id: Q9DFH1
gene_symbol: sox9b
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:7955
  label: Danio rerio
description: 'Sox9b is one of two zebrafish co-orthologs of vertebrate SOX9, produced by the teleost-specific
  genome duplication. It is an SRY-related HMG-box (SoxE group) transcription factor whose HMG box is
  nearly identical to that of Sox9a and human SOX9 and binds the Sox consensus DNA motif; it acts in the
  nucleus to activate target genes such as col2a1a and col11a2. Sox9b is expressed in pharyngeal endoderm
  and epithelia, subsets of craniofacial and pectoral cartilage, otic placode, retina, heart myocardium,
  the hepatopancreatic, intrahepatic and intrapancreatic ducts including pancreatic centroacinar progenitor
  cells, and adult oocytes. It is needed for proper chondrocyte numbers in a subset of craniofacial cartilages,
  and it has roles that zebrafish sox9a does not share: development of the pancreaticobiliary ductal system,
  maintenance of Notch signalling in biliary cells, restraint of endocrine differentiation from ductal
  progenitors downstream of Notch and retinoic acid signalling, liver regeneration by biliary transdifferentiation,
  retinal differentiation, and proepicardium, epicardium and heart valve formation. It acts partly redundantly
  with sox9a in otic development.'
existing_annotations:
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - PANTHER:PTN000741645
  - UniProtKB:P48436
  review:
    summary: 'IBA: negative regulation of transcription by RNA polymerase II (PTN000741645, human SOX9
      donor).'
    action: KEEP_AS_NON_CORE
    reason: SOX9 represses some targets in mammals and the HMG box is conserved in Sox9b (file:DANRE/sox9a/sox9a-bioinformatics/RESULTS.md).
      In zebrafish, Sox9b is part of a Runx3-Egr1-Sox9b cascade that represses fsta in pharyngeal endoderm,
      though direct repression by Sox9b is not shown. Kept as an inherited, non-core property.
    supported_by:
    - reference_id: PMID:23209659
      supporting_text: the endodermal factors Runx3 and Sox9b form a regulatory cascade with Egr1 resulting
        in transcriptional repression of the fsta gene, encoding a BMP antagonist, in pharyngeal endoderm.
- 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:
  - MGI:MGI:98358
  - MGI:MGI:98370
  - MGI:MGI:98371
  - PANTHER:PTN002910095
  - PomBase:SPBC32C12.02
  - UniProtKB:P48436
  review:
    summary: 'IBA: RNA polymerase II cis-regulatory region sequence-specific DNA binding.'
    action: ACCEPT
    reason: Sox9b binds HMG consensus DNA in vitro; its HMG box is 98.6% identical to Sox9a and human
      SOX9.
    supported_by:
    - &id001
      reference_id: PMID:11180959
      supporting_text: Both Sox9a and Sox9b proteins bind to the HMG consensus DNA sequences in vitro.
    - &id020
      reference_id: PMID:19210963
      supporting_text: After the sox9 gene duplication event, regulatory elements controlling the expression
        of sox9 co-orthologs apparently partitioned in a tissue-specific fashion, but the Sox9 proteins
        encoded by sox9a and sox9b retained the ability to regulate col11a2, presumably by binding to
        regulatory sites for the col11a2 gene.
- 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:
  - MGI:MGI:98358
  - MGI:MGI:98370
  - MGI:MGI:98371
  - PANTHER:PTN002910095
  - PomBase:SPBC32C12.02
  - RGD:620474
  - UniProtKB:O18896
  - UniProtKB:P48436
  review:
    summary: 'IBA: DNA-binding transcription factor activity, RNA polymerase II-specific.'
    action: ACCEPT
    reason: 'Core molecular function: DNA binding plus a mapped transactivation domain, and loss of sox9b
      reduces expression of Sox9 target genes such as col11a2 in the cartilages it is expressed in.'
    supported_by:
    - *id001
    - &id019
      reference_id: PMID:11180959
      supporting_text: We tested different domains for transactivation potential and identified a potential
        activation domain located in the middle of both Sox9a and Sox9b.
