id: Q9IAK8 gene_symbol: tbx5a product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:7955 label: Danio rerio description: >- T-box transcription factor TBX5-A (heartstrings), one of two zebrafish co-orthologs of human TBX5 retained from the teleost genome duplication (paralog tbx5b). A nuclear, sequence-specific DNA-binding transcription factor with a T-box domain. It binds T-box elements and activates targets including tbx2b at the atrioventricular boundary, fgf24/fgf10 in the fin field and ndrg4 in the heart tube. A cytoplasmic pool is held on actin by the LIM protein Pdlim7, and its activity is repressed by Kctd10. It is expressed in the heart field and heart (both chambers; trabecular myocardium in adults), the pectoral fin field of the lateral plate mesoderm, and the dorsal retina. tbx5a is essential for pectoral fin bud initiation: it drives fgf24 and the antero-posterior convergence of fin-field cells, and loss of function abolishes the pectoral fin. It is needed for cardiac looping and chamber and AV canal patterning, for proepicardium specification, and for adult heart regeneration. Together with tbx5b it contributes to dorsoventral patterning of the retina and to heart looping. The two paralogs are not interchangeable: each is required, and injected mRNA of one does not rescue loss of the other. existing_annotations: - term: id: GO:0000785 label: chromatin evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - MGI:MGI:102539 - MGI:MGI:1201683 - MGI:MGI:98472 - PANTHER:PTN004251338 - UniProtKB:O15178 - ZFIN:ZDB-GENE-020416-5 - ZFIN:ZDB-GENE-980526-437 - ZFIN:ZDB-GENE-990615-5 review: summary: Active in chromatin (IBA). action: ACCEPT reason: >- Tbx5a is a T-box transcription factor that binds regulatory DNA (PMID:18347092). Being active in chromatin is expected of a sequence-specific transcription factor. The IBA is the family-level call for the Tbx2/3/4/5 node. supported_by: - reference_id: PMID:18347092 supporting_text: >- In electromobility shift assays (EMSA) to test DNA-binding affinity, Foxn4 and Tbx5 bound efficiently to their labeled putative binding sites, and binding was efficiently competed with excess unlabeled cognate competitors, but not with mutated oligonucleotides - 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:102539 - MGI:MGI:102541 - MGI:MGI:107404 - MGI:MGI:1277234 - MGI:MGI:1888496 - MGI:MGI:1891158 - MGI:MGI:1923615 - MGI:MGI:98472 - MGI:MGI:98494 - MGI:MGI:98495 - PANTHER:PTN004251338 - UniProtKB:O15119 - UniProtKB:O15178 - UniProtKB:Q13207 - UniProtKB:Q99593 review: summary: >- Sequence-specific binding of RNA polymerase II cis-regulatory DNA through the T-box domain (IBA). action: ACCEPT reason: >- tbx5a carries a complete T-box DNA-binding domain (UniProt residues 62-237). Tbx5 binds the conserved T-box element of the tbx2b atrioventricular canal enhancer in EMSA, and that site is needed for the enhancer to work in zebrafish transgenics (PMID:18347092). The IBA node (PTN004251338) covers the Tbx2/3/4/5 subfamily, and nothing suggests loss of DNA binding in either zebrafish copy. Core molecular function, shared with tbx5b. supported_by: - reference_id: PMID:18347092 supporting_text: >- In electromobility shift assays (EMSA) to test DNA-binding affinity, Foxn4 and Tbx5 bound efficiently to their labeled putative binding sites, and binding was efficiently competed with excess unlabeled cognate competitors, but not with mutated oligonucleotides - reference_id: PMID:18347092 supporting_text: >- Thus, the putative Foxn4 and Tbx5 DNA-binding sites are required for the precise control of this highly conserved tbx2b enhancer during AV canal development. - term: id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables supporting_entities: - InterPro:IPR001699 review: summary: >- Sequence-specific binding of RNA polymerase II cis-regulatory DNA through the T-box domain (IEA, InterPro T-box). action: ACCEPT reason: >- tbx5a carries a complete T-box DNA-binding domain (UniProt residues 62-237). Tbx5 binds the conserved T-box element of the tbx2b atrioventricular canal enhancer in EMSA, and that site is needed for the enhancer to work in zebrafish transgenics (PMID:18347092). The IBA node (PTN004251338) covers the Tbx2/3/4/5 subfamily, and nothing suggests loss of DNA binding in either zebrafish copy. Core molecular function, shared with tbx5b. supported_by: - reference_id: PMID:18347092 supporting_text: >- In electromobility shift assays (EMSA) to test DNA-binding affinity, Foxn4 and Tbx5 bound efficiently to their labeled putative binding sites, and binding was efficiently competed with excess unlabeled cognate competitors, but not with mutated oligonucleotides - reference_id: PMID:18347092 supporting_text: >- Thus, the putative Foxn4 and Tbx5 DNA-binding sites are required for the precise control of this highly conserved tbx2b enhancer during AV canal development. - term: id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables supporting_entities: - UniProtKB:Q99593 review: summary: >- Sequence-specific binding of RNA polymerase II cis-regulatory DNA through the T-box domain (ISS from human TBX5). action: ACCEPT reason: >- tbx5a carries a complete T-box DNA-binding domain (UniProt residues 62-237). Tbx5 binds the conserved T-box element of the tbx2b atrioventricular canal enhancer in EMSA, and that site is needed for the enhancer to work in zebrafish transgenics (PMID:18347092). The IBA node (PTN004251338) covers the Tbx2/3/4/5 subfamily, and nothing suggests loss of DNA binding in either zebrafish copy. Core