain boundary and hindbrain, and, uniquely among the two copies, in pancreatic and intestinal endocrine cells. It is required for lens and anterior eye segment (cornea, iris) development, a role that depends on its homeodomain, and for the differentiation of pancreatic endocrine cells, where it promotes beta and delta cell fates and restrains ghrelin-expressing epsilon cells, a role that does not require the homeodomain. It similarly balances enteroendocrine cell subtypes in the intestine, and it initiates proliferation of Muller glia-derived neuronal progenitors during adult retinal regeneration. The homozygous-viable sunrise mutant carries a pax6b homeodomain missense allele (L244P). existing_annotations: - term: id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables supporting_entities: - FB:FBgn0005558 - MGI:MGI:97485 - MGI:MGI:97486 - MGI:MGI:97488 - MGI:MGI:97489 - MGI:MGI:97490 - PANTHER:PTN002552508 - RGD:3258 - RGD:620434 - UniProtKB:P26367 - UniProtKB:Q06710 - WB:WBGene00001204 - WB:WBGene00003938 review: summary: >- Sequence-specific binding of RNA polymerase II cis-regulatory DNA via the paired domain and homeodomain. action: ACCEPT 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. The sunrise L244P mutation reduces binding to the P2/P3 homeodomain target sites in EMSA (PMID:18282108). supported_by: - reference_id: PMID:18282108 supporting_text: >- 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]. - reference_id: PMID:18282108 supporting_text: >- Sequencing of sri homozygotes and heterozygotes identified a leucine to proline missense mutation in a highly conserved residue of the pax6b homeodomain (Figures 1B, S1B, and S1C). - term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables supporting_entities: - FB:FBgn0003145 - FB:FBgn0005558 - FB:FBgn0005561 - MGI:MGI:97485 - MGI:MGI:97486 - MGI:MGI:97487 - MGI:MGI:97488 - MGI:MGI:97489 - MGI:MGI:97490 - MGI:MGI:97491 - MGI:MGI:97493 - PANTHER:PTN002552508 - RGD:3258 - RGD:620434 - UniProtKB:O43316 - UniProtKB:P26367 - ZFIN:ZDB-GENE-001031-1 - ZFIN:ZDB-GENE-990415-200 review: summary: >- pax6b encodes a paired/homeodomain DNA-binding transcription factor with directly measured transactivation activity. action: ACCEPT 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. The sunrise L244P homeodomain mutation reduces DNA binding and abolishes P3 activation, confirming that the activity depends on the DNA-binding domains. supported_by: - reference_id: PMID:18282108 supporting_text: >- 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]. - reference_id: PMID:9831649 supporting_text: >- Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. - reference_id: PMID:18282108 supporting_text: >- Sequencing of sri homozygotes and heterozygotes identified a leucine to proline missense mutation in a highly conserved residue of the pax6b homeodomain (Figures 1B, S1B, and S1C). - term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific evidence_type: IDA original_reference_id: PMID:18282108 qualifier: enables review: summary: >- pax6b encodes a paired/homeodomain DNA-binding transcription factor with directly measured transactivation activity. action: ACCEPT 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. The sunrise L244P homeodomain mutation reduces DNA binding and abolishes P3 activation, confirming that the activity depends on the DNA-binding domains. supported_by: - reference_id: PMID:18282108 supporting_text: >- 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]. - reference_id: PMID:9831649 supporting_text: >- Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. - reference_id: PMID:18282108 supporting_text: >- Sequencing of sri homozygotes and heterozygotes identified a leucine to proline missense mutation in a highly conserved residue of the pax6b homeodomain (Figures 1B, S1B, and S1C). - term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific evidence_type: IDA original_reference_id: PMID:9831649 qualifier: enables review: summary: >- pax6b encodes a paired/homeodomain DNA-binding transcription factor with directly measured transactivation activity. action: ACCEPT 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. The sunrise L244P homeodomain mutation reduces DNA binding and abolishes P3 activation, confirming that the activity depends on the DNA-binding domains. supported_by: - reference_id: PMID:18282108 supporting_text: >- 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]. - reference_id: PMID:9831649 supporting_text: >- Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. - reference_id: PMID:18282108 supporting_text: >- Sequencing of sri homozygotes and heterozygotes identified a leucine to proline missense mutation in a highly conserved residue of the pax6b homeodomain (Figures 1B, S1B, and S1C). - term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables supporting_entities: - InterPro:IPR017970 review: summary: >- pax6b encodes a paired/homeodomain DNA-binding transcription factor with directly measured transactivation activity. action: ACCEPT 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. The sunrise L244P homeodomain mutation reduces DNA binding and abolishes P3 activation, confirming that the activity depends on the DNA-binding domains. supported_by: - reference_id: PMID:18282108 supporting_text: >- 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]. - reference_id: PMID:9831649 supporting_text: >- Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. - reference_id: PMID:18282108 supporting_text: >- Sequencing of sri homozygotes and heterozygotes identified a leucine to proline missense mutation in a highly conserved residue of the pax6b homeodomain (Figures 1B, S1B, and S1C). - term: id: GO:0001654 label: eye development evidence_type: IMP original_reference_id: PMID:18282108 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100610-2 review: summary: >- pax6b sunrise mutants and pax6b morphants have small eyes with lens and cornea defects. action: ACCEPT reason: >- sunrise (pax6b L244P) homozygotes show a fully penetrant microphthalmia with abnormal lens and cornea; two pax6b morpholinos give a more severe reduction in eye size (PMID:18282108). Eye development is a core, ancestral Pax6 role shared with pax6a; the milder phenotype than in mammals reflects role-sharing with pax6a. supported_by: - reference_id: PMID:18282108 supporting_text: >- Sequencing of sri homozygotes and heterozygotes identified a leucine to proline missense mutation in a highly conserved residue of the pax6b homeodomain (Figures 1B, S1B, and S1C). - reference_id: PMID:18282108 supporting_text: >- First, pax6b morpholino injections, using two different morpholinos, resulted in reduced eye size, a phenotype overlapping the sri phenotype, but somewhat more severe, as total eye size reduction (Figure 3A and 3B) rather than just small lens size [27] (Figure 1A) was observed. - reference_id: PMID:18282108 supporting_text: The mild phenotype emphasizes role-sharing between the co-orthologues. - term: id: GO:0001654 label: eye development evidence_type: IMP original_reference_id: PMID:18282108 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-080925-4 review: summary: >- pax6b sunrise mutants and pax6b morphants have small eyes with lens and cornea defects. action: ACCEPT reason: >- sunrise (pax6b L244P) homozygotes show a fully penetrant microphthalmia with abnormal lens and cornea; two pax6b morpholinos give a more severe reduction in eye size (PMID:18282108). Eye development is a core, ancestral Pax6 role shared with pax6a; the milder phenotype than in mammals reflects role-sharing with pax6a. supported_by: - reference_id: PMID:18282108 supporting_text: >- Sequencing of