    - &id002
      reference_id: PMID:19210963
      supporting_text: col11a2 expression was greatly reduced in the mandibular and ceratohyal cartilages
        in sox9b mutants, but was retained in the ethmoid plate and trabeculae of the neurocranium
- term:
    id: GO:0002009
    label: morphogenesis of an epithelium
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - MGI:MGI:98358
  - MGI:MGI:98370
  - MGI:MGI:98371
  - PANTHER:PTN000741645
  - UniProtKB:B7ZR65
  - UniProtKB:P48434
  - ZFIN:ZDB-GENE-001103-1
  - ZFIN:ZDB-GENE-001103-2
  - ZFIN:ZDB-GENE-011207-1
  review:
    summary: 'IBA: morphogenesis of an epithelium (donors include both zebrafish sox9a and sox9b).'
    action: KEEP_AS_NON_CORE
    reason: Well supported for Sox9b, which is required for morphogenesis of the intrahepatic, intrapancreatic
      and hepatopancreatic ductal epithelia and contributes to otic epithelium formation; kept as a broad,
      non-core term.
    supported_by:
    - &id009
      reference_id: PMID:22537488
      supporting_text: All these observations reveal that sox9b is required not only for the morphogenesis
        of the IHD but also for morphogenesis and differentiation of the IPD and HPD system.
    - &id015
      reference_id: PMID:12668634
      supporting_text: These cells fail to form if sox9b function is also blocked.
- term:
    id: GO:0002062
    label: chondrocyte differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - MGI:MGI:98371
  - PANTHER:PTN002910118
  - UniProtKB:P48434
  - UniProtKB:P48436
  review:
    summary: 'IBA: chondrocyte differentiation.'
    action: ACCEPT
    reason: Sox9b is required for proper chondrocyte numbers and col2a1/col11a2 expression in a subset
      of craniofacial cartilages; together with sox9a it is required for all cartilage.
    supported_by:
    - &id012
      reference_id: PMID:15689370
      supporting_text: Chondrocytes failed to stack in sox9a mutants, failed to attain proper numbers
        in sox9b mutants and failed in both morphogenetic processes in double mutants.
    - &id013
      reference_id: PMID:23209659
      supporting_text: while in zebrafish both sox9a and sox9b are required for col2a1 expression.
    - *id002
- term:
    id: GO:0003170
    label: heart valve development
  evidence_type: IMP
  original_reference_id: PMID:23775563
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-MRPHLNO-050322-1
  review:
    summary: 'IMP: heart valve development (sox9b morpholino).'
    action: KEEP_AS_NON_CORE
    reason: 'Sox9b morphants and mutants fail to form valve cushions and leaflets. This is a copy-specific
      role: sox9a knockdown had no cardiac effect.'
    supported_by:
    - reference_id: PMID:23775563
      supporting_text: Fish lacking sox9b failed to form valve cushions and leaflets.
    - &id008
      reference_id: PMID:23775563
      supporting_text: Knock down of sox9a expression did not cause cardiac malformations, or defects
        in epicardium development.
- term:
    id: GO:0003309
    label: type B pancreatic cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:27565026
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-161220-13
  review:
    summary: 'IMP: type B pancreatic cell differentiation (transgenic dominant-negative/overexpression
      genotype).'
    action: KEEP_AS_NON_CORE
    reason: Sox9b acts in ductal centroacinar progenitors to restrain their differentiation into endocrine
      (including beta) cells downstream of Notch and retinoic acid signalling; loss of Sox9b activity
      depletes the progenitor pool. The acts_upstream_of_or_within relation accommodates this negative,
      progenitor-level role. Non-core.
    supported_by:
    - &id010
      reference_id: PMID:27565026
      supporting_text: Blocking Sox9b activity either in sox9bfh313 homozygous mutant fish or by over
        expression of truncated sox9b results in fewer CAC progenitors available to produce new endocrine
        cells
    - reference_id: PMID:27565026
      supporting_text: Importantly, Sox9b activity is necessary and sufficient for RA signaling to impart
        this effect.
- term:
    id: GO:0003342
    label: proepicardium development
  evidence_type: IMP
  original_reference_id: PMID:23775563
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-050322-1
  review:
    summary: 'IMP: proepicardium development.'
    action: KEEP_AS_NON_CORE
    reason: Loss of sox9b prevents formation of the proepicardium and epicardium. Sox9b is expressed in
      ventricular myocardium but not in the proepicardium itself, and cardiomyocyte-restricted dominant-negative
      Sox9b disrupts cardiac morphogenesis, so the effect on the proepicardium is likely non-cell-autonomous;
      acts_upstream_of_or_within is appropriate. Copy-specific.
    supported_by:
    - &id003
      reference_id: PMID:23775563
      supporting_text: Loss of sox9b prevented the formation of epicardium progenitors comprising the
        proepicardium on the pericardial wall, and prevented the formation and migration of the epicardial
        layer around the heart.