molecular function, shared with tbx5b. supported_by: - reference_id: PMID:18347092 supporting_text: >- In electromobility shift assays (EMSA) to test DNA-binding affinity, Foxn4 and Tbx5 bound efficiently to their labeled putative binding sites, and binding was efficiently competed with excess unlabeled cognate competitors, but not with mutated oligonucleotides - reference_id: PMID:18347092 supporting_text: >- Thus, the putative Foxn4 and Tbx5 DNA-binding sites are required for the precise control of this highly conserved tbx2b enhancer during AV canal development. - 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:FBgn0011723 - FB:FBgn0028789 - FB:FBgn0035956 - FB:FBgn0261963 - MGI:MGI:102541 - MGI:MGI:1277234 - MGI:MGI:1352483 - MGI:MGI:1888496 - MGI:MGI:1888984 - MGI:MGI:1891158 - MGI:MGI:1923615 - MGI:MGI:98472 - MGI:MGI:98493 - PANTHER:PTN004251338 - UniProtKB:O15119 - UniProtKB:O15178 - UniProtKB:Q13207 - UniProtKB:Q99593 - UniProtKB:Q9UL17 - UniProtKB:Q9UMR3 - ZFIN:ZDB-GENE-001228-1 review: summary: RNA polymerase II-specific DNA-binding transcription factor activity (IBA). action: ACCEPT reason: >- The core activity of Tbx5. In zebrafish, Tbx5 binds and is needed for the tbx2b AV-canal enhancer (PMID:18347092), activates tbx2b at the AV boundary (PMID:19895804), and is repressed by Kctd10 (PMID:24430697). Shared with tbx5b by IBA; the T-box domain is 83% identical between the paralogs (PMID:39079985). supported_by: - reference_id: PMID:18347092 supporting_text: >- In electromobility shift assays (EMSA) to test DNA-binding affinity, Foxn4 and Tbx5 bound efficiently to their labeled putative binding sites, and binding was efficiently competed with excess unlabeled cognate competitors, but not with mutated oligonucleotides - reference_id: PMID:19895804 supporting_text: >- The presence of a Tbx5-binding-element in the promoter of tbx2b along with the reduction of expression in hst heterozygous mutants and complete loss in homozygotes reveals that Tbx5 regulates tbx2b at the AV boundary. - reference_id: PMID:24430697 supporting_text: >- We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. - term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables supporting_entities: - UniProtKB:Q99593 review: summary: >- RNA polymerase II-specific DNA-binding transcription factor activity (ISS from human TBX5). action: ACCEPT reason: >- The core activity of Tbx5. In zebrafish, Tbx5 binds and is needed for the tbx2b AV-canal enhancer (PMID:18347092), activates tbx2b at the AV boundary (PMID:19895804), and is repressed by Kctd10 (PMID:24430697). Shared with tbx5b by IBA; the T-box domain is 83% identical between the paralogs (PMID:39079985). supported_by: - reference_id: PMID:18347092 supporting_text: >- In electromobility shift assays (EMSA) to test DNA-binding affinity, Foxn4 and Tbx5 bound efficiently to their labeled putative binding sites, and binding was efficiently competed with excess unlabeled cognate competitors, but not with mutated oligonucleotides - reference_id: PMID:19895804 supporting_text: >- The presence of a Tbx5-binding-element in the promoter of tbx2b along with the reduction of expression in hst heterozygous mutants and complete loss in homozygotes reveals that Tbx5 regulates tbx2b at the AV boundary. - reference_id: PMID:24430697 supporting_text: >- We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. - term: id: GO:0001708 label: cell fate specification evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - FB:FBgn0261963 - MGI:MGI:102539 - MGI:MGI:1201683 - MGI:MGI:98493 - PANTHER:PTN000137774 - WB:WBGene00003106 - WB:WBGene00003376 - WB:WBGene00006543 - WB:WBGene00006554 - ZFIN:ZDB-GENE-001228-1 - ZFIN:ZDB-GENE-990726-27 review: summary: Cell fate specification (IBA, T-box family node). action: KEEP_AS_NON_CORE reason: >- Fate specification is a deep, family-wide T-box function. In zebrafish, tbx5a is needed for proepicardium specification (PMID:20413782) and for specification of late-added cardiac cells from the anterior LPM (PMID:33482174). This is correct but broad, so it is kept as non-core. supported_by: - reference_id: PMID:20413782 supporting_text: We further show that tbx5a mutants also have severe defects in PE specification. - reference_id: PMID:33482174 supporting_text: >- our present data also implicate tbx5a function in cell specification, establishment and maintenance of cardiac left-right asymmetry. - term: id: GO:0001947 label: heart looping evidence_type: IGI original_reference_id: PMID:19895804 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-040426-2092 review: summary: Heart looping (IGI with pdlim7). action: ACCEPT reason: >- Pdlim7 and Tbx5 act in one pathway at the AV boundary, and both are needed for looping by 48 hpf (PMID:19895804). Heart looping is a well-established tbx5a requirement (PMID:12223419, PMID:34372968). supported_by: - reference_id: PMID:19895804 supporting_text: >- Both genes, on the other hand, are required for proper heart morphology, with pdlim7 playing an earlier role at or slightly before 24 hpf and both pdlim7 and tbx5 being essential by 48 hpf for heart-looping. - reference_id: PMID:12223419 supporting_text: >- However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. - term: id: GO:0001947 label: heart looping evidence_type: IGI original_reference_id: PMID:24430697 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-040426-2843 review: summary: Heart looping (IGI with kctd10). action: ACCEPT reason: >- Knocking down tbx5a relieves the heart defects of kctd10 mutants, placing