Sox9-a is the L-subgenome homeolog of Xenopus laevis Sox9 (the S homeolog is sox9-b). It is a SoxE-group HMG-box transcription factor that binds ACAAAG/AACAAT-type motifs in enhancers and activates RNA polymerase II transcription through C-terminal transactivation domains. Maternal transcripts are present, and zygotic expression begins at mid-gastrula at the lateral edges of the neural plate, after Sox8 and before Sox10. It persists in migrating cranial neural crest cells as they populate the pharyngeal arches and is also expressed in the otic placode and vesicle, eye, genital ridges, notochord and pancreas. Sox9 is a neural crest specifier. It is required for Wnt-dependent induction and specification of neural crest progenitors, but not for their migration; when it is depleted, crest progenitors are lost and the neural plate expands. Sox9 is later required for chondrogenesis of crest-derived cranial cartilage, its deeply conserved vertebrate role. It is also required for otic placode specification. Its developmental output is modulated by SUMOylation at K61 and K365, which biases the protein between crest and melanocyte-promoting activities and otic-promoting activities. SoxE proteins are largely interchangeable in these assays. The chondrogenic SoxE programme is ancestral: lamprey Sox9 is co-expressed with type II collagen, and amphioxus SoxE lacks neural crest enhancers. Its deployment in the neural crest therefore arose through vertebrate-specific cis-regulatory recruitment.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference that Sox9 negatively regulates RNA polymerase II transcription. Reason: Xenopus Sox9 has no reported repressor activity; the experimental Xenopus data show it acting as an activator. Some vertebrate SoxE proteins repress particular targets, so the IBA is plausible for the family, but it is not the core activity of this gene. Supporting Evidence: PMID:15464575 we demonstrate that Sox9 functions as a transcriptional activator during neural crest formation |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000118 | KEEP AS NON CORE | Summary: TreeGrafter transfer of negative regulation of Pol II transcription. Reason: Xenopus Sox9 has no reported repressor activity; the experimental Xenopus data show it acting as an activator. Some vertebrate SoxE proteins repress particular targets, so the IBA is plausible for the family, but it is not the core activity of this gene. Supporting Evidence: PMID:15464575 we demonstrate that Sox9 functions as a transcriptional activator during neural crest formation |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Sox9 binds cis-regulatory DNA of Pol II genes via its HMG box. Reason: The HMG box (residues 105-173) is the defining sequence-specific DNA-binding domain of Sox proteins. SoxE proteins bind the ACAAAG/AACAAT motifs in enhancers. The IBA node is well placed, and Xenopus Sox9 needs its HMG box to act in the neural crest: an HMG box fused to the engrailed repressor is dominant negative. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers PMID:15464575 Expression of a construct in which Sox9 DNA-binding domain (HMG box) is fused to the repressor domain of Drosophila engrailed blocked neural crest formation |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000118 | ACCEPT | Summary: TreeGrafter transfer of Pol II cis-regulatory region sequence-specific DNA binding. Reason: The HMG box (residues 105-173) is the defining sequence-specific DNA-binding domain of Sox proteins. SoxE proteins bind the ACAAAG/AACAAT motifs in enhancers. The IBA node is well placed, and Xenopus Sox9 needs its HMG box to act in the neural crest: an HMG box fused to the engrailed repressor is dominant negative. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of DNA-binding transcription factor activity, RNA polymerase II-specific. Reason: Sox9 is a Pol II-specific DNA-binding transcription factor. The more precise activator term (GO:0001228) is supported in Xenopus by the engrailed-fusion experiment and is added as NEW. This broader IBA term is correct and stays. Supporting Evidence: PMID:15464575 we demonstrate that Sox9 functions as a transcriptional activator during neural crest formation file:XENLA/sox9-a/sox9-a-uniprot.txt Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000118 | ACCEPT | Summary: TreeGrafter transfer of Pol II-specific DNA-binding transcription factor activity. Reason: Sox9 is a Pol II-specific DNA-binding transcription factor. The more precise activator term (GO:0001228) is supported in Xenopus by the engrailed-fusion experiment and is added as NEW. This broader IBA term is correct and stays. Supporting Evidence: PMID:15464575 we demonstrate that Sox9 functions as a transcriptional activator during neural crest formation |