    - &id007
      reference_id: PMID:23775563
      supporting_text: Furthermore, sox9b is required for PE, epicardium, and valve formation.
    - &id004
      reference_id: PMID:23775563
      supporting_text: Furthermore, while sox9b expression was critical for the formation of the epicardium,
        we found sox9b expressed in ventricular cardiomyocytes but not in cells of the PE or epicardium.
    - &id005
      reference_id: PMID:30224706
      supporting_text: We generated a dominant-negative sox9b (dnsox9b) to inhibit sox9b target gene expression
        and used the Gal4/UAS system to drive dnsox9b specifically in cardiomyocytes.
- term:
    id: GO:0003342
    label: proepicardium development
  evidence_type: IMP
  original_reference_id: PMID:23775563
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-MRPHLNO-050322-1
  review:
    summary: 'IMP: proepicardium development.'
    action: KEEP_AS_NON_CORE
    reason: Loss of sox9b prevents formation of the proepicardium and epicardium. Sox9b is expressed in
      ventricular myocardium but not in the proepicardium itself, and cardiomyocyte-restricted dominant-negative
      Sox9b disrupts cardiac morphogenesis, so the effect on the proepicardium is likely non-cell-autonomous;
      acts_upstream_of_or_within is appropriate. Copy-specific.
    supported_by:
    - *id003
    - *id004
    - *id005
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  qualifier: enables
  supporting_entities:
  - UniRule:UR000400811
  review:
    summary: 'IEA (UniRule): DNA binding.'
    action: ACCEPT
    reason: Correct, general.
    supported_by:
    - *id001
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  supporting_entities:
  - MGI:MGI:98358
  - MGI:MGI:98370
  - MGI:MGI:98371
  - PANTHER:PTN002910095
  - PomBase:SPBC32C12.02
  - RGD:3735
  - UniProtKB:B7ZR65
  - UniProtKB:O18896
  - UniProtKB:P48434
  - UniProtKB:P48436
  - UniProtKB:P56693
  - UniProtKB:P57073
  - Xenbase:XB-GENE-1034769
  review:
    summary: 'IBA: nucleus (is_active_in).'
    action: ACCEPT
    reason: Sox9b immunostaining co-localizes with nuclear markers in pancreatic centroacinar cells; consistent
      with its transcription-factor function.
    supported_by:
    - &id006
      reference_id: PMID:27565026
      supporting_text: As can be seen in Figure 6A, Sox9b co-localized to nuclear mCherry within CACs.
- 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:UR000400811
  review:
    summary: 'IEA: nucleus.'
    action: ACCEPT
    reason: Consistent with direct observation.
    supported_by:
    - *id006
- term:
    id: GO:0007507
    label: heart development
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - MGI:MGI:98371
  - PANTHER:PTN002910118
  - UniProtKB:P48434
  - UniProtKB:P48436
  - ZFIN:ZDB-GENE-001103-2
  review:
    summary: 'IBA: heart development (sox9b itself among donors).'
    action: KEEP_AS_NON_CORE
    reason: Sox9b has experimental support for proepicardium, epicardium and valve development, so it
      is correctly inside the clade inheriting this function; the zebrafish cardiac role is held by sox9b,
      not sox9a (see the sox9a review).
    supported_by:
    - *id007
    - *id008
    - *id005
    - reference_id: PMID:30224706
      supporting_text: Thus, indicating that the truncated sox9b variant is able to act as a dominant
        negative as predicted and significantly reduce sox9b-mediated transcription.
- term:
    id: GO:0030318
    label: melanocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:15689370
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-050322-1
  review:
    summary: 'IMP: melanocyte differentiation (Yan et al. 2005, sox9b b971 genotype).'
    action: UNDECIDED
    reason: Only the abstract is cached and it does not describe a pigment-cell phenotype, although it
      reports that sox9 regulates the early neural crest genes foxd3 and sox10. The curator likely used
      the full text, which could not be accessed. Also, the b971 allele deletes sox9b together with sox8
      and other genes, so a pigment phenotype may not be attributable to sox9b alone. Not removed; left
      undecided.
    supported_by:
    - &id017
      reference_id: PMID:15689370
      supporting_text: sox9 helps regulate other early crest genes, including foxd3, sox10, snai1b and
        crestin, as well as the cartilage gene col2a1 and the bone gene runx2a
    - reference_id: PMID:22719264
      supporting_text: the chromosomal deletion which underlies the b971 lesion removes eleven other genes,
        greatly limiting the use of this allele to study the function of Sox9b.