sri homozygotes and heterozygotes identified a leucine to proline missense mutation in a highly conserved residue of the pax6b homeodomain (Figures 1B, S1B, and S1C). - reference_id: PMID:18282108 supporting_text: >- First, pax6b morpholino injections, using two different morpholinos, resulted in reduced eye size, a phenotype overlapping the sri phenotype, but somewhat more severe, as total eye size reduction (Figure 3A and 3B) rather than just small lens size [27] (Figure 1A) was observed. - reference_id: PMID:18282108 supporting_text: The mild phenotype emphasizes role-sharing between the co-orthologues. - term: id: GO:0001654 label: eye development evidence_type: IMP original_reference_id: PMID:18282108 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-080925-5 review: summary: >- pax6b sunrise mutants and pax6b morphants have small eyes with lens and cornea defects. action: ACCEPT reason: >- sunrise (pax6b L244P) homozygotes show a fully penetrant microphthalmia with abnormal lens and cornea; two pax6b morpholinos give a more severe reduction in eye size (PMID:18282108). Eye development is a core, ancestral Pax6 role shared with pax6a; the milder phenotype than in mammals reflects role-sharing with pax6a. supported_by: - reference_id: PMID:18282108 supporting_text: >- Sequencing of sri homozygotes and heterozygotes identified a leucine to proline missense mutation in a highly conserved residue of the pax6b homeodomain (Figures 1B, S1B, and S1C). - reference_id: PMID:18282108 supporting_text: >- First, pax6b morpholino injections, using two different morpholinos, resulted in reduced eye size, a phenotype overlapping the sri phenotype, but somewhat more severe, as total eye size reduction (Figure 3A and 3B) rather than just small lens size [27] (Figure 1A) was observed. - reference_id: PMID:18282108 supporting_text: The mild phenotype emphasizes role-sharing between the co-orthologues. - term: id: GO:0001755 label: neural crest cell migration evidence_type: IGI original_reference_id: PMID:32555736 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-220927-6 review: summary: pax6a/pax6b compound mutants misroute two periocular neural crest populations. action: KEEP_AS_NON_CORE reason: >- Supported by compound-mutant analysis with a gene-dose-dependent effect (PMID:32555736). The role is partly indirect (via the pax6-dependent lens and guidance cues), and it is shared with pax6a, whose equivalent ZFIN annotation is missing from the Swiss-Prot pax6a entry. supported_by: - reference_id: PMID:32555736 supporting_text: >- 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. - reference_id: PMID:32555736 supporting_text: >- 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. - term: id: GO:0002088 label: lens development in camera-type eye evidence_type: IMP original_reference_id: PMID:17397257 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-070917-1 review: summary: Hsp90 inhibition worsens lens size reduction in sunrise pax6b mutants. action: ACCEPT reason: >- sunrise homozygotes have reduced lens size relative to retina, worsened by Hsp90 inhibition (PMID:17397257). Lens development is a core pax6b function (also PMID:20177065). supported_by: - reference_id: PMID:17397257 supporting_text: >- Under these conditions the severity of the recessive eye phenotype in sunrise, caused by a pax6b mutation, was increased - reference_id: PMID:17397257 supporting_text: >- Upon Hsp90 functional reduction, lens size relative to the area of the retina was significantly decreased in homozygous sri embryos while homozygous dre remained unaltered (Figure 3I; Table 2). - reference_id: PMID:20177065 supporting_text: >- Crosses between pax6b sa0086 carrier fish generated homozygous mutant embryos, all displaying severe lens defects - term: id: GO:0002089 label: lens morphogenesis in camera-type eye evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100507-7 review: summary: >- pax6b null mutants and pax6b morphants (including homeodomain-deleting splice morpholinos) have strongly affected lens formation. action: ACCEPT reason: >- All pax6b sa0086 (Y109*) homozygotes display severe lens defects, and deletion of the Pax6b homeodomain strongly affects lens formation while leaving the pancreas intact (PMID:20177065). The lens requires the homeodomain; the pancreas does not. supported_by: - reference_id: PMID:20177065 supporting_text: >- Crosses between pax6b sa0086 carrier fish generated homozygous mutant embryos, all displaying severe lens defects - reference_id: PMID:20177065 supporting_text: >- we show that deletion of the Pax6b homeodomain in zebrafish embryos does not disturb pancreas development, whereas lens formation is strongly affected. - term: id: GO:0002089 label: lens morphogenesis in camera-type eye evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-4 review: summary: >- pax6b null mutants and pax6b morphants (including homeodomain-deleting splice morpholinos) have strongly affected lens formation. action: ACCEPT reason: >- All pax6b sa0086 (Y109*) homozygotes display severe lens defects, and deletion of the Pax6b homeodomain strongly affects lens formation while leaving the pancreas intact (PMID:20177065). The lens requires the homeodomain; the pancreas does not. supported_by: - reference_id: PMID:20177065 supporting_text: >- Crosses between pax6b sa0086 carrier fish generated homozygous mutant embryos, all displaying severe lens defects - reference_id: PMID:20177065 supporting_text: >- we show that deletion of the Pax6b homeodomain in zebrafish embryos does not disturb pancreas development, whereas lens formation is strongly affected. - term: id: GO:0002089 label: lens morphogenesis in camera-type eye evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-4 - ZFIN:ZDB-MRPHLNO-100610-7 review: summary: >- pax6b null mutants and pax6b morphants (including homeodomain-deleting splice morpholinos) have strongly affected lens formation. action: ACCEPT reason: >- All pax6b sa0086 (Y109*) homozygotes display severe lens defects, and deletion of the Pax6b homeodomain strongly affects lens formation while leaving the pancreas intact (PMID:20177065). The lens requires the homeodomain; the pancreas does not. supported_by: - reference_id: PMID:20177065 supporting_text: >- Crosses between pax6b sa0086 carrier fish generated homozygous mutant embryos, all displaying severe lens defects - reference_id: PMID:20177065 supporting_text: >- we show that deletion of the Pax6b homeodomain in zebrafish embryos does not disturb pancreas development, whereas lens formation is strongly affected. - term: id: GO:0002089 label: lens morphogenesis in camera-type eye evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-5 review: summary: >- pax6b null mutants and pax6b morphants (including homeodomain-deleting splice morpholinos) have strongly affected lens formation. action: ACCEPT reason: >- All pax6b sa0086 (Y109*) homozygotes display severe lens defects, and deletion of the Pax6b homeodomain strongly affects lens formation while leaving the pancreas intact (PMID:20177065). The lens requires the homeodomain; the pancreas does not. supported_by: - reference_id: PMID:20177065 supporting_text: >- Crosses between pax6b sa0086 carrier fish generated homozygous mutant embryos, all displaying severe lens defects - reference_id: PMID:20177065 supporting_text: >- we show that deletion of the Pax6b homeodomain in zebrafish embryos does not disturb pancreas development, whereas lens formation is strongly affected. - term: id: GO:0002089 label: lens morphogenesis in camera-type eye evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-5 - ZFIN:ZDB-MRPHLNO-100610-6 review: summary: >- pax6b null mutants