| GO:0002009 morphogenesis of an epithelium | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference of a role in epithelial morphogenesis. Reason: SoxE genes take part in several epithelial programmes in vertebrates, and Xenopus sox9 is expressed in the otic vesicle and pancreatic epithelium. However, there is no Xenopus evidence that Sox9 directs epithelial morphogenesis, and the term is broad. It is retained as a plausible family-level, non-core role. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt also acts as a regulator of proliferation and differentiation in epithelial stem/progenitor cells |
| GO:0002009 morphogenesis of an epithelium | IEA GO_REF:0000118 | KEEP AS NON CORE | Summary: TreeGrafter transfer of morphogenesis of an epithelium. Reason: SoxE genes take part in several epithelial programmes in vertebrates, and Xenopus sox9 is expressed in the otic vesicle and pancreatic epithelium. However, there is no Xenopus evidence that Sox9 directs epithelial morphogenesis, and the term is broad. It is retained as a plausible family-level, non-core role. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt also acts as a regulator of proliferation and differentiation in epithelial stem/progenitor cells |
| GO:0002062 chondrocyte differentiation | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of a role in chondrocyte differentiation. Reason: Chondrogenesis is the conserved core role of Sox9 across vertebrates. In Xenopus, Sox9 depletion removes neural crest-derived cranial skeletal elements, including Meckel's cartilage. Lamprey Sox9 is co-expressed with Col2a1 throughout skeletogenesis, so the chondrogenic programme predates the agnathan-gnathostome split. Sox9 acts directly in this process as the transcriptional activator of the chondrocyte programme. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Transcription factor that plays a key role in chondrocytes differentiation and skeletal development PMID:11807034 morpholino-treated embryos have a specific loss or reduction of neural crest-derived skeletal elements PMID:16492784 the genetic pathway for chondrogenesis is conserved in lampreys and gnathostomes from earliest Sox9 expression through cartilage matrix gene activation |
| GO:0002062 chondrocyte differentiation | IEA GO_REF:0000118 | ACCEPT | Summary: TreeGrafter transfer of chondrocyte differentiation. Reason: Chondrogenesis is the conserved core role of Sox9 across vertebrates. In Xenopus, Sox9 depletion removes neural crest-derived cranial skeletal elements, including Meckel's cartilage. Lamprey Sox9 is co-expressed with Col2a1 throughout skeletogenesis, so the chondrogenic programme predates the agnathan-gnathostome split. Sox9 acts directly in this process as the transcriptional activator of the chondrocyte programme. Supporting Evidence: PMID:11807034 morpholino-treated embryos have a specific loss or reduction of neural crest-derived skeletal elements |
| GO:0002062 chondrocyte differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from mouse Sox9 (Q04887) of chondrocyte differentiation. Reason: Chondrogenesis is the conserved core role of Sox9 across vertebrates. In Xenopus, Sox9 depletion removes neural crest-derived cranial skeletal elements, including Meckel's cartilage. Lamprey Sox9 is co-expressed with Col2a1 throughout skeletogenesis, so the chondrogenic programme predates the agnathan-gnathostome split. Sox9 acts directly in this process as the transcriptional activator of the chondrocyte programme. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Transcription factor that plays a key role in chondrocytes differentiation and skeletal development file:XENLA/sox9-a/sox9-a-deep-research-falcon.md A review of Xenopus loss-of-function work reports severe craniofacial chondrogenic defects in Sox9 morphants |
| GO:0003430 growth plate cartilage chondrocyte growth | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transfer from mouse Sox9 of growth plate cartilage chondrocyte growth. Reason: Mouse genetics shows that Sox9 controls growth-plate chondrocyte behaviour. Frogs make endochondral bones, so a comparable role is plausible, but no Xenopus study has addressed it. The term describes a late, tissue-specific step of chondrogenesis rather than the core activity, so it is kept as non-core. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt maintains chondrocyte columnar proliferation, delays prehypertrophy and then prevents osteoblastic differentiation of chondrocytes |
| GO:0003677 DNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: DNA binding transferred from mouse Sox9. Reason: Correct, though generic. The HMG box binds DNA, and the more informative terms GO:0000978 and GO:0043565 are also present. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers |
| GO:0005515 protein binding | IPI PMID:16256735 SoxE factors function equivalently during neural crest and i... | REMOVE | Summary: Interaction of Sox9 with SUMO-1 (Sumo1-a, O57686) from the SUMOylation study. Reason: Generic protein binding is uninformative. The interaction reflects Sox9 being covalently SUMOylated at K61 and K365, which makes it a substrate of the SUMO pathway. It is not a binding activity that Sox9 uses to do its job. The SUMOylation finding itself is well supported, so removing this row does not dispute the interaction. Supporting Evidence: PMID:16256735 the activities of individual SoxE factors are well conserved and are regulated by SUMOylation file:XENLA/sox9-a/sox9-a-uniprot.txt Lys-365 is the major site of sumoylation, although sumoylation at Lys-61 also occurs |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that Sox9 is active in the nucleus. Reason: Sox9 is a nuclear transcription factor; its HMG box carries the nuclear localisation signals typical of Sox proteins. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Nucleus {ECO:0000255|PROSITE-ProRule:PRU00267 |
| GO:0005634 nucleus | IDA PMID:11807034 The transcription factor Sox9 is required for cranial neural... | ACCEPT | Summary: Nuclear localisation of Xenopus Sox9 (Spokony et al. 2002). Reason: Sox9 is a nuclear transcription factor; its HMG box carries the nuclear localisation signals typical of Sox proteins. The abstract-only cache does not show the localisation data. UniProt cites this paper as experimental evidence for nuclear localisation, and the result is consistent with the protein's function, so we defer to the curator. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Nucleus {ECO:0000255|PROSITE-ProRule:PRU00267 |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation to nucleus. Reason: Sox9 is a nuclear transcription factor; its HMG box carries the nuclear localisation signals typical of Sox proteins. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Nucleus {ECO:0000255|PROSITE-ProRule:PRU00267 |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: Nucleus transferred from X. tropicalis Sox9 (Q6F2E7). Reason: Sox9 is a nuclear transcription factor; its HMG box carries the nuclear localisation signals typical of Sox proteins. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Nucleus {ECO:0000255|PROSITE-ProRule:PRU00267 |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to cytoplasm. Reason: X. tropicalis Sox9 (Q6F2E7) is cytoplasmic in previtellogenic oocytes and moves into the nucleus in vitellogenic oocytes. Xenopus laevis sox9 is maternally expressed, so the transfer between the two Xenopus species is reasonable. The cytoplasmic pool is a storage or regulatory state in oocytes, not where Sox9 acts, so the annotation is kept as non-core. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt localizes to the cytoplasm of previtellogenic oocytes in the ovary |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cytoplasm transferred from X. tropicalis Sox9 (Q6F2E7). Reason: X. tropicalis Sox9 (Q6F2E7) is cytoplasmic in previtellogenic oocytes and moves into the nucleus in vitellogenic oocytes. Xenopus laevis sox9 is maternally expressed, so the transfer between the two Xenopus species is reasonable. The cytoplasmic pool is a storage or regulatory state in oocytes, not where Sox9 acts, so the annotation is kept as non-core. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt localizes to the cytoplasm of previtellogenic oocytes in the ovary |
| GO:0006357 regulation of transcription by RNA polymerase II | IEA GO_REF:0000118 | ACCEPT | Summary: TreeGrafter transfer of regulation of transcription by RNA polymerase II. Reason: Correct but general. Xenopus Sox9 regulates Pol II transcription as an activator. Supporting Evidence: PMID:15464575 we demonstrate that Sox9 functions as a transcriptional activator during neural crest formation |
| GO:0007507 heart development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference of a role in heart development. Reason: The IBA comes from mouse and zebrafish SoxE members; mammalian Sox9 functions in heart valve development. There are no Xenopus data on Sox9 in heart development. The term is plausible for the family but peripheral to this gene's crest and cartilage roles. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Transcription factor that plays a key role in chondrocytes differentiation and skeletal development |
| GO:0007507 heart development | IEA GO_REF:0000118 | KEEP AS NON CORE | Summary: TreeGrafter transfer of heart development. Reason: The IBA comes from mouse and zebrafish SoxE members; mammalian Sox9 functions in heart valve development. There are no Xenopus data on Sox9 in heart development. The term is plausible for the family but peripheral to this gene's crest and cartilage roles. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Transcription factor that plays a key role in chondrocytes differentiation and skeletal development |