- term:
    id: GO:0030916
    label: otic vesicle formation
  evidence_type: IGI
  original_reference_id: PMID:15689370
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-030219-2
  review:
    summary: 'IGI: otic vesicle formation (sox9a;sox9b double mutant).'
    action: KEEP_AS_NON_CORE
    reason: 'Ears are reduced in each single mutant and mostly absent in double mutants: shared, partly
      redundant function with sox9a.'
    supported_by:
    - reference_id: PMID:15689370
      supporting_text: Ears are somewhat reduced in each single mutant but are mostly absent in the double
        mutant.
- term:
    id: GO:0031016
    label: pancreas development
  evidence_type: IMP
  original_reference_id: PMID:22537488
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-120612-2
  review:
    summary: 'IMP: pancreas development (sox9b fh313).'
    action: ACCEPT
    reason: 'Copy-specific core role: Sox9b is required for morphogenesis and differentiation of the intrapancreatic
      and hepatopancreatic ducts and for duct-derived endocrine cells; sox9a is not expressed in the digestive
      organs.'
    supported_by:
    - *id009
    - reference_id: PMID:22537488
      supporting_text: Finally, we show that sox9b is essential for endocrine cell formation from the
        pancreatic ducts and for beta cell regeneration.
    - &id021
      reference_id: PMID:22719264
      supporting_text: As in wild-type, sox9a expression appears to be excluded from the digestive organs
        in sox9bfh313 mutants, suggesting that sox9a expression does not compensate for the reduction
        of Sox9b function in these mutants.
- term:
    id: GO:0031016
    label: pancreas development
  evidence_type: IMP
  original_reference_id: PMID:22719264
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-120612-2
  review:
    summary: 'IMP: pancreas development (sox9b fh313).'
    action: ACCEPT
    reason: As above; independent study with the same nonsense allele.
    supported_by:
    - &id011
      reference_id: PMID:22719264
      supporting_text: Altogether, these data indicate that Sox9b function is required for the development
        of the intrapancreatic ductal system as well as - directly or indirectly - for the formation of
        secondary islets.
    - &id018
      reference_id: PMID:22719264
      supporting_text: Strikingly, sox9b(fh313) homozygous mutants survive to adulthood and exhibit cholestasis
        associated with hepatic and pancreatic duct proliferation, cyst formation, and fibrosis.
- term:
    id: GO:0031018
    label: endocrine pancreas development
  evidence_type: IMP
  original_reference_id: PMID:27565026
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-161220-6
  review:
    summary: 'IMP: endocrine pancreas development (transgenic Sox9b gain/loss of function).'
    action: KEEP_AS_NON_CORE
    reason: Sox9b controls the number of ductal centroacinar progenitors and restrains their endocrine
      differentiation; secondary islet formation depends on it. Supported; non-core relative to its ductal
      morphogenesis role.
    supported_by:
    - *id010
    - *id011
- term:
    id: GO:0031018
    label: endocrine pancreas development
  evidence_type: IMP
  original_reference_id: PMID:27565026
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-161220-7
  review:
    summary: 'IMP: endocrine pancreas development (transgenic Sox9b gain/loss of function).'
    action: KEEP_AS_NON_CORE
    reason: Sox9b controls the number of ductal centroacinar progenitors and restrains their endocrine
      differentiation; secondary islet formation depends on it. Supported; non-core relative to its ductal
      morphogenesis role.
    supported_by:
    - *id010
    - *id011
- term:
    id: GO:0031099
    label: regeneration
  evidence_type: IMP
  original_reference_id: PMID:24315993
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-151231-8
  review:
    summary: 'IMP: regeneration (biliary transdifferentiation after hepatocyte ablation).'
    action: MODIFY
    reason: The term is very general. The study concerns liver regeneration after extreme hepatocyte loss,
      which requires Notch signalling and Sox9b activation in cholangiocytes. GO:0097421 liver regeneration
      is the appropriate, more specific term. Full text not cached; the abstract supports this.
    proposed_replacement_terms:
    - id: GO:0097421
      label: liver regeneration
    supported_by:
    - reference_id: PMID:24315993
      supporting_text: this process required Notch signaling and, in turn, activation of Sox9b in cholangiocytes.