and pax6b morphants (including homeodomain-deleting splice morpholinos) have strongly affected lens formation. action: ACCEPT reason: >- All pax6b sa0086 (Y109*) homozygotes display severe lens defects, and deletion of the Pax6b homeodomain strongly affects lens formation while leaving the pancreas intact (PMID:20177065). The lens requires the homeodomain; the pancreas does not. supported_by: - reference_id: PMID:20177065 supporting_text: >- Crosses between pax6b sa0086 carrier fish generated homozygous mutant embryos, all displaying severe lens defects - reference_id: PMID:20177065 supporting_text: >- we show that deletion of the Pax6b homeodomain in zebrafish embryos does not disturb pancreas development, whereas lens formation is strongly affected. - term: id: GO:0003309 label: type B pancreatic cell differentiation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:97488 - MGI:MGI:97490 - PANTHER:PTN002900580 - RGD:3258 - ZFIN:ZDB-GENE-001031-1 review: summary: IBA transfer of beta-cell differentiation; confirmed experimentally for pax6b. action: ACCEPT reason: >- The IBA is consistent with pax6b's own IMP evidence (PMID:20177065, PMID:32867764); pax6b appearing among the IBA sources reflects experimental grounding on the target itself. Within the zebrafish pair, pax6b is the only copy expressed in the pancreas. supported_by: - reference_id: PMID:20177065 supporting_text: >- We show here that pax6b does play an essential role in pancreatic endocrine cell differentiation, as revealed by the phenotype of a novel zebrafish pax6b null mutant and of embryos injected with pax6b morpholinos. - reference_id: PMID:18282108 supporting_text: >- 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 - term: id: GO:0003309 label: type B pancreatic cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100507-7 review: summary: >- pax6b is required for pancreatic beta-cell differentiation; pax6b-deficient embryos have almost no beta cells. action: ACCEPT reason: >- Null mutant (sa0086) and three morpholinos give near-absence of beta cells (PMID:20177065), confirmed by RNA-seq of purified pancreatic endocrine cells (PMID:32867764). pax6b is the only pax6 copy expressed in the pancreas (PMID:18282108, PMID:18485195), so in zebrafish this ancestral PAX6 role is pax6b-specific. supported_by: - reference_id: PMID:20177065 supporting_text: >- We show here that pax6b does play an essential role in pancreatic endocrine cell differentiation, as revealed by the phenotype of a novel zebrafish pax6b null mutant and of embryos injected with pax6b morpholinos. - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - reference_id: PMID:18282108 supporting_text: >- 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 - term: id: GO:0003309 label: type B pancreatic cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-3 review: summary: >- pax6b is required for pancreatic beta-cell differentiation; pax6b-deficient embryos have almost no beta cells. action: ACCEPT reason: >- Null mutant (sa0086) and three morpholinos give near-absence of beta cells (PMID:20177065), confirmed by RNA-seq of purified pancreatic endocrine cells (PMID:32867764). pax6b is the only pax6 copy expressed in the pancreas (PMID:18282108, PMID:18485195), so in zebrafish this ancestral PAX6 role is pax6b-specific. supported_by: - reference_id: PMID:20177065 supporting_text: >- We show here that pax6b does play an essential role in pancreatic endocrine cell differentiation, as revealed by the phenotype of a novel zebrafish pax6b null mutant and of embryos injected with pax6b morpholinos. - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - reference_id: PMID:18282108 supporting_text: >- 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 - term: id: GO:0003309 label: type B pancreatic cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-4 review: summary: >- pax6b is required for pancreatic beta-cell differentiation; pax6b-deficient embryos have almost no beta cells. action: ACCEPT reason: >- Null mutant (sa0086) and three morpholinos give near-absence of beta cells (PMID:20177065), confirmed by RNA-seq of purified pancreatic endocrine cells (PMID:32867764). pax6b is the only pax6 copy expressed in the pancreas (PMID:18282108, PMID:18485195), so in zebrafish this ancestral PAX6 role is pax6b-specific. supported_by: - reference_id: PMID:20177065 supporting_text: >- We show here that pax6b does play an essential role in pancreatic endocrine cell differentiation, as revealed by the phenotype of a novel zebrafish pax6b null mutant and of embryos injected with pax6b morpholinos. - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - reference_id: PMID:18282108 supporting_text: >- 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 - term: id: GO:0003309 label: type B pancreatic cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-4 - ZFIN:ZDB-MRPHLNO-100610-7 review: summary: >- pax6b is required for pancreatic beta-cell differentiation; pax6b-deficient embryos have almost no beta cells. action: ACCEPT reason: >- Null mutant (sa0086) and three morpholinos give near-absence of beta cells (PMID:20177065), confirmed by RNA-seq of purified pancreatic endocrine cells (PMID:32867764). pax6b is the only pax6 copy expressed in the pancreas (PMID:18282108, PMID:18485195), so in zebrafish this ancestral PAX6 role is pax6b-specific. supported_by: - reference_id: PMID:20177065 supporting_text: >- We show here that pax6b does play an essential role in pancreatic endocrine cell differentiation, as revealed by the phenotype of a novel zebrafish pax6b null mutant and of embryos injected with pax6b morpholinos. - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - reference_id: PMID:18282108 supporting_text: >- 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 - term: id: GO:0003309 label: type B pancreatic cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-5 review: summary: >- pax6b is required for pancreatic beta-cell differentiation; pax6b-deficient embryos have almost no beta cells. action: ACCEPT reason: >- Null mutant (sa0086) and three morpholinos give near-absence of beta cells (PMID:20177065), confirmed by RNA-seq of purified pancreatic endocrine cells (PMID:32867764). pax6b is the only pax6 copy expressed in the pancreas (PMID:18282108, PMID:18485195), so in zebrafish this ancestral PAX6 role is pax6b-specific. supported_by: - reference_id: PMID:20177065 supporting_text: >- We show here that pax6b does play an essential role in pancreatic endocrine cell differentiation, as revealed by the phenotype of a novel zebrafish pax6b null mutant and of embryos injected with pax6b morpholinos. - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - reference_id: PMID:18282108 supporting_text: >- 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 - term: id: GO:0003309 label: type B pancreatic cell differentiation evidence_type: IMP original_reference_id: PMID:32867764 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100507-7 review: summary: >- pax6b is required for pancreatic beta-cell differentiation; pax6b-deficient embryos have almost no beta cells. action: ACCEPT reason: >- Null mutant (sa0086) and three morpholinos give near-absence of beta cells (PMID:20177065), confirmed by RNA-seq of purified pancreatic endocrine cells (PMID:32867764). pax6b is the only pax6 copy expressed in the pancreas (PMID:18282108, PMID:18485195), so in zebrafish this ancestral PAX6 role is pax6b-specific. supported_by: - reference_id: PMID:20177065 supporting_text: >- We show here that pax6b does play an essential role in pancreatic endocrine cell differentiation, as revealed by the phenotype of a novel zebrafish pax6b null mutant and of embryos