tbx5a activity in this morphogenesis (PMID:24430697; abstract only). The curator had the full text, and looping is a well-established tbx5a requirement (PMID:12223419). supported_by: - reference_id: PMID:24430697 supporting_text: >- The knockdown of tbx5 rescues the ectopic expression of has2, and knockdown of either tbx5a or has2 alleviates the heart defects. - reference_id: PMID:12223419 supporting_text: >- However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. - term: id: GO:0001947 label: heart looping evidence_type: IGI original_reference_id: PMID:24759614 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 - ZFIN:ZDB-MRPHLNO-130123-3 review: summary: Heart looping (IGI, tbx5a + tbx5b double morphants). action: ACCEPT reason: >- Failure of cardiac looping is the defining heart phenotype of tbx5a loss in zebrafish. It is seen in heartstrings (PMID:12223419), in the T-box-truncating oug allele (PMID:34372968) and in morphants (PMID:24759614). Looping also needs tbx5b (PMID:30532148), so the term is correctly shared by the pair. supported_by: - reference_id: PMID:24759614 supporting_text: >- By contrast, 88% (n = 121) of the tbx5a MO-injected embryos had incomplete cardiac looping, and within these 57% showed D-loop, 24% showed L-loop and 19% showed no looping at all - reference_id: PMID:24759614 supporting_text: >- Although, in agreement with a previous report [17], the severity of the phenotype was not enhanced by double knock-down, downregulation of both genes increased the penetrance of the phenotype (figure 1i). - term: id: GO:0001947 label: heart looping evidence_type: IMP original_reference_id: PMID:12399308 qualifier: acts_upstream_of_or_within review: summary: Heart looping (IMP, PMID:12399308). action: ACCEPT reason: >- Only the abstract of PMID:12399308 is cached, and it covers the limb/fin role. The curator had the full text, which used heartstrings mutants, and heart looping is a well-established tbx5a requirement (PMID:12223419, PMID:34372968). Accepted, deferring to the curator. supported_by: - reference_id: PMID:12223419 supporting_text: >- However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. - reference_id: PMID:34372968 supporting_text: >- In such a screen we identified the oudegracht (oug) mutant in which cardiac jogging was unaffected while cardiac looping was compromised. - term: id: GO:0001947 label: heart looping evidence_type: IMP original_reference_id: PMID:20413782 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-080813-1 review: summary: Heart looping (IMP, heartstrings). action: ACCEPT reason: >- Failure of cardiac looping is the defining heart phenotype of tbx5a loss in zebrafish. It is seen in heartstrings (PMID:12223419), in the T-box-truncating oug allele (PMID:34372968) and in morphants (PMID:24759614). Looping also needs tbx5b (PMID:30532148), so the term is correctly shared by the pair. supported_by: - reference_id: PMID:20413782 supporting_text: >- The major cardiac morphogenetic defect of tbx5a mutants at the stage when the PE starts to form in wildtype is a failure to complete cardiac looping - reference_id: PMID:12223419 supporting_text: >- However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. - term: id: GO:0001947 label: heart looping evidence_type: IMP original_reference_id: PMID:24759614 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Heart looping (IMP, tbx5a morpholino). action: ACCEPT reason: >- Failure of cardiac looping is the defining heart phenotype of tbx5a loss in zebrafish. It is seen in heartstrings (PMID:12223419), in the T-box-truncating oug allele (PMID:34372968) and in morphants (PMID:24759614). Looping also needs tbx5b (PMID:30532148), so the term is correctly shared by the pair. supported_by: - reference_id: PMID:24759614 supporting_text: >- By contrast, 88% (n = 121) of the tbx5a MO-injected embryos had incomplete cardiac looping, and within these 57% showed D-loop, 24% showed L-loop and 19% showed no looping at all - term: id: GO:0003007 label: heart morphogenesis evidence_type: IGI original_reference_id: PMID:21715426 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 - ZFIN:ZDB-MRPHLNO-060522-2 - ZFIN:ZDB-MRPHLNO-070409-1 review: summary: Heart morphogenesis (IGI with smarcd3b/gata5). action: ACCEPT reason: >- Combined loss of cardiac BAF (cBAF) components, including tbx5a, inhibits cardiac differentiation (PMID:21715426; abstract only). Heart morphogenesis is a well-supported tbx5a process. supported_by: - reference_id: PMID:21715426 supporting_text: >- Overexpression of smarcd3b and gata5 in zebrafish results in an enlarged heart, whereas combinatorial loss of cBAF components inhibits cardiac differentiation. - reference_id: PMID:12223419 supporting_text: >- However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. - term: id: GO:0003007 label: heart morphogenesis evidence_type: IMP original_reference_id: PMID:23226307 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Heart morphogenesis (IMP, morpholino). action: ACCEPT reason: >- tbx5a morphants and embryos overexpressing tbx5a both show looping and chamber defects, and miR-218 interacts with tbx5a in heart morphogenesis (PMID:23226307). supported_by: - reference_id: PMID:23226307 supporting_text: >- Co-injection of 8 ng of either MOD-218a or MOM-218a along with 100 pg of tbx5a mRNA restored normal heart morphology and looping in a high percentage of injected embryos - reference_id: PMID:23226307 supporting_text: >- However, the injection of both MO-Tbx5a and miR-218a mimic at these doses dramatically