- term:
    id: GO:0032332
    label: positive regulation of chondrocyte differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - MGI:MGI:98371
  - PANTHER:PTN002910118
  - UniProtKB:P48436
  review:
    summary: 'IBA: positive regulation of chondrocyte differentiation.'
    action: ACCEPT
    reason: Consistent with Sox9b promotion of chondrocyte differentiation and target gene expression
      in the cartilages it is expressed in.
    supported_by:
    - *id012
    - *id013
- term:
    id: GO:0035118
    label: embryonic pectoral fin morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:15689370
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-050322-1
  review:
    summary: 'IMP: embryonic pectoral fin morphogenesis (sox9b mutant/morphants).'
    action: KEEP_AS_NON_CORE
    reason: Each co-ortholog is expressed in and required for a distinct subset of the pectoral appendage.
    supported_by:
    - &id014
      reference_id: PMID:15689370
      supporting_text: Distinct subsets of the craniofacial skeleton, otic placode and pectoral appendage
        express each gene, and are defective in each single mutant.
- term:
    id: GO:0035118
    label: embryonic pectoral fin morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:15689370
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-MRPHLNO-041110-4
  - ZFIN:ZDB-MRPHLNO-050322-1
  review:
    summary: 'IMP: embryonic pectoral fin morphogenesis (sox9b mutant/morphants).'
    action: KEEP_AS_NON_CORE
    reason: Each co-ortholog is expressed in and required for a distinct subset of the pectoral appendage.
    supported_by:
    - *id014
- term:
    id: GO:0043049
    label: otic placode formation
  evidence_type: IGI
  original_reference_id: PMID:12668634
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-030219-2
  review:
    summary: 'IGI: otic placode formation (combined loss with Df(b380)).'
    action: KEEP_AS_NON_CORE
    reason: Residual otic cells in embryos lacking dlx3b, dlx4b and sox9a fail to form when sox9b is also
      blocked; unlike sox9a, sox9b expression is Fgf3/8-independent.
    supported_by:
    - reference_id: PMID:12668634
      supporting_text: Removal of dlx3b, dlx4b and sox9a genes together also blocks ear development, although
        a few residual cells form an otic epithelium.
    - *id015
    - reference_id: PMID:12668634
      supporting_text: Expression of sox9a but not dlx3b, dlx4b or sox9b requires Fgf3 and Fgf8.
- term:
    id: GO:0043049
    label: otic placode formation
  evidence_type: IMP
  original_reference_id: PMID:12668634
  qualifier: acts_upstream_of_or_within
  review:
    summary: 'IMP: otic placode formation.'
    action: KEEP_AS_NON_CORE
    reason: As above.
    supported_by:
    - *id015
- term:
    id: GO:0048709
    label: oligodendrocyte differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - MGI:MGI:98371
  - PANTHER:PTN002910118
  - ZFIN:ZDB-GENE-001103-1
  review:
    summary: 'IBA: oligodendrocyte differentiation (PTN002910118; zebrafish donor sox9a).'
    action: KEEP_AS_NON_CORE
    reason: Sox9b is expressed with sox9a in hindbrain rhombomere-centre glial progenitor domains, and
      residual glial marker expression in sox9a mutants is attributed to sox9b, but sox9b loss has not
      been tested directly for gliogenesis (its mutant has excess CNS apoptosis). The IBA is plausible
      and there is no evidence of loss; kept as non-core.
    supported_by:
    - reference_id: PMID:20023158
      supporting_text: although sox9a was delayed relative to sox9b , both genes were expressed in rhombomere
        centres
    - reference_id: PMID:20023158
      supporting_text: residual expression of glial markers in these mutants is probably due to the sox9b
        co-orthologue, which has an overlapping expression profile.