injected with pax6b morpholinos. - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - reference_id: PMID:18282108 supporting_text: >- 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 - term: id: GO:0003310 label: pancreatic A cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100507-7 review: summary: >- pax6b influences alpha-cell differentiation: partial knockdown increases alpha cells, while null mutants have misdifferentiated alpha cells. action: ACCEPT reason: >- The phenotype is dose-dependent and variable: small morpholino doses raise alpha-cell number and glucagon, about 40% of null mutants have fewer alpha cells, and alpha cells in null mutants are misdifferentiated (PMID:20177065, PMID:32867764). pax6b clearly acts upstream of or within alpha-cell differentiation, although less decisively than for beta cells. supported_by: - reference_id: PMID:20177065 supporting_text: >- partial reduction of Pax6b function in zebrafish embryos performed by injection of small amounts of pax6b morpholinos caused a clear rise in alpha cell number and in glucagon expression - reference_id: PMID:20177065 supporting_text: >- On the other hand, the fact that α cell differentiation is not strongly affected in about 60% of pax6b sa0086 mutants indicates that a Pax6b-independent pathway may also be used to generate glucagon cells. - reference_id: PMID:32867764 supporting_text: >- Alpha cells are still generated in the pax6bsa0086 mutants, but these cells are misdifferentiated. - term: id: GO:0003310 label: pancreatic A cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-4 review: summary: >- pax6b influences alpha-cell differentiation: partial knockdown increases alpha cells, while null mutants have misdifferentiated alpha cells. action: ACCEPT reason: >- The phenotype is dose-dependent and variable: small morpholino doses raise alpha-cell number and glucagon, about 40% of null mutants have fewer alpha cells, and alpha cells in null mutants are misdifferentiated (PMID:20177065, PMID:32867764). pax6b clearly acts upstream of or within alpha-cell differentiation, although less decisively than for beta cells. supported_by: - reference_id: PMID:20177065 supporting_text: >- partial reduction of Pax6b function in zebrafish embryos performed by injection of small amounts of pax6b morpholinos caused a clear rise in alpha cell number and in glucagon expression - reference_id: PMID:20177065 supporting_text: >- On the other hand, the fact that α cell differentiation is not strongly affected in about 60% of pax6b sa0086 mutants indicates that a Pax6b-independent pathway may also be used to generate glucagon cells. - reference_id: PMID:32867764 supporting_text: >- Alpha cells are still generated in the pax6bsa0086 mutants, but these cells are misdifferentiated. - term: id: GO:0003310 label: pancreatic A cell differentiation evidence_type: IMP original_reference_id: PMID:32867764 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100507-7 review: summary: >- pax6b influences alpha-cell differentiation: partial knockdown increases alpha cells, while null mutants have misdifferentiated alpha cells. action: ACCEPT reason: >- The phenotype is dose-dependent and variable: small morpholino doses raise alpha-cell number and glucagon, about 40% of null mutants have fewer alpha cells, and alpha cells in null mutants are misdifferentiated (PMID:20177065, PMID:32867764). pax6b clearly acts upstream of or within alpha-cell differentiation, although less decisively than for beta cells. supported_by: - reference_id: PMID:20177065 supporting_text: >- partial reduction of Pax6b function in zebrafish embryos performed by injection of small amounts of pax6b morpholinos caused a clear rise in alpha cell number and in glucagon expression - reference_id: PMID:20177065 supporting_text: >- On the other hand, the fact that α cell differentiation is not strongly affected in about 60% of pax6b sa0086 mutants indicates that a Pax6b-independent pathway may also be used to generate glucagon cells. - reference_id: PMID:32867764 supporting_text: >- Alpha cells are still generated in the pax6bsa0086 mutants, but these cells are misdifferentiated. - term: id: GO:0003311 label: pancreatic D cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100507-7 review: summary: pax6b-deficient embryos have strongly reduced delta cells. action: ACCEPT reason: >- Null mutants and morphants have a strongly reduced number of delta cells (PMID:20177065), and delta-cell genes are downregulated in sorted mutant endocrine cells (PMID:32867764). supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:0003311 label: pancreatic D cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-3 review: summary: pax6b-deficient embryos have strongly reduced delta cells. action: ACCEPT reason: >- Null mutants and morphants have a strongly reduced number of delta cells (PMID:20177065), and delta-cell genes are downregulated in sorted mutant endocrine cells (PMID:32867764). supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:0003311 label: pancreatic D cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-4 review: summary: pax6b-deficient embryos have strongly reduced delta cells. action: ACCEPT reason: >- Null mutants and morphants have a strongly reduced number of delta cells (PMID:20177065), and delta-cell genes are downregulated in sorted mutant endocrine cells (PMID:32867764). supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:0003311 label: pancreatic D cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-4 - ZFIN:ZDB-MRPHLNO-100610-7 review: summary: pax6b-deficient embryos have strongly reduced delta cells. action: ACCEPT reason: >- Null mutants and morphants have a strongly reduced number of delta cells (PMID:20177065), and delta-cell genes are downregulated in sorted mutant endocrine cells (PMID:32867764). supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:0003311 label: pancreatic D cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-5 review: summary: pax6b-deficient embryos have strongly reduced delta cells. action: ACCEPT reason: >- Null mutants and morphants have a strongly reduced number of delta cells (PMID:20177065), and delta-cell genes are downregulated in sorted mutant endocrine cells (PMID:32867764). supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:0003311 label: pancreatic D cell differentiation evidence_type: IMP original_reference_id: PMID:32867764 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100507-7 review: summary: pax6b-deficient embryos have strongly reduced delta cells. action: ACCEPT reason: >- Null mutants and morphants have a strongly reduced number of delta cells (PMID:20177065), and delta-cell genes are downregulated in sorted mutant endocrine cells (PMID:32867764). supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:0003677 label: DNA binding evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables supporting_entities: - ARBA:ARBA00029224 - InterPro:IPR001356 - InterPro:IPR001523 - InterPro:IPR043565 - UniRule:UR000401037 review: summary: DNA binding; correct but general. action: ACCEPT reason: >- Broad electronic term consistent with the more specific GO:0000978; pax6b binds P2/P3 homeodomain sites (PMID:18282108). supported_by: - reference_id: PMID:18282108 supporting_text: >- Sequencing of sri homozygotes and heterozygotes identified a leucine to proline missense mutation in a highly conserved residue of the pax6b homeodomain (Figures 1B, S1B, and S1C). - term: id: GO:0005634 label: nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - FB:FBgn0000625 - FB:FBgn0001147 - FB:FBgn0001148 - FB:FBgn0003129 - FB:FBgn0003130 - FB:FBgn0005561 - FB:FBgn0036285 - MGI:MGI:97486 - MGI:MGI:97487 - MGI:MGI:97489 - MGI:MGI:97490 - MGI:MGI:97491 - MGI:MGI:97492 - PANTHER:PTN002552508 - RGD:3258 - RGD:620434 - UniProtKB:P23760 - UniProtKB:P26367 - UniProtKB:P55771 - UniProtKB:Q02548 - UniProtKB:Q02962 - UniProtKB:Q06710 - UniProtKB:Q8QGS3 - WB:WBGene00001204 - WB:WBGene00003937 - WB:WBGene00003939 - WB:WBGene00006870 - ZFIN:ZDB-GENE-980526-52 - ZFIN:ZDB-GENE-990415-200 - ZFIN:ZDB-GENE-990415-201 - ZFIN:ZDB-GENE-990415-8 review: summary: Nuclear localization expected for a sequence-specific transcription factor. action: ACCEPT reason: >- PAX6 family transcription factors act in the nucleus; consistent with demonstrated transactivation (PMID:18282108). supported_by: - reference_id: PMID:18282108 supporting_text: >- 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]. - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0191 - UniRule:UR000401037 review: summary: Nuclear localization expected for a sequence-specific transcription factor. action: ACCEPT reason: >- PAX6 family transcription factors act in the nucleus; consistent with demonstrated transactivation (PMID:18282108). supported_by: - reference_id: PMID:18282108 supporting_text: >- 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]. - term: id: GO:0006351 label: DNA-templated transcription evidence_type: IEA original_reference_id: GO_REF:0000104 qualifier: involved_in supporting_entities: - UniRule:UR000416039 review: summary: UniRule-based annotation to DNA-templated transcription. action: MODIFY reason: >- pax6b is a sequence-specific transcription factor: it regulates transcription rather than carrying out the synthesis of RNA itself. The regulatory term is the appropriate process. proposed_replacement_terms: - id: GO:0006357 label: regulation of transcription by RNA polymerase II supported_by: - reference_id: PMID:9831649 supporting_text: >- Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. - term: id: GO:0006355 label: regulation of DNA-templated transcription evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in supporting_entities: - InterPro:IPR001523 - InterPro:IPR017970 - InterPro:IPR043565 - UniRule:UR000416039 review: summary: pax6b regulates transcription as a DNA-binding transcription factor. action: ACCEPT reason: >- Correct process for a transcription factor with demonstrated activator activity (PMID:9831649, PMID:18282108). supported_by: - reference_id: PMID:9831649 supporting_text: >- Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. - reference_id: PMID:18282108 supporting_text: >- 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]. - term: id: GO:0006357 label: regulation of transcription by RNA polymerase II evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - FB:FBgn0000625 - FB:FBgn0003145 - FB:FBgn0005558 - FB:FBgn0005561 - FB:FBgn0019650 - FB:FBgn0036285 - MGI:MGI:97485 - MGI:MGI:97486 - MGI:MGI:97487 - MGI:MGI:97488 - MGI:MGI:97489 - MGI:MGI:97490 - MGI:MGI:97491 - MGI:MGI:97493 - PANTHER:PTN002552508 - RGD:3258 - RGD:620434 - UniProtKB:P23760 - UniProtKB:P26367 - UniProtKB:Q02962 - UniProtKB:Q06710 - WB:WBGene00001204 - WB:WBGene00003938 - WB:WBGene00006870 - ZFIN:ZDB-GENE-001031-1 - ZFIN:ZDB-GENE-990415-200 review: summary: pax6b regulates transcription as a DNA-binding transcription factor. action: ACCEPT reason: >- Correct process for a transcription factor with demonstrated activator activity (PMID:9831649, PMID:18282108). supported_by: - reference_id: PMID:9831649 supporting_text: >- Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. - reference_id: PMID:18282108 supporting_text: >- 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]. - term: id: GO:0007420 label: brain development evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - FB:FBgn0005558 - MGI:MGI:97490 - PANTHER:PTN008693041 - RGD:3258 - ZFIN:ZDB-GENE-001031-1 - ZFIN:ZDB-GENE-990415-200 review: summary: >- pax6b is expressed in restricted brain domains (dorsal diencephalon, MHB, hindbrain) and contributes to brain development jointly with pax6a. action: ACCEPT reason: >- Correct at the ancestral node. pax6b has lost several brain-specific cis-elements and has a narrower brain expression than pax6a (PMID:18282108), but it keeps brain expression and takes part with pax6a in diencephalic and hindbrain patterning (PMID:24528677, PMID:17010333). supported_by: - reference_id: PMID:18282108 supporting_text: >- pax6b is the “minor” co-orthologue, expressed in the developing eye (retina and early lens placode), and also in thin strips of dorsal diencephalon, at the midbrain-hindbrain boundary (MHB), and in the pancreas. - reference_id: PMID:18282108 supporting_text: >- This may be the situation where several brain-specific elements, with spatiotemporal overlap in expression pattern, have been lost from pax6b. - reference_id: PMID:24528677 supporting_text: >- 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 - term: id: GO:0007423 label: sensory organ development evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - FB:FBgn0000625 - FB:FBgn0005558 - FB:FBgn0036285 - MGI:MGI:97490 - PANTHER:PTN008693041 - RGD:3258 - RGD:620433 - UniProtKB:A0A1L8GJ29 - UniProtKB:P26367 - WB:WBGene00006870 - ZFIN:ZDB-GENE-001031-1 - ZFIN:ZDB-GENE-081022-10 - ZFIN:ZDB-GENE-990415-200 review: summary: pax6b is required for eye (lens, cornea, iris) development, a sensory organ. action: ACCEPT reason: >- General but correct; supported by sunrise and null-mutant eye phenotypes (PMID:18282108, PMID:25692557). supported_by: - reference_id: PMID:18282108 supporting_text: >- Sequencing of sri homozygotes and heterozygotes identified a leucine to proline missense mutation in a highly conserved residue of the pax6b homeodomain (Figures 1B, S1B, and S1C). - reference_id: PMID:25692557 supporting_text: >- We also characterised homozygous pax6b mutants. Mutant embryos have a thick cornea, iris hypoplasia, a shallow anterior chamber and a small lens. - term: id: GO:0009952 label: anterior/posterior pattern specification evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00027259 review: summary: >- Reduced pax6a and/or pax6b activity anteriorizes the hoxd4a expression border and malforms rhombomere boundaries. action: KEEP_AS_NON_CORE reason: >- Supported by morpholino evidence (PMID:17010333; abstract only, curator's IMP deferred to), but a peripheral patterning role shared with pax6a. supported_by: - reference_id: PMID:17010333 supporting_text: >- Additionally, stage-matched zebrafish embryos having decreased pax6a and/or pax6b activity display malformed rhombomere boundaries and an anteriorized hoxd4a expression border. - term: id: GO:0009952 label: anterior/posterior pattern specification evidence_type: IMP original_reference_id: PMID:17010333 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041116-2 review: summary: >- Reduced pax6a and/or pax6b activity anteriorizes the hoxd4a expression border and malforms rhombomere boundaries. action: KEEP_AS_NON_CORE reason: >- Supported by morpholino evidence (PMID:17010333; abstract only, curator's IMP deferred to), but a peripheral patterning role shared with pax6a. supported_by: - reference_id: PMID:17010333 supporting_text: >- Additionally, stage-matched zebrafish embryos having decreased pax6a and/or pax6b activity display malformed rhombomere boundaries and an anteriorized hoxd4a expression border. - term: id: GO:0010468 label: regulation of gene expression evidence_type: IGI original_reference_id: PMID:24528677 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041116-1 - ZFIN:ZDB-MRPHLNO-041116-2 review: summary: >- Double knockdown of pax6a/pax6b changes expression of shh, otx5 and cxcr4b in the diencephalon. action: KEEP_AS_NON_CORE reason: >- The observation