| GO:0014029 neural crest formation | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learning annotation to neural crest formation. Reason: Correct but imprecise. Combined Xenopus evidence places Sox9 in the crest specifier layer. Loss of Sox9 removes crest progenitors and expands the neural plate; Sox9 is required for Wnt-driven induction and for specification, but not for migration. GO:0014036 neural crest cell fate specification, a descendant of neural crest formation, describes the work Sox9 does, so the IEA is refined to it. Proposed replacements: neural crest cell fate specification Supporting Evidence: PMID:11807034 causes a dramatic loss of neural crest progenitors and an expansion of the neural plate PMID:15464575 we show that Sox9 function is required for neural crest specification but not for its subsequent migration |
| GO:0014029 neural crest formation | IMP PMID:11807034 The transcription factor Sox9 is required for cranial neural... | MODIFY | Summary: Sox9 morpholino causes loss of neural crest progenitors and expansion of the neural plate. Reason: Correct, but more precise annotation is possible. The phenotype is a fate switch: crest progenitors are lost and the neural plate expands. This is the signature of a neural crest specifier, not a border specifier. The same laboratory then showed that Sox9 is required for crest specification but not for migration, and that it is needed for Wnt-driven crest induction. Sox9 comes on at the border after Sox8 and before Sox10. Taken together with this evidence, Sox9 belongs in the specifier layer of the network, and GO:0014036 neural crest cell fate specification, a descendant of neural crest formation, describes the work it does. Proposed replacements: neural crest cell fate specification Supporting Evidence: PMID:11807034 causes a dramatic loss of neural crest progenitors and an expansion of the neural plate PMID:15464575 we show that Sox9 function is required for neural crest specification but not for its subsequent migration PMID:15464575 Wnt-mediated neural crest induction is inhibited in the context of Sox9-depleted embryos |
| GO:0014029 neural crest formation | IMP PMID:16256735 SoxE factors function equivalently during neural crest and i... | MODIFY | Summary: SoxE (Sox9/Sox10) knockdown and rescue experiments on neural crest precursors (Taylor and LaBonne 2005). Reason: Taylor and LaBonne show that Sox9 and Sox10 are essential for forming neural crest precursor cells and that SoxE activities are interchangeable. Only the abstract is cached. The requirement for forming precursors is a fate-specification role, consistent with Lee et al. 2004, so the refinement to GO:0014036 is a gene-level judgement across studies. It does not dispute the curator's evidence. Proposed replacements: neural crest cell fate specification Supporting Evidence: PMID:16256735 Sox9 and the closely related factor Sox10 are essential for the formation of neural crest precursor cells PMID:15464575 we show that Sox9 function is required for neural crest specification but not for its subsequent migration |
| GO:0014029 neural crest formation | IMP PMID:16943273 Functional analysis of Sox8 during neural crest development ... | MODIFY | Summary: Sox8 functional study, in which Sox9 is assayed alongside Sox8 (O'Donnell et al. 2006). Reason: The abstract focuses on Sox8, but SoxE factors overlap in crest progenitors. The curator had the full text, which probably includes Sox9 perturbations, and the crest role is clearly correct for Sox9. We keep the annotation and refine the term to GO:0014036, based on the combined evidence that Sox9 acts in crest specification (Lee et al. 2004). This is a gene-level judgement, not a dispute of the curator's evidence. Proposed replacements: neural crest cell fate specification Supporting Evidence: PMID:16943273 Sox8, Sox9 and Sox10, exhibit overlapping expression domains in neural crest progenitors PMID:15464575 we show that Sox9 function is required for neural crest specification but not for its subsequent migration |
| GO:0032332 positive regulation of chondrocyte differentiation | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of positive regulation of chondrocyte differentiation. Reason: Sox9 directly activates the chondrocyte programme (Col2a1 and other matrix genes) in vertebrates. Positive regulation of chondrocyte differentiation is how GO captures a transcription factor that drives the programme. The term is consistent with the core role. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Transcription factor that plays a key role in chondrocytes differentiation and skeletal development PMID:16492784 the genetic pathway for chondrogenesis is conserved in lampreys and gnathostomes from earliest Sox9 expression through cartilage matrix gene activation |
| GO:0032332 positive regulation of chondrocyte differentiation | IEA GO_REF:0000118 | ACCEPT | Summary: TreeGrafter transfer of positive regulation of chondrocyte differentiation. Reason: Sox9 directly activates the chondrocyte programme (Col2a1 and other matrix genes) in vertebrates. Positive regulation of chondrocyte differentiation is how GO captures a transcription factor that drives the programme. The term is consistent with the core role. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Transcription factor that plays a key role in chondrocytes differentiation and skeletal development |
| GO:0043049 otic placode formation | IMP PMID:15084460 Specification of the otic placode depends on Sox9 function i... | KEEP AS NON CORE | Summary: Sox9 depletion abolishes otic placode markers and the otic vesicle. Reason: Sox9 is well supported as required for otic placode specification in Xenopus. Morpholino knockdown loses Pax8 and Tbx2, and an inducible dominant-negative shows that Sox9 is needed for specification but not for later patterning. Lamprey Sox9 is also expressed in otic placodes. This is a real, direct role, but it is a separate deployment from the neural crest and chondrogenic programmes, so it is kept as non-core for this pleiotropic gene. Supporting Evidence: PMID:15084460 we demonstrate that Sox9 function is required for otic placode specification but not for its subsequent patterning PMID:15084460 causes a dramatic loss of the early otic placode markers Pax8 and Tbx2 |
| GO:0043049 otic placode formation | IMP PMID:16256735 SoxE factors function equivalently during neural crest and i... | KEEP AS NON CORE | Summary: SoxE activities in inner ear development, modulated by SUMOylation. Reason: Sox9 is well supported as required for otic placode specification in Xenopus. Morpholino knockdown loses Pax8 and Tbx2, and an inducible dominant-negative shows that Sox9 is needed for specification but not for later patterning. Lamprey Sox9 is also expressed in otic placodes. This is a real, direct role, but it is a separate deployment from the neural crest and chondrogenic programmes, so it is kept as non-core for this pleiotropic gene. Taylor and LaBonne report that the SUMOylation state of Sox9 shifts its output between crest and otic fates. Supporting Evidence: PMID:16256735 the activities of individual SoxE factors are well conserved and are regulated by SUMOylation PMID:15084460 we demonstrate that Sox9 function is required for otic placode specification but not for its subsequent patterning |
| GO:0043565 sequence-specific DNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-specific DNA binding transferred from human SOX9. Reason: The HMG box (residues 105-173) is the defining sequence-specific DNA-binding domain of Sox proteins. SoxE proteins bind the ACAAAG/AACAAT motifs in enhancers. The IBA node is well placed, and Xenopus Sox9 needs its HMG box to act in the neural crest: an HMG box fused to the engrailed repressor is dominant negative. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers |
| GO:0044389 ubiquitin-like protein ligase binding | IPI PMID:16256735 SoxE factors function equivalently during neural crest and i... | MODIFY | Summary: Interaction of Sox9 with Ube2i/Ubc9 (P63282). Reason: Ubc9 is the SUMO E2 conjugating enzyme. Its interaction with Sox9 reflects Sox9 being a SUMOylation substrate. If an enzyme-binding term is kept, ubiquitin-like protein conjugating enzyme binding (GO:0044390) describes the partner more accurately than ligase binding. This is a regulatory input to Sox9, not part of its core function. Proposed replacements: ubiquitin-like protein conjugating enzyme binding Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Lys-365 is the major site of sumoylation, although sumoylation at Lys-61 also occurs PMID:16256735 the activities of individual SoxE factors are well conserved and are regulated by SUMOylation |
| GO:0045668 negative regulation of osteoblast differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of osteoblast differentiation transferred from mouse Sox9. Reason: In mouse growth plates, Sox9 keeps chondrocytes in their lineage and blocks osteoblastic differentiation. This is plausible for frogs but not tested in Xenopus. It is a downstream aspect of chondrocyte lineage maintenance. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt maintains chondrocyte columnar proliferation, delays prehypertrophy and then prevents osteoblastic differentiation of chondrocytes |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:12812785 Sox10 regulates the development of neural crest-derived mela... | ACCEPT | Summary: Positive regulation of transcription inferred from the Sox10/Sox9 neural crest study (Aoki et al. 2003). Reason: Sox9 acts as a transcriptional activator in the Xenopus neural crest: the HMG-box/engrailed-repressor fusion phenocopies the knockdown, and the transactivation domain is needed. The positive regulation of transcription annotations are correct. The Aoki 2003 abstract mentions Sox9 only as co-expressed with Sox10. The curator presumably used full-text Sox9 data, and the function is clearly correct, so we defer. Supporting Evidence: PMID:12812785 colocalizes with two major regulators of neural crest formation, Slug and Sox9 PMID:15464575 we demonstrate that Sox9 functions as a transcriptional activator during neural crest formation |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:15464575 Early requirement of the transcriptional activator Sox9 for ... | ACCEPT | Summary: Sox9 functions as a transcriptional activator in neural crest formation. Reason: Sox9 acts as a transcriptional activator in the Xenopus neural crest: the HMG-box/engrailed-repressor fusion phenocopies the knockdown, and the transactivation domain is needed. The positive regulation of transcription annotations are correct. Supporting Evidence: PMID:15464575 we demonstrate that Sox9 functions as a transcriptional activator during neural crest formation PMID:15464575 Expression of a construct in which Sox9 DNA-binding domain (HMG box) is fused to the repressor domain of Drosophila engrailed blocked neural crest formation |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:12812785 Sox10 regulates the development of neural crest-derived mela... | ACCEPT | Summary: Positive regulation of Pol II transcription (Aoki et al. 2003). Reason: Sox9 acts as a transcriptional activator in the Xenopus neural crest: the HMG-box/engrailed-repressor fusion phenocopies the knockdown, and the transactivation domain is needed. The positive regulation of transcription annotations are correct. Aoki 2003 is abstract-only in our cache; we defer to the curator. Supporting Evidence: PMID:12812785 colocalizes with two major regulators of neural crest formation, Slug and Sox9 PMID:15464575 we demonstrate that Sox9 functions as a transcriptional activator during neural crest formation |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:15464575 Early requirement of the transcriptional activator Sox9 for ... | ACCEPT | Summary: Sox9 functions as a Pol II transcriptional activator in neural crest formation. Reason: Sox9 acts as a transcriptional activator in the Xenopus neural crest: the HMG-box/engrailed-repressor fusion phenocopies the knockdown, and the transactivation domain is needed. The positive regulation of transcription annotations are correct. Supporting Evidence: PMID:15464575 we demonstrate that Sox9 functions as a transcriptional activator during neural crest formation PMID:15464575 Expression of a construct in which Sox9 DNA-binding domain (HMG box) is fused to the repressor domain of Drosophila engrailed blocked neural crest formation |
| GO:0046322 negative regulation of fatty acid oxidation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of fatty acid oxidation transferred from mouse Sox9. Reason: In mouse skeletal progenitors, Sox9 induced under low-lipid conditions suppresses fatty acid oxidation as part of chondrogenic commitment. The effect is real in mouse, but it is a metabolic consequence of the chondrogenic programme and has not been tested in Xenopus. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt when lipids levels are low, FOXO transcription factors promote expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation |
| GO:0048709 oligodendrocyte differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference of a role in oligodendrocyte differentiation. Reason: SoxE-driven glial (oligodendrocyte) differentiation is conserved in mouse and zebrafish, and the IBA node placement is reasonable. There are no Xenopus data; this is a pleiotropic, non-core role. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Transcription factor that plays a key role in chondrocytes differentiation and skeletal development |
| GO:0048709 oligodendrocyte differentiation | IEA GO_REF:0000118 | KEEP AS NON CORE | Summary: TreeGrafter transfer of oligodendrocyte differentiation. Reason: SoxE-driven glial differentiation is conserved in vertebrates. There are no Xenopus data; this is a non-core role. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt Transcription factor that plays a key role in chondrocytes differentiation and skeletal development |
| GO:0051216 cartilage development | ISS GO_REF:0000024 | ACCEPT | Summary: Cartilage development transferred from mouse Sox9 (Q04887). Reason: Cartilage development is a core, deeply conserved Sox9 role. Xenopus morphants lose crest-derived cranial cartilage, and lamprey Sox9 is co-expressed with Col2a1 during skeletogenesis. Supporting Evidence: PMID:11807034 morpholino-treated embryos have a specific loss or reduction of neural crest-derived skeletal elements PMID:16492784 the genetic pathway for chondrogenesis is conserved in lampreys and gnathostomes from earliest Sox9 expression through cartilage matrix gene activation |
| GO:0051216 cartilage development | ISS GO_REF:0000024 | ACCEPT | Summary: Cartilage development transferred from X. tropicalis Sox9 (Q6F2E7). Reason: Cartilage development is a core, deeply conserved Sox9 role. Xenopus morphants lose crest-derived cranial cartilage, and lamprey Sox9 is co-expressed with Col2a1 during skeletogenesis. Supporting Evidence: PMID:11807034 morpholino-treated embryos have a specific loss or reduction of neural crest-derived skeletal elements file:XENLA/sox9-a/sox9-a-deep-research-falcon.md A review of Xenopus loss-of-function work reports severe craniofacial chondrogenic defects in Sox9 morphants |
| GO:0070542 response to fatty acid | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Response to fatty acid transferred from mouse Sox9. Reason: In mouse, low lipid availability raises SOX9 expression through FOXO; the cells respond, and Sox9 is a readout or effector of that response. Calling this a Sox9 'response to fatty acid' describes the regulation of Sox9 rather than Sox9's function. No Xenopus evidence exists. Supporting Evidence: file:XENLA/sox9-a/sox9-a-uniprot.txt when lipids levels are low, FOXO transcription factors promote expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of canonical Wnt signalling transferred from mouse Sox9. Reason: Mammalian SOX9 antagonises beta-catenin in chondrocytes. In the Xenopus neural crest, by contrast, Sox9 is required downstream of Wnt-mediated crest induction rather than acting as an antagonist. The annotation may hold in the chondrocyte context but is not a core role in this frog. Supporting Evidence: PMID:15464575 Wnt-mediated neural crest induction is inhibited in the context of Sox9-depleted embryos |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IMP PMID:15464575 Early requirement of the transcriptional activator Sox9 for ... | NEW | Summary: Xenopus Sox9 acts as a transcriptional activator: replacing its transactivation function with the engrailed repressor domain blocks neural crest formation and phenocopies the knockdown. Reason: The existing MF annotations stop at the generic Pol II DNA-binding transcription factor activity. In vivo domain-swap evidence in Xenopus (HMG box fused to the engrailed repressor is dominant negative), together with the conserved TAM/TAC transactivation domains and the positive-regulation IMPs, supports the more precise activator term. This is the molecular activity behind both the neural crest and the chondrogenic roles. Supporting Evidence: PMID:15464575 we demonstrate that Sox9 functions as a transcriptional activator during neural crest formation PMID:15464575 Expression of a construct in which Sox9 DNA-binding domain (HMG box) is fused to the repressor domain of Drosophila engrailed blocked neural crest formation file:XENLA/sox9-a/sox9-a-uniprot.txt The 9aaTAD motif is a transactivation domain |
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Download this section (compressed HTML)Q: Will GO accept refining the Xenopus SoxE experimental annotations from GO:0014029 neural crest formation to GO:0014036 neural crest cell fate specification, as part of the proposed obsoletion of GO:0014029? Border specifiers (Pax3, Zic1, Msx1) and crest specifiers (Sox9, Sox10, Snai2, FoxD3) currently both end up under neural crest formation, which conflates two network layers.
Q: Do the Sox9 morpholinos and mRNAs used in the Xenopus studies (PMID:11807034, PMID:15464575, PMID:15084460) target both sox9-a (L) and sox9-b (S)? If so, should the experimental annotations be shared with the sox9-b homeolog (Q6DFF5)?
Q: Lamprey SoxE paralogs arose by duplications independent of the gnathostome Sox8/9/10 split (PMID:21889937). Which lamprey SoxE gene carries the Sox9-like chondrogenic crest role, and can any PAINT node assert neural crest specification above the gnathostome SoxE duplication?
Q: Which crest enhancers does Sox9 directly occupy in Xenopus (e.g. sox10, snai2, foxd3)? Does the SUMO switch at K61/K365 alter DNA occupancy or co-factor recruitment?
Experiment: CUT&RUN or ChIP-seq for Sox9 (homeolog-resolved by tagged sox9-a/sox9-b alleles) in dissected Xenopus neural folds at stage 13-15, combined with ATAC-seq after Sox9 knockdown, to identify directly bound and Sox9-dependent crest enhancers.
Hypothesis: Sox9 directly activates crest specifier genes at the neural plate border.
Type: ChIP-seq
Experiment: Homeolog-specific CRISPR F0 knockouts of sox9-a, sox9-b and both together, scoring sox10/snai2/foxd3 expression at the border, otic Pax8 expression and Alcian blue-stained cranial cartilage.
Hypothesis: sox9-a and sox9-b are functionally equivalent and jointly required.
Type: genetic knockout
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