- term:
    id: GO:0048839
    label: inner ear development
  evidence_type: IGI
  original_reference_id: PMID:19132125
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-980202-1565
  - ZFIN:ZDB-MRPHLNO-070130-7
  - ZFIN:ZDB-MRPHLNO-090422-9
  review:
    summary: 'IGI: inner ear development (with sox10 mutant).'
    action: KEEP_AS_NON_CORE
    reason: Group E sox genes, including sox9b, act redundantly in otic patterning.
    supported_by:
    - &id016
      reference_id: PMID:19132125
      supporting_text: they act redundantly to maintain sox10 expression throughout otic tissue and to
        restrict fgf8 expression to anterior macula regions
- term:
    id: GO:0048839
    label: inner ear development
  evidence_type: IMP
  original_reference_id: PMID:19132125
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-MRPHLNO-070130-7
  - ZFIN:ZDB-MRPHLNO-090422-9
  review:
    summary: 'IMP: inner ear development (morpholinos).'
    action: KEEP_AS_NON_CORE
    reason: As above.
    supported_by:
    - *id016
- term:
    id: GO:0050935
    label: iridophore differentiation
  evidence_type: IMP
  original_reference_id: PMID:15689370
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-050322-1
  review:
    summary: 'IMP: iridophore differentiation (Yan et al. 2005, sox9b b971 genotype).'
    action: UNDECIDED
    reason: 'As for melanocyte differentiation: the cached abstract does not describe the pigment phenotype,
      and the b971 deletion removes sox8 and other genes as well as sox9b. Full text needed.'
    supported_by:
    - *id017
    - reference_id: PMID:19210963
      supporting_text: The b971 mutant allele of sox9b used in this study deletes sox9b and some surrounding
        genes including sox8
- term:
    id: GO:0051216
    label: cartilage development
  evidence_type: IMP
  original_reference_id: PMID:15689370
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-050322-1
  review:
    summary: 'IMP: cartilage development (sox9b b971 mutant).'
    action: ACCEPT
    reason: 'Sox9b is required for normal chondrocyte numbers in a subset of craniofacial cartilages;
      col11a2 is lost from mandibular and ceratohyal cartilage in sox9b mutants. Caveats: b971 is a multi-gene
      deletion (morpholino phenocopy supports attribution to sox9b), and a later study (Lin et al. 2021,
      Aquaculture and Fisheries, no PMID; known here only via the deep-research summary) reported grossly
      normal cartilage in CRISPR sox9b frameshift mutants. That discrepancy may reflect genetic compensation
      in PTC alleles, the extra genes deleted in b971, or a subtler phenotype (chondrocyte number) not
      scored in gross staining; it does not override the curated IMP.'
    supported_by:
    - *id012
    - *id014
    - *id002
    - reference_id: file:DANRE/sox9b/sox9b-deep-research-falcon.md
      supporting_text: CRISPR *sox9b* Δ11 and Δ20 alleles deleting the HMG and Q/S domains produced grossly
        normal maxillary, mandibular, and pectoral-fin cartilage, whereas *sox9a* mutants had misshapen
        pectoral fins and lacked scapulocoracoid cartilage.
- term:
    id: GO:0051216
    label: cartilage development
  evidence_type: IMP
  original_reference_id: PMID:15689370
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-MRPHLNO-041110-4
  - ZFIN:ZDB-MRPHLNO-050322-1
  review:
    summary: 'IMP: cartilage development (sox9b morpholinos).'
    action: ACCEPT
    reason: Morpholino knockdown phenocopies the mutant cartilage defects; reduced sox9b expression also
      underlies TCDD-induced jaw malformation.
    supported_by:
    - *id012
    - reference_id: PMID:18784347
      supporting_text: Sox9b, a critical chondrogenic transcription factor, was the most significantly
        reduced transcript in the jaw.
- term:
    id: GO:0060021
    label: roof of mouth development
  evidence_type: IMP
  original_reference_id: PMID:22052544
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-100428-3
  review:
    summary: 'IMP: roof of mouth development (sox9b mutant palate).'
    action: KEEP_AS_NON_CORE
    reason: sox9b mutants have malformed small palates, a consequence of its chondrogenic role in anterior
      neurocranial cartilage.
    supported_by:
    - reference_id: PMID:22052544
      supporting_text: mutation of Sox9b reduces cartilage development, especially having malformed small
        palates
- term:
    id: GO:0060041
    label: retina development in camera-type eye
  evidence_type: IMP
  original_reference_id: PMID:19210963
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-081106-1
  review:
    summary: 'IMP: retina development in camera-type eye.'
    action: KEEP_AS_NON_CORE
    reason: 'sox9b mutants have smaller eyes and lose retinal expression of neurod, crx, vsx1 and calb2a/b,
      whereas sox9a mutant retinas are normal: a copy-specific role.'
    supported_by:
    - reference_id: PMID:19210963
      supporting_text: Considering the expression pattern of sox9b, the expression of candidate genes
        in sox9b mutants, and the phenotype observed in the retina of sox9b mutants, we conclude that
        sox9b is essential for retinal development.