increased the number of embryos with looping defects - term: id: GO:0003143 label: embryonic heart tube morphogenesis evidence_type: IGI original_reference_id: PMID:19895804 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-080813-1 - ZFIN:ZDB-MRPHLNO-100524-7 review: summary: Embryonic heart tube morphogenesis (IGI with pdlim7). action: ACCEPT reason: >- Pdlim7 and Tbx5 interact genetically and physically to shape the heart tube and the AV boundary (PMID:19895804). supported_by: - reference_id: PMID:19895804 supporting_text: >- Both genes, on the other hand, are required for proper heart morphology, with pdlim7 playing an earlier role at or slightly before 24 hpf and both pdlim7 and tbx5 being essential by 48 hpf for heart-looping. - term: id: GO:0003143 label: embryonic heart tube morphogenesis evidence_type: IMP original_reference_id: PMID:19895804 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-080813-1 review: summary: Embryonic heart tube morphogenesis (IMP, heartstrings). action: ACCEPT reason: >- heartstrings mutants lose tbx2b at the AV boundary and fail to loop (PMID:19895804). supported_by: - reference_id: PMID:19895804 supporting_text: >- The presence of a Tbx5-binding-element in the promoter of tbx2b along with the reduction of expression in hst heterozygous mutants and complete loss in homozygotes reveals that Tbx5 regulates tbx2b at the AV boundary. - reference_id: PMID:19895804 supporting_text: >- Both genes, on the other hand, are required for proper heart morphology, with pdlim7 playing an earlier role at or slightly before 24 hpf and both pdlim7 and tbx5 being essential by 48 hpf for heart-looping. - term: id: GO:0003146 label: heart jogging evidence_type: IGI original_reference_id: PMID:24759614 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 - ZFIN:ZDB-MRPHLNO-130123-3 review: summary: Heart jogging (IGI, tbx5a + tbx5b double morphants). action: UNDECIDED reason: >- Jogging defects in tbx5a loss have been reported only with morpholinos (PMID:24759614). The mutants do not show them. heartstrings mutants jog normally (PMID:24759614, PMID:30532148). Pi-Roig et al. argued that hst is hypomorphic for laterality. However, the oug allele truncates Tbx5a inside the T-box and loses about 75% of the protein, and it also has "cardiac jogging unaffected while cardiac looping was compromised" (PMID:34372968). So the most null-like mutant contradicts the morphant result. This could be a morpholino off-target effect, or transcriptional adaptation in the mutants. Left undecided rather than removed, pending a mutant test that excludes genetic compensation (for example a promoter-less allele). supported_by: - reference_id: PMID:24759614 supporting_text: >- The cardiac phenotypes caused by tbx5a and/or tbx5b knock-down (namely cardiac jogging and looping orientation defects) demonstrate that tbx5 genes are required to direct both asymmetric events the zebrafish heart undergoes - reference_id: PMID:24759614 supporting_text: >- We have ourselves analysed heart tube jogging in hst mutants (n = 38) and all of them displayed a normal left-jog as visualized by myl7 expression in 26 hpf embryos (figure 3c,d). - reference_id: PMID:34372968 supporting_text: >- In such a screen we identified the oudegracht (oug) mutant in which cardiac jogging was unaffected while cardiac looping was compromised. - reference_id: PMID:34372968 supporting_text: >- Indeed, in oug approximately 75% of the gene product is lost, including a large portion of the DNA-binding T-box domain. - term: id: GO:0003146 label: heart jogging evidence_type: IMP original_reference_id: PMID:24759614 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Heart jogging (IMP, tbx5a morpholino). action: UNDECIDED reason: >- Same issue as the IGI row. The morphant jogging defects (PMID:24759614) are not reproduced in heartstrings or in the T-box-truncating oug mutant, which both jog normally (PMID:34372968). supported_by: - reference_id: PMID:24759614 supporting_text: >- Overall, these data demonstrate not only the specificity of the cardiac phenotypes caused by MO-mediated knock-down of tbx5a and/or tbx5b, but also that the hst mutation behaves as a hypomorphic allele with regard to cardiac laterality. - reference_id: PMID:34372968 supporting_text: >- In such a screen we identified the oudegracht (oug) mutant in which cardiac jogging was unaffected while cardiac looping was compromised. - term: id: GO:0003190 label: atrioventricular valve formation evidence_type: IMP original_reference_id: PMID:19895804 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-080813-1 review: summary: Atrioventricular valve formation (IMP, heartstrings). action: KEEP_AS_NON_CORE reason: >- hst mutants make too much AV valve tissue, the opposite of pdlim7 morphants (PMID:19895804). Tbx5a patterns the AV boundary through tbx2b. Supported, but downstream of the core boundary-patterning role. supported_by: - reference_id: PMID:19895804 supporting_text: >- Knock-down of Pdlim7 results in loss of detectable valve structures while lack of Tbx5 function leads to increased amounts of valve tissue. - reference_id: PMID:19895804 supporting_text: >- The presence of a Tbx5-binding-element in the promoter of tbx2b along with the reduction of expression in hst heterozygous mutants and complete loss in homozygotes reveals that Tbx5 regulates tbx2b at the AV boundary. - term: id: GO:0003206 label: cardiac chamber morphogenesis evidence_type: IMP original_reference_id: PMID:34372968 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-240102-1 