is sound (PMID:24528677), but 'regulation of gene expression' is a very general term for a transcription factor; the informative content is captured by the transcription-factor MF and the epithalamus annotation. supported_by: - reference_id: PMID:24528677 supporting_text: >- 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 - term: id: GO:0021538 label: epithalamus development evidence_type: IGI original_reference_id: PMID:24528677 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041116-1 - ZFIN:ZDB-MRPHLNO-041116-2 review: summary: >- Double pax6a/pax6b knockdown expands MDO shh expression and disrupts epithalamus formation. action: KEEP_AS_NON_CORE reason: >- The IGI is based on combined knockdown of both co-orthologues (PMID:24528677), so it establishes a joint Pax6 requirement. A later study showed that pax6b null mutants have normal habenular markers while pax6a knockdown abolishes them (PMID:27387288), so the epithalamic role rests mainly with pax6a. Kept, as non-core for pax6b. supported_by: - reference_id: PMID:24528677 supporting_text: >- 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 - reference_id: PMID:24528677 supporting_text: >- we show that pax6 controls the formation of the epithalamus mostly via the regulation of MDO shh expression in zebrafish. - reference_id: PMID:27387288 supporting_text: >- 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). - term: id: GO:0030154 label: cell differentiation evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00027429 review: summary: >- General term; pax6b acts in differentiation of pancreatic endocrine, enteroendocrine and ocular cells. action: KEEP_AS_NON_CORE reason: >- Correct but uninformative; specific cell differentiation terms are annotated separately. supported_by: - reference_id: PMID:20177065 supporting_text: >- We show here that pax6b does play an essential role in pancreatic endocrine cell differentiation, as revealed by the phenotype of a novel zebrafish pax6b null mutant and of embryos injected with pax6b morpholinos. - term: id: GO:0030900 label: forebrain development evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:97490 - PANTHER:PTN002900580 - RGD:3258 - ZFIN:ZDB-GENE-001031-1 - ZFIN:ZDB-GENE-990415-200 review: summary: >- pax6b is expressed in dorsal diencephalon and telencephalon-directed enhancers, and participates with pax6a in forebrain development. action: ACCEPT reason: >- The IBA is consistent with pax6b expression in the dorsal diencephalon (PMID:18282108) and with the double-knockdown diencephalic phenotype (PMID:24528677). The main forebrain role in zebrafish sits with pax6a. supported_by: - reference_id: PMID:18282108 supporting_text: >- pax6b is the “minor” co-orthologue, expressed in the developing eye (retina and early lens placode), and also in thin strips of dorsal diencephalon, at the midbrain-hindbrain boundary (MHB), and in the pancreas. - reference_id: PMID:24528677 supporting_text: >- 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 - term: id: GO:0030902 label: hindbrain development evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00088342 review: summary: pax6b is expressed in hindbrain and knockdown affected rhombomere boundaries. action: KEEP_AS_NON_CORE reason: >- pax6b hindbrain expression increases by 32 hpf (PMID:18282108) and pax6a/pax6b knockdown malforms rhombomere boundaries (PMID:17010333). Peripheral, and shared with pax6a. supported_by: - reference_id: PMID:17010333 supporting_text: >- Additionally, stage-matched zebrafish embryos having decreased pax6a and/or pax6b activity display malformed rhombomere boundaries and an anteriorized hoxd4a expression border. - term: id: GO:0030902 label: hindbrain development evidence_type: IMP original_reference_id: PMID:17010333 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-041116-2 review: summary: pax6b is expressed in hindbrain and knockdown affected rhombomere boundaries. action: KEEP_AS_NON_CORE reason: >- pax6b hindbrain expression increases by 32 hpf (PMID:18282108) and pax6a/pax6b knockdown malforms rhombomere boundaries (PMID:17010333). Peripheral, and shared with pax6a. supported_by: - reference_id: PMID:17010333 supporting_text: >- Additionally, stage-matched zebrafish embryos having decreased pax6a and/or pax6b activity display malformed rhombomere boundaries and an anteriorized hoxd4a expression border. - term: id: GO:0035883 label: enteroendocrine cell differentiation evidence_type: IMP original_reference_id: PMID:32867764 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100507-7 review: summary: >- pax6b loss disrupts the balance of enteroendocrine cell subtypes in the intestine. action: ACCEPT reason: >- pax6b null mutants gain ghrelin/motilin-like-expressing cells at the expense of other subtypes such as pyyb cells, in both intestine and pancreas (PMID:32867764); the pax6b P0 promoter drives enteroendocrine expression (PMID:18485195). A pax6b-specific role in zebrafish, matching the ancestral PAX6 role in gut endocrine cells. supported_by: - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - reference_id: PMID:18485195 supporting_text: >- We show that the pax6b P0 promoter targets expression to endocrine pancreatic cells and also to enteroendocrine cells, retinal neurons and the telencephalon of transgenic zebrafish. - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: IDA original_reference_id: PMID:9831649 qualifier: acts_upstream_of_or_within review: summary: pax6b (Pax6.2) activates transcription in reporter assays. action: ACCEPT reason: >- Directly shown (PMID:9831649); the later side-by-side assay found pax6a and pax6b equally active (PMID:18282108). supported_by: - reference_id: PMID:9831649 supporting_text: >- Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. - reference_id: PMID:18282108 supporting_text: >- 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]. - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00027996 review: summary: pax6b activates transcription from Pax6 target sites. action: ACCEPT reason: Consistent with experimental activator data (PMID:9831649, PMID:18282108). supported_by: - reference_id: PMID:9831649 supporting_text: >- Both Pax6.1 and Pax6.2 can act as transcriptional activators with Pax6.2 being more efficient than Pax6.1. - term: id: GO:0048593 label: camera-type eye morphogenesis evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00091222 review: summary: pax6b takes part in camera-type eye morphogenesis. action: ACCEPT reason: >- pax6b mutants have small lens, thick cornea, iris hypoplasia and shallow anterior chamber (PMID:25692557). supported_by: - reference_id: PMID:25692557 supporting_text: >- We also characterised homozygous pax6b mutants. Mutant embryos have a thick cornea, iris hypoplasia, a shallow anterior chamber and a small lens. - term: id: GO:0060041 label: retina development in camera-type eye evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:97490 - PANTHER:PTN002900580 - RGD:3258 - RGD:620433 - ZFIN:ZDB-GENE-081022-10 - ZFIN:ZDB-GENE-990415-200 review: summary: >- pax6b is expressed in the developing retina and contributes to retinal development together with pax6a. action: ACCEPT reason: >- Retinal expression of pax6b is established (PMID:18282108); severe sunrise alleles show retinal malformation and double mutants lack the ganglion cell layer (PMID:32555736). supported_by: - reference_id: PMID:18282108 supporting_text: >- pax6b is the “minor” co-orthologue, expressed in the developing eye (retina and early lens placode), and also in thin strips of dorsal diencephalon, at the midbrain-hindbrain boundary (MHB), and in the pancreas. - reference_id: PMID:32555736 supporting_text: >- 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. - term: id: GO:0061303 label: cornea development in camera-type eye evidence_type: IMP original_reference_id: PMID:25692557 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100610-2 review: summary: >- pax6b mutants have a thick cornea with disrupted corneal endothelium and loss of corneal epithelial gene expression. action: ACCEPT reason: Directly shown in homozygous pax6b mutants (PMID:25692557). supported_by: - reference_id: PMID:25692557 supporting_text: >- We also characterised homozygous pax6b mutants. Mutant embryos have a thick cornea, iris hypoplasia, a shallow anterior chamber and a small lens. - reference_id: PMID:25692557 supporting_text: >- Lack of pax6b function leads to severe disturbance of the corneal gene regulatory programme. - term: id: GO:0090104 label: pancreatic epsilon cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100507-7 review: summary: >- pax6b loss increases ghrelin-expressing epsilon cells at the expense of beta and delta cells. action: ACCEPT reason: >- pax6b restricts the epsilon fate: its loss causes a significant increase of epsilon cells (PMID:20177065, PMID:32867764). The annotation (acts upstream of or within epsilon cell differentiation) correctly records involvement without implying promotion. supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- Thus, these data also indicate an increase of epsilon cells in pax6bsa0086 mutant embryos. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:0090104 label: pancreatic epsilon cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-3 review: summary: >- pax6b loss increases ghrelin-expressing epsilon cells at the expense of beta and delta cells. action: ACCEPT reason: >- pax6b restricts the epsilon fate: its loss causes a significant increase of epsilon cells (PMID:20177065, PMID:32867764). The annotation (acts upstream of or within epsilon cell differentiation) correctly records involvement without implying promotion. supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- Thus, these data also indicate an increase of epsilon cells in pax6bsa0086 mutant embryos. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:0090104 label: pancreatic epsilon cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-4 review: summary: >- pax6b loss increases ghrelin-expressing epsilon cells at the expense of beta and delta cells. action: ACCEPT reason: >- pax6b restricts the epsilon fate: its loss causes a significant increase of epsilon cells (PMID:20177065, PMID:32867764). The annotation (acts upstream of or within epsilon cell differentiation) correctly records involvement without implying promotion. supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- Thus, these data also indicate an increase of epsilon cells in pax6bsa0086 mutant embryos. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:0090104 label: pancreatic epsilon cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-4 - ZFIN:ZDB-MRPHLNO-100610-7 review: summary: >- pax6b loss increases ghrelin-expressing epsilon cells at the expense of beta and delta cells. action: ACCEPT reason: >- pax6b restricts the epsilon fate: its loss causes a significant increase of epsilon cells (PMID:20177065, PMID:32867764). The annotation (acts upstream of or within epsilon cell differentiation) correctly records involvement without implying promotion. supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- Thus, these data also indicate an increase of epsilon cells in pax6bsa0086 mutant embryos. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:0090104 label: pancreatic epsilon cell differentiation evidence_type: IMP original_reference_id: PMID:20177065 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-100610-5 review: summary: >- pax6b loss increases ghrelin-expressing epsilon cells at the expense of beta and delta cells. action: ACCEPT reason: >- pax6b restricts the epsilon fate: its loss causes a significant increase of epsilon cells (PMID:20177065, PMID:32867764). The annotation (acts upstream of or within epsilon cell differentiation) correctly records involvement without implying promotion. supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- Thus, these data also indicate an increase of epsilon cells in pax6bsa0086 mutant embryos. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:0090104 label: pancreatic epsilon cell differentiation evidence_type: IMP original_reference_id: PMID:32867764 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-100507-7 review: summary: >- pax6b loss increases ghrelin-expressing epsilon cells at the expense of beta and delta cells. action: ACCEPT reason: >- pax6b restricts the epsilon fate: its loss causes a significant increase of epsilon cells (PMID:20177065, PMID:32867764). The annotation (acts upstream of or within epsilon cell differentiation) correctly records involvement without implying promotion. supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:32867764 supporting_text: >- Thus, these data also indicate an increase of epsilon cells in pax6bsa0086 mutant embryos. - reference_id: PMID:32867764 supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. - term: id: GO:2000179 label: positive regulation of neural precursor cell proliferation evidence_type: IMP original_reference_id: PMID:20152834 review: summary: >- pax6b is required for the first division of Muller glia-derived neuronal progenitors during photoreceptor regeneration. action: NEW reason: >- pax6b knockdown in the light-damaged adult retina blocked the first division of neuronal progenitors without affecting Muller glia division (PMID:20152834). The same paper supports the (modified) pax6a annotation; the pax6b counterpart is missing from GOA because only the Swiss-Prot pax6a entry was annotated from this paper. Non-core (regeneration context). supported_by: - reference_id: PMID:20152834 supporting_text: >- Loss of Pax6b expression did not affect Müller glial cell division, but blocked the subsequent first cell division of the neuronal progenitors. - reference_id: PMID:20152834 supporting_text: >- This work also defines distinct roles for Pax6a and Pax6b in regulating neuronal progenitor cell proliferation in the adult zebrafish retina references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000104 title: >- Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features 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:9831649 title: Zebrafish contains two pax6 genes involved in eye development. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only; Pax6.2 = pax6b. - id: PMID:17010333 title: >- Stereospecificity and PAX6 function direct Hoxd4 neural enhancer activity along the antero-posterior axis. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract only. - id: PMID:17397257 title: Hsp90 selectively modulates phenotype in vertebrate development. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text; sunrise lens phenotype under Hsp90 inhibition. - id: PMID:18282108 title: >- Subfunctionalization of duplicated zebrafish pax6 genes by cis-regulatory divergence. findings: - statement: sunrise is a pax6b homeodomain missense (L244P) allele. supporting_text: >- Sequencing of sri homozygotes and heterozygotes identified a leucine to proline missense mutation in a highly conserved residue of the pax6b homeodomain (Figures 1B, S1B, and S1C). - statement: Only pax6b is expressed in the pancreas. supporting_text: >- 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 - statement: pax6a and pax6b activate reporters at equivalent levels. supporting_text: >- 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]. - statement: The pax6b locus lost many ancestral cis-regulatory elements. supporting_text: >- On LG7 the pax6b locus and rcn1 and elp4 exons have been retained, but many of the pax6b control elements, as well as the wt1 homolog, have been lost. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text read; defines sunrise allele and the pair's cis-regulatory partition. - id: PMID:18485195 title: >- Expression of zebrafish pax6b in pancreas is regulated by two enhancers containing highly conserved cis-elements bound by PDX1, PBX and PREP factors. findings: - statement: pax6b pancreatic expression is driven by enhancers A and C. supporting_text: >- 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. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text; mechanism of pax6b-only pancreatic expression. - id: PMID:20152834 title: >- Pax6a and Pax6b are required at different points in neuronal progenitor cell proliferation during zebrafish photoreceptor regeneration. findings: - statement: >- pax6b is required for the first neuronal progenitor division in retinal regeneration. supporting_text: >- Loss of Pax6b expression did not affect Müller glial cell division, but blocked the subsequent first cell division of the neuronal progenitors. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text; retinal regeneration, both copies. - id: PMID:20177065 title: >- The Pax6b homeodomain is dispensable for pancreatic endocrine cell differentiation in zebrafish. findings: - statement: pax6b null mutants and morphants lack beta cells and gain epsilon cells. supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - statement: The Pax6b homeodomain is needed for lens but not pancreas. supporting_text: >- we show that deletion of the Pax6b homeodomain in zebrafish embryos does not disturb pancreas development, whereas lens formation is strongly affected. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text read; pax6b null allele sa0086 and pancreatic phenotype. - id: PMID:23359656 title: >- Sequencing of Pax6 loci from the elephant shark reveals a family of Pax6 genes in vertebrate genomes, forged by ancient duplications and divergences. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Pax6 family evolution; zebrafish pair from FSGD. - id: PMID:24528677 title: >- Pax6 regulates the formation of the habenular nuclei by controlling the temporospatial expression of Shh in the diencephalon in vertebrates. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Double knockdown only. - id: PMID:24951566 title: >- Evolution of the vertebrate Pax4/6 class of genes with focus on its novel member, the Pax10 gene. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: TGD origin of the pair. - id: PMID:25692557 title: >- Molecular description of eye defects in the zebrafish Pax6b mutant, sunrise, reveals a Pax6b-dependent genetic network in the developing anterior chamber. findings: - statement: pax6b mutants have anterior segment defects. supporting_text: >- We also characterised homozygous pax6b mutants. Mutant embryos have a thick cornea, iris hypoplasia, a shallow anterior chamber and a small lens. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text; pax6b mutant anterior segment phenotype. - id: PMID:27387288 title: >- Habenular Neurogenesis in Zebrafish Is Regulated by a Hedgehog, Pax6 Proneural Gene Cascade. findings: - statement: pax6b null mutants have normal habenular markers. supporting_text: >- 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). reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text; shows habenula role is pax6a, not pax6b. - id: PMID:32555736 title: >- Pax6 organizes the anterior eye segment by guiding two distinct neural crest waves. findings: - statement: pax6a/b dosage controls anterior segment development. supporting_text: >- 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]. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text; pax6a/b compound mutants. - id: PMID:32867764 title: >- Pancreatic and intestinal endocrine cells in zebrafish share common transcriptomic signatures and regulatory programmes. findings: - statement: pax6b balances endocrine subtypes in pancreas and intestine. supporting_text: >- pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between endocrine cell subtypes, leading to an increase of ghrelin- and motilin-like-expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta and delta cells in the pancreas and pyyb-expressing cells in the intestine. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text read; RNA-seq of pax6b mutant endocrine cells. - id: PMID:37094695 title: >- Medaka (Oryzias latipes) Olpax6.2 acquires maternal inheritance and germ cells expression, but functionally degenerate in the eye. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Medaka lineage contrast; abstract only. core_functions: - description: >- Sequence-specific DNA-binding transcription factor (paired domain plus homeodomain), activity equivalent to pax6a. 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:0005634 label: nucleus supported_by: - reference_id: PMID:18282108 supporting_text: >- 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 - description: >- The only zebrafish pax6 copy acting in endocrine cells: specifies beta and delta cells and restrains epsilon (ghrelin) cells in the pancreas, and balances enteroendocrine subtypes; homeodomain-independent. molecular_function: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific directly_involved_in: - id: GO:0003309 label: type B pancreatic cell differentiation - id: GO:0003311 label: pancreatic D cell differentiation - id: GO:0035883 label: enteroendocrine cell differentiation locations: - id: GO:0005634 label: nucleus supported_by: - reference_id: PMID:20177065 supporting_text: >- Pax6b-depleted embryos have almost no beta cells, a strongly reduced number of delta cells, and a significant increase of epsilon cells. - reference_id: PMID:18485195 supporting_text: only pax6b is expressed in the endocrine cells of the pancreas - description: >- Lens and anterior eye segment (cornea, iris) development, homeodomain-dependent; shared with pax6a in a dose-dependent way. molecular_function: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific directly_involved_in: - id: GO:0002088 label: lens development in camera-type eye - id: GO:0061303 label: cornea development in camera-type eye locations: - id: GO:0005634 label: nucleus supported_by: - reference_id: PMID:25692557 supporting_text: >- Mutant embryos have a thick cornea, iris hypoplasia, a shallow anterior chamber and a small lens. - reference_id: PMID:20177065 supporting_text: >- deletion of the Pax6b homeodomain in zebrafish embryos does not disturb pancreas development, whereas lens formation is strongly affected suggested_questions: - question: >- Which Pax6b DNA-binding mode (paired domain alone, or the 5a isoform) drives pancreatic and enteroendocrine target genes, given that the homeodomain is dispensable there? experts: - Peers B - Manfroid I - question: >- Is the mild sunrise eye phenotype partly buffered by pax6a, and does pax6a expression rise in pax6b null (sa0086) eyes? suggested_experiments: - hypothesis: >- Pancreatic endocrine differentiation requires Pax6 protein of either copy, and pax6a would rescue pax6b loss if expressed in the pancreas. description: >- Express pax6a coding sequence from pax6b pancreatic enhancers (regions A/C) in pax6b sa0086 mutants and score beta, delta and epsilon cells. experiment_type: cross-rescue - hypothesis: pax6b binds endocrine target enhancers through its paired domain. description: CUT&RUN for Pax6b in sorted wild-type and sunrise pancreatic endocrine cells. experiment_type: genome-wide DNA-binding profiling