    - reference_id: PMID:19210963
      supporting_text: In contrast, sox9a mutant retinas had no obvious defects, even though sox9a is
        expressed in the inner nuclear layer at 68 hpf
- term:
    id: GO:0061008
    label: hepaticobiliary system development
  evidence_type: IMP
  original_reference_id: PMID:22719264
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-120612-2
  review:
    summary: 'IMP: hepaticobiliary system development (sox9b fh313).'
    action: ACCEPT
    reason: 'Copy-specific core role: Sox9b is required for morphogenesis of the hepatopancreatic ductal
      system and intrahepatic biliary network; mutants develop cholestasis, duct cysts and fibrosis.'
    supported_by:
    - *id018
    - reference_id: PMID:22719264
      supporting_text: Altogether, these data indicate that Sox9b is required for the maintenance but
        not the initiation of Notch signaling in the intrahepatic biliary cells.
    - *id009
- term:
    id: GO:0061032
    label: visceral serous pericardium development
  evidence_type: IMP
  original_reference_id: PMID:23775563
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-GENO-050322-1
  review:
    summary: 'IMP: visceral serous pericardium development (epicardium).'
    action: KEEP_AS_NON_CORE
    reason: Loss of sox9b prevents formation and migration of the epicardial layer; copy-specific cardiac
      role.
    supported_by:
    - *id003
- term:
    id: GO:0061032
    label: visceral serous pericardium development
  evidence_type: IMP
  original_reference_id: PMID:23775563
  qualifier: acts_upstream_of_or_within
  supporting_entities:
  - ZFIN:ZDB-MRPHLNO-050322-1
  review:
    summary: 'IMP: visceral serous pericardium development (epicardium).'
    action: KEEP_AS_NON_CORE
    reason: Loss of sox9b prevents formation and migration of the epicardial layer; copy-specific cardiac
      role.
    supported_by:
    - *id003
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: IDA
  original_reference_id: PMID:11180959
  review:
    summary: 'Proposed: Sox9b is a sequence-specific transcriptional activator.'
    action: NEW
    reason: Chiang et al. 2001 showed that both zebrafish Sox9 proteins bind HMG consensus DNA and mapped
      a transactivation domain in the middle of each; both proteins retain the ability to regulate the
      Sox9 target col11a2. Proposed identically for sox9a so that the shared molecular function is annotated
      consistently across the pair.
    supported_by:
    - *id001
    - *id019
    - *id020
references:
- 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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12668634
  title: Fgf3 and Fgf8 dependent and independent transcription factors are required for otic placode specification.
  findings: []
- id: PMID:15689370
  title: 'A pair of Sox: distinct and overlapping functions of zebrafish sox9 co-orthologs in craniofacial
    and pectoral fin development.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract only; key pair paper. Pigment-cell annotations from it could not be checked.
- id: PMID:19132125
  title: A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic
    vesicle.
  findings: []
- id: PMID:19210963
  title: Expression profiling of zebrafish sox9 mutants reveals that Sox9 is required for retinal differentiation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text.
- id: PMID:22052544
  title: Sox9 is upstream of microRNA-140 in cartilage.
  findings: []
- id: PMID:22537488
  title: Zebrafish sox9b is crucial for hepatopancreatic duct development and pancreatic endocrine cell
    regeneration.
  findings: []
- id: PMID:22719264
  title: Sox9b is a key regulator of pancreaticobiliary ductal system development.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text; fh313 nonsense allele; notes b971 deletion caveat and absence of sox9a compensation.
- id: PMID:23775563
  title: Sox9b is required for epicardium formation and plays a role in TCDD-induced heart malformation
    in zebrafish.
  findings: []
- id: PMID:24315993
  title: Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation
    in zebrafish.
  findings: []
- id: PMID:27565026
  title: Sox9b is a mediator of retinoic acid signaling restricting endocrine progenitor differentiation.
  findings: []
- id: PMID:11180959
  title: 'Two sox9 genes on duplicated zebrafish chromosomes: expression of similar transcription activators
    in distinct sites.'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract only; duplicated-chromosome origin, DNA binding and transactivation of both
      copies.