review: summary: Cardiac chamber morphogenesis (IMP, oug mutant). action: ACCEPT reason: >- oug/tbx5a mutants lose chamber differentiation (nppa), expand the AV canal and fail to twist the heart tube during looping (PMID:34372968). This is strong mutant evidence. supported_by: - reference_id: PMID:34372968 supporting_text: >- Hence, the ventricle and the atrium undergo asymmetric rotational movements around the atrioventricular canal, effectively transmitting a twisting transformation to the heart tube, a process which we show to be defective in tbx5a-/- zebrafish mutants. - reference_id: PMID:34372968 supporting_text: >- In the zebrafish oug mutant, the absence of Tbx5a results in the expansion of the AV canal as illustrated by expanded domains of expression of tbx2b, bmp4, and has2 - term: id: GO:0003218 label: cardiac left ventricle formation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:102541 - PANTHER:PTN002601200 - UniProtKB:Q9PWE8 review: summary: Cardiac left ventricle formation (IBA). action: MARK_AS_OVER_ANNOTATED reason: >- The PAINT node (PTN002601200) comes from mouse Tbx5, which is needed to form the left ventricle. Zebrafish has a single ventricle and no left/right ventricle split. In tbx5a mutants a ventricle forms, and the heart tube is normal until looping (PMID:12223419). The ancestral function, patterning the chambers, is inherited, but a left-ventricle term does not apply to a teleost heart. The same action is taken for tbx5b. supported_by: - reference_id: PMID:12223419 supporting_text: >- However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. - reference_id: PMID:29382818 supporting_text: >- Here we find, using genetic tbx5a lineage tracing tools, that the ventricular myocardium in the adult zebrafish is mainly derived from tbx5a+ cells, with a small contribution from tbx5a- SHF progenitors. propagation_review: root_cause: TERM_SCOPING_PROBLEM failure_modes: - LINEAGE_OR_TAXON_MISMATCH source_entities: - source_id: PANTHER:PTN002601200 source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET comment: >- The Tbx5-clade node is sound for amniote hearts, which have a left ventricle; teleost hearts have a single ventricle, so the left-ventricle-specific term does not apply to the zebrafish descendants. - source_id: MGI:MGI:102541 source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET comment: >- Mouse experimental evidence for left ventricle formation; the anatomy is absent in zebrafish. - term: id: GO:0003294 label: atrial ventricular junction remodeling evidence_type: IMP original_reference_id: PMID:19895804 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-080813-1 review: summary: Atrial ventricular junction remodeling (IMP, heartstrings). action: KEEP_AS_NON_CORE reason: >- AV boundary defects in hst: loss of tbx2b and excess valve tissue (PMID:19895804). supported_by: - reference_id: PMID:19895804 supporting_text: >- The presence of a Tbx5-binding-element in the promoter of tbx2b along with the reduction of expression in hst heterozygous mutants and complete loss in homozygotes reveals that Tbx5 regulates tbx2b at the AV boundary. - reference_id: PMID:19895804 supporting_text: >- Knock-down of Pdlim7 results in loss of detectable valve structures while lack of Tbx5 function leads to increased amounts of valve tissue. - term: id: GO:0003342 label: proepicardium development evidence_type: IMP original_reference_id: PMID:20413782 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-120516-2 review: summary: Proepicardium development (IMP, tbx5a mutants and dominant negative). action: ACCEPT reason: >- tbx5a mutants barely express the proepicardium (PE) markers tbx18 and tcf21. A heat-shock dominant negative shows Tbx5a is needed at early somite stages for PE specification (PMID:20413782). Strong genetic evidence of a specific cardiac role. supported_by: - reference_id: PMID:20413782 supporting_text: We further show that tbx5a mutants also have severe defects in PE specification. - term: id: GO:0003344 label: pericardium morphogenesis evidence_type: IMP original_reference_id: PMID:12399308 qualifier: acts_upstream_of_or_within review: summary: Pericardium morphogenesis (IMP, PMID:12399308). action: KEEP_AS_NON_CORE reason: >- Only the abstract of PMID:12399308 is cached. Pericardial edema is common in tbx5a loss-of-function embryos (PMID:18661250) and may be secondary to heart failure. However, anterior LPM fate mapping shows that tbx5a-dependent precursors give rise to the pericardial sac and that tbx5a controls their migration (PMID:33482174). Kept as non-core. supported_by: - reference_id: PMID:33482174 supporting_text: >- These data suggest that tbx5a functions normally to enable persistent migration of lateral aLPM precursors that give rise to cardiac, pharyngeal arch and pericardial sac. - reference_id: PMID:18661250 supporting_text: >- injection of tbx5 morpholino antisense RNA caused changes of heart conformation, defect of heart looping, pericardium effusion, dropsy of ventral position and decreased heart rate. - term: id: GO:0003700 label: DNA-binding transcription factor activity evidence_type: IDA original_reference_id: PMID:18347092 qualifier: enables review: summary: DNA-binding transcription factor activity (IDA, EMSA on the tbx2b enhancer). action: ACCEPT reason: >- Tbx5 binds the T-box element of the tbx2b enhancer in EMSA, and that element is needed for in vivo enhancer activity (PMID:18347092). Core function. supported_by: - reference_id: PMID:18347092 supporting_text: >- In electromobility