- id: PMID:14579386
  title: 'Genome duplication, subfunction partitioning, and lineage divergence: Sox9 in stickleback and
    zebrafish.'
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract only.
- id: PMID:15818483
  title: Divergent expression patterns of Sox9 duplicates in teleosts indicate a lineage specific subfunctionalization.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract only.
- id: PMID:15939378
  title: Characterization and expression pattern of zebrafish Anti-Müllerian hormone (Amh) relative to
    sox9a, sox9b, and cyp19a1a, during gonad development.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract only; sox9b in oocytes.
- id: PMID:18784347
  title: Aryl hydrocarbon receptor-mediated down-regulation of sox9b causes jaw malformation in zebrafish
    embryos.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text; sox9b dosage sensitivity in jaw.
- id: PMID:23209659
  title: RUNX3, EGR1 and SOX9B form a regulatory cascade required to modulate BMP-signaling during cranial
    cartilage development in zebrafish.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text; endodermal Sox9b in cartilage development.
- id: PMID:20023158
  title: FGF-receptor signalling controls neural cell diversity in the zebrafish hindbrain by regulating
    olig2 and sox9.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Full text; sox9b expression in hindbrain glial progenitor domains.
- id: file:DANRE/sox9a/sox9a-bioinformatics/RESULTS.md
  title: Region-wise identity of zebrafish Sox9a, Sox9b and human SOX9
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Manual audit verified the sidecar supports conservation of the SOX9 HMG DNA-binding box in both
      zebrafish copies while noting that region identity alone does not compare transactivation strength.
  findings:
  - statement: HMG box 98.6% identical between Sox9a, Sox9b and human SOX9; Sox9b is 55 aa shorter than
      Sox9a and more diverged from human SOX9 outside the HMG box.
- id: PMID:30224706
  title: sox9b is required in cardiomyocytes for cardiac morphogenesis and function.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text; cardiomyocyte-specific dominant-negative Sox9b. A dominant-negative HMG-box
      construct might also interfere with Sox9a, so copy specificity rests on the earlier morpholino/mutant
      data.
- id: file:DANRE/sox9b/sox9b-deep-research-falcon.md
  title: Deep research report on sox9b (Falcon)
core_functions:
- description: Sequence-specific DNA-binding transcriptional activator acting through the conserved SOX
    HMG box; promotes chondrocyte differentiation in a subset of craniofacial cartilages (with sox9a).
  molecular_function:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  directly_involved_in:
  - id: GO:0002062
    label: chondrocyte differentiation
  - id: GO:0051216
    label: cartilage development
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - *id001
  - *id019
  - *id012
  - *id002
- description: 'Copy-specific transcriptional regulator of pancreaticobiliary ductal system development:
    required for hepatopancreatic, intrahepatic and intrapancreatic duct morphogenesis and maintenance
    of biliary Notch signalling, and restrains endocrine differentiation of ductal progenitors.'
  molecular_function:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  directly_involved_in:
  - id: GO:0061008
    label: hepaticobiliary system development
  - id: GO:0031016
    label: pancreas development
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - *id018
  - *id009
  - *id021
  - *id006
suggested_questions:
- question: Are the cartilage, pigment and otic phenotypes originally attributed to the sox9b b971 deletion
    reproduced by sox9b point or frameshift alleles, given that b971 also removes sox8 and other genes?
- question: Would Sox9a protein rescue sox9b-specific ductal, retinal and cardiac phenotypes if expressed
    from sox9b regulatory elements?
- question: 'Why do CRISPR sox9b frameshift mutants reportedly have grossly normal cartilage while b971
    deletion mutants and morphants do not: transcriptional adaptation (e.g. sox9a or sox8 upregulation),
    the extra genes removed by b971, or morpholino off-target effects?'
suggested_experiments:
- description: Knock sox9a coding sequence into the sox9b locus and assay pancreaticobiliary duct, retina
    and epicardium, to test whether copy-specific roles are due only to expression partition.
- description: Analyse pigment-cell (melanophore, iridophore) phenotypes in sox9b fh313 homozygotes to
    resolve whether the b971-based pigment annotations reflect sox9b.