shift assays (EMSA) to test DNA-binding affinity, Foxn4 and Tbx5 bound efficiently to their labeled putative binding sites, and binding was efficiently competed with excess unlabeled cognate competitors, but not with mutated oligonucleotides - reference_id: PMID:18347092 supporting_text: >- Thus, the putative Foxn4 and Tbx5 DNA-binding sites are required for the precise control of this highly conserved tbx2b enhancer during AV canal development. - term: id: GO:0003700 label: DNA-binding transcription factor activity evidence_type: IDA original_reference_id: PMID:24430697 qualifier: enables review: summary: DNA-binding transcription factor activity (IDA, PMID:24430697). action: ACCEPT reason: >- Kctd10 represses Tbx5a transcriptional activity, which implies reporter activation by Tbx5a (PMID:24430697; abstract only). Consistent with the core function. supported_by: - reference_id: PMID:24430697 supporting_text: >- We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. - term: id: GO:0003700 label: DNA-binding transcription factor activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables supporting_entities: - InterPro:IPR001699 - InterPro:IPR008967 - InterPro:IPR018186 - InterPro:IPR036960 - InterPro:IPR046360 review: summary: DNA-binding transcription factor activity (IEA, InterPro T-box). action: ACCEPT reason: >- The core activity of Tbx5. In zebrafish, Tbx5 binds and is needed for the tbx2b AV-canal enhancer (PMID:18347092), activates tbx2b at the AV boundary (PMID:19895804), and is repressed by Kctd10 (PMID:24430697). Shared with tbx5b by IBA; the T-box domain is 83% identical between the paralogs (PMID:39079985). supported_by: - reference_id: PMID:18347092 supporting_text: >- In electromobility shift assays (EMSA) to test DNA-binding affinity, Foxn4 and Tbx5 bound efficiently to their labeled putative binding sites, and binding was efficiently competed with excess unlabeled cognate competitors, but not with mutated oligonucleotides - reference_id: PMID:19895804 supporting_text: >- The presence of a Tbx5-binding-element in the promoter of tbx2b along with the reduction of expression in hst heterozygous mutants and complete loss in homozygotes reveals that Tbx5 regulates tbx2b at the AV boundary. - reference_id: PMID:24430697 supporting_text: >- We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24430697 qualifier: enables supporting_entities: - ZFIN:ZDB-GENE-040426-2843 review: summary: Protein binding (IPI with Kctd10). action: REMOVE reason: >- Generic protein binding is uninformative. The interaction itself is reported: Kctd10 binds Tbx5a and represses its activity (PMID:24430697). But it says nothing about a Tbx5a molecular function beyond being a target of a repressor. Removal does not dispute the interaction. supported_by: - reference_id: PMID:24430697 supporting_text: >- We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. - term: id: GO:0005634 label: nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - FB:FBgn0000179 - FB:FBgn0011723 - FB:FBgn0035954 - FB:FBgn0035956 - FB:FBgn0266083 - MGI:MGI:102539 - MGI:MGI:102541 - MGI:MGI:107404 - MGI:MGI:1201683 - MGI:MGI:1277234 - MGI:MGI:1888496 - MGI:MGI:1888984 - MGI:MGI:1923615 - MGI:MGI:98472 - MGI:MGI:98493 - MGI:MGI:98494 - MGI:MGI:98495 - PANTHER:PTN004251338 - RGD:1308264 - UniProtKB:O15119 - UniProtKB:O15178 - UniProtKB:O93288 - UniProtKB:O95935 - UniProtKB:P87377 - UniProtKB:Q13207 - UniProtKB:Q16650 - UniProtKB:Q8IWI9 - UniProtKB:Q8UW76 - UniProtKB:Q99593 - UniProtKB:Q9PWE8 - UniProtKB:Q9UL17 - UniProtKB:Q9Y458 - WB:WBGene00003106 - WB:WBGene00003376 - WB:WBGene00004750 - WB:WBGene00006543 - WB:WBGene00006545 - WB:WBGene00006546 - WB:WBGene00006556 - WB:WBGene00006557 - ZFIN:ZDB-GENE-001228-1 - ZFIN:ZDB-GENE-980526-437 - ZFIN:ZDB-GENE-990615-5 - ZFIN:ZDB-GENE-991124-7 review: summary: Nuclear localization (IBA). action: ACCEPT reason: >- Tbx5a is a nuclear transcription factor. Full-length zebrafish Tbx5 is detected in the nucleus, and a fraction also on cytoplasmic actin with Pdlim7 (PMID:19895804). supported_by: - reference_id: PMID:19895804 supporting_text: >- As expected, comparable to the chicken protein, full-length Tbx5 was detected in the nucleus but also in the cytoplasm colocalized with Pdlim7 along the actin cytoskeleton - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:19895804 qualifier: located_in review: summary: Nucleus (IDA, transfected Tbx5 and hst-like Tbx5). action: ACCEPT reason: >- Full-length Tbx5 is nuclear, with a cytoplasmic pool on actin with Pdlim7. The hst-truncated protein is strictly nuclear (PMID:19895804). supported_by: - reference_id: PMID:19895804 supporting_text: >- As expected, comparable to the chicken protein, full-length Tbx5 was detected in the nucleus but also in the cytoplasm colocalized with Pdlim7 along the actin cytoskeleton - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in supporting_entities: - InterPro:IPR018186 - InterPro:IPR036960 - UniProtKB-SubCell:SL-0191 review: summary: Nuclear localization (IEA). action: ACCEPT reason: >- Tbx5a is a nuclear transcription factor. Full-length zebrafish Tbx5 is detected in the nucleus, and a fraction also on cytoplasmic actin with Pdlim7 (PMID:19895804). supported_by: - reference_id: PMID:19895804 supporting_text: >- As expected, comparable to the chicken protein, full-length Tbx5 was detected in the nucleus but also in the cytoplasm colocalized with Pdlim7 along the actin cytoskeleton - term: id: GO:0005634 label: nucleus evidence_type: IEP original_reference_id: PMID:24430697 qualifier: is_active_in review: summary: Nucleus (IEP, PMID:24430697). action: ACCEPT reason: >- Nuclear localization is correct for Tbx5a (PMID:19895804), although IEP is an unusual evidence code for a location. supported_by: - reference_id: PMID:19895804 supporting_text: >- As expected, comparable to the chicken protein, full-length Tbx5 was detected in the nucleus but also in the cytoplasm colocalized with Pdlim7 along the actin cytoskeleton - term: id: GO:0005634 label: nucleus evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in supporting_entities: - UniProtKB:Q99593 review: summary: Nuclear localization (ISS). action: ACCEPT reason: >- Tbx5a is a nuclear transcription factor. Full-length zebrafish Tbx5 is detected in the nucleus, and a fraction also on cytoplasmic actin with Pdlim7 (PMID:19895804). supported_by: - reference_id: PMID:19895804 supporting_text: >- As expected, comparable to the chicken protein, full-length Tbx5 was detected in the nucleus but also in the cytoplasm colocalized with Pdlim7 along the actin cytoskeleton - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0086 review: summary: Cytoplasmic localization (IEA). action: KEEP_AS_NON_CORE reason: >- Tbx5 shuttles: a pool is held on cytoplasmic actin filaments by Pdlim7, which keeps it from its nuclear targets (PMID:19895804). Correct, but a regulatory location rather than where the protein acts. supported_by: - reference_id: PMID:19895804 supporting_text: >- As expected, comparable to the chicken protein, full-length Tbx5 was detected in the nucleus but also in the cytoplasm colocalized with Pdlim7 along the actin cytoskeleton - reference_id: PMID:19895804 supporting_text: >- Regulated by yet unknown signals, Tbx5 exits the nucleus and binds to Pdlim7 along cytoplasmic actin filaments. - term: id: GO:0005737 label: cytoplasm evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in supporting_entities: - UniProtKB:Q99593 review: summary: Cytoplasmic localization (ISS). action: KEEP_AS_NON_CORE reason: >- Tbx5 shuttles: a pool is held on cytoplasmic actin filaments by Pdlim7, which keeps it from its nuclear targets (PMID:19895804). Correct, but a regulatory location rather than where the protein acts. supported_by: - reference_id: PMID:19895804 supporting_text: >- As expected, comparable to the chicken protein, full-length Tbx5 was detected in the nucleus but also in the cytoplasm colocalized with Pdlim7 along the actin cytoskeleton - reference_id: PMID:19895804 supporting_text: >- Regulated by yet unknown signals, Tbx5 exits the nucleus and binds to Pdlim7 along cytoplasmic actin filaments. - term: id: GO:0006351 label: DNA-templated transcription evidence_type: IMP original_reference_id: PMID:16501170 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: DNA-templated transcription (IMP, sall4 expression depends on tbx5). action: MODIFY reason: >- The paper shows that sall4/sall1 act downstream of tbx5 in the pectoral fin (PMID:16501170). tbx5a regulates transcription of target genes. It does not carry out "DNA-templated transcription", which is the RNA polymerase process itself. The better term is regulation of transcription by RNA polymerase II. proposed_replacement_terms: - id: GO:0006357 label: regulation of transcription by RNA polymerase II supported_by: - reference_id: PMID:16501170 supporting_text: >- We demonstrate that sall4 and a related gene sall1 act downstream of tbx5 and are required for pectoral fin development. - term: id: GO:0006355 label: regulation of DNA-templated transcription evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in supporting_entities: - InterPro:IPR001699 - InterPro:IPR008967 - InterPro:IPR018186 - InterPro:IPR036960 review: summary: Regulation of transcription (IEA, InterPro). action: ACCEPT reason: >- Tbx5a is a DNA-binding transcription factor. Target genes in zebrafish include tbx2b, fgf24/fgf10 and ndrg4 (PMID:19895804, PMID:12810598, PMID:18407257). supported_by: - reference_id: PMID:19895804 supporting_text: >- The presence of a Tbx5-binding-element in the promoter of tbx2b along with the reduction of expression in hst heterozygous mutants and complete loss in homozygotes reveals that Tbx5 regulates tbx2b at the AV boundary. - reference_id: PMID:12810598 supporting_text: >- We show that the zebrafish fgf24 gene, which belongs to the Fgf8/17/18 subfamily of Fgf ligands, acts downstream of tbx5 to activate fgf10 expression in the lateral plate mesoderm. - term: id: GO:0006355 label: regulation of DNA-templated transcription evidence_type: IMP original_reference_id: PMID:18661250 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Regulation of DNA-templated transcription (IMP, morpholino). action: ACCEPT reason: >- Cardiac myogenesis genes (amhc, vmhc, cmlc2) are under-expressed in tbx5 morphants (PMID:18661250; abstract only). The regulation may be indirect, but the term is correct for a transcription factor. supported_by: - reference_id: PMID:18661250 supporting_text: >- Our data suggests that the heart failure caused by the knockdown of tbx5 gene might result from the down-regulation of cardiac myogenesis genes. - 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:FBgn0000179 - FB:FBgn0011723 - FB:FBgn0016660 - FB:FBgn0021767 - FB:FBgn0028789 - FB:FBgn0035954 - FB:FBgn0035956 - FB:FBgn0261963 - MGI:MGI:102539 - MGI:MGI:102541 - MGI:MGI:107404 - MGI:MGI:1201683 - MGI:MGI:1277234 - MGI:MGI:1352483 - MGI:MGI:1888496 - MGI:MGI:1888984 - MGI:MGI:1891158 - MGI:MGI:1923615 - MGI:MGI:98472 - MGI:MGI:98493 - MGI:MGI:98494 - MGI:MGI:98495 - PANTHER:PTN004251338 - RGD:735203 - UniProtKB:O15119 - UniProtKB:O15178 - UniProtKB:O95936 - UniProtKB:P24781 - UniProtKB:P87377 - UniProtKB:Q13207 - UniProtKB:Q8AV66 - UniProtKB:Q8AX98 - UniProtKB:Q99593 - UniProtKB:Q9UL17 - UniProtKB:Q9Y458 - WB:WBGene00003106 - WB:WBGene00004750 - WB:WBGene00006554 - ZFIN:ZDB-GENE-991124-7 review: summary: Regulation of transcription (IBA). action: ACCEPT reason: >- Tbx5a is a DNA-binding transcription factor. Target genes in zebrafish include tbx2b, fgf24/fgf10 and ndrg4 (PMID:19895804, PMID:12810598, PMID:18407257). supported_by: - reference_id: PMID:19895804 supporting_text: >- The presence of a Tbx5-binding-element in the promoter of tbx2b along with the reduction of expression in hst heterozygous mutants and complete loss in homozygotes reveals that Tbx5 regulates tbx2b at the AV boundary. - reference_id: PMID:12810598 supporting_text: >- We show that the zebrafish fgf24 gene, which belongs to the Fgf8/17/18 subfamily of Fgf ligands, acts downstream of tbx5 to activate fgf10 expression in the lateral plate mesoderm. - term: id: GO:0007389 label: pattern specification process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:102541 - PANTHER:PTN002601200 - ZFIN:ZDB-GENE-991124-7 review: summary: Pattern specification process (IBA). action: KEEP_AS_NON_CORE reason: >- Tbx5a contributes to axis patterning in the fin field and to dorsoventral patterning of the retina (PMID:24759614, PMID:34756968). Broad but correct. supported_by: - reference_id: PMID:24759614 supporting_text: >- suggesting that tbx5 paralogues act redundantly in the dorsal retina to ensure efnb2a expression in this territory. - reference_id: PMID:34756968 supporting_text: >- Our data suggest that zebrafish tbx5a and tbx5b have functionally separated migration direction vectors, that when combined recapitulate the migration of the wt fin field. - term: id: GO:0007507 label: heart development evidence_type: IGI original_reference_id: PMID:19204083 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 - ZFIN:ZDB-MRPHLNO-091230-1 review: summary: >- Heart development (IGI with mef2c). Tbx5 and Mef2c cooperate on myh6 and on early heart development. action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:19204083 supporting_text: >- Morpholino-mediated knockdowns of Tbx5 and Mef2c in zebrafish suggest that the genetic interaction of these proteins is not only required for MYH6 expression but also essential for the early stages of heart development and survival. - term: id: GO:0007507 label: heart development evidence_type: IGI original_reference_id: PMID:23226307 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-110628-4 review: summary: Heart development (IGI with miR-218). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:23226307 supporting_text: >- However, the injection of both MO-Tbx5a and miR-218a mimic at these doses dramatically increased the number of embryos with looping defects - term: id: GO:0007507 label: heart development evidence_type: IGI original_reference_id: PMID:26657204 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-050103-6 - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Heart development (IGI with miR-19a). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:26657204 supporting_text: >- Co-injection of the sub-phenotypic dose of MO-Tbx5a with 8 ng of MO-19a strongly increased the number of heart and pectoral fin defects suggesting a synergistic interaction between miR-19a and Tbx5a. - term: id: GO:0007507 label: heart development evidence_type: IGI original_reference_id: PMID:26657204 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 - ZFIN:ZDB-MRPHLNO-160218-4 review: summary: Heart development (IGI with miR-19a morpholino). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:26657204 supporting_text: >- Co-injection of the sub-phenotypic dose of MO-Tbx5a with 8 ng of MO-19a strongly increased the number of heart and pectoral fin defects suggesting a synergistic interaction between miR-19a and Tbx5a. - term: id: GO:0007507 label: heart development evidence_type: IGI original_reference_id: PMID:29922649 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-001228-2 review: summary: Heart development (IGI with s1pr1). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:29922649 supporting_text: >- The engagement of s1pr1 in the Tbx5 regulatory circuit is supported by data showing an increase of this receptor in zebrafish Tbx5a mutant embryos and by rescue experiments. - term: id: GO:0007507 label: heart development evidence_type: IMP original_reference_id: PMID:12223419 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-030627-1 review: summary: Heart development (IMP, heartstrings). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:12223419 supporting_text: >- However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. - reference_id: PMID:12223419 supporting_text: >- we isolated the recessive lethal mutant heartstrings, which lacks pectoral fins and exhibits severe cardiac dysfunction - term: id: GO:0007507 label: heart development evidence_type: IMP original_reference_id: PMID:12223419 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Heart development (IMP, morpholino). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:12223419 supporting_text: >- However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. - term: id: GO:0007507 label: heart development evidence_type: IMP original_reference_id: PMID:18661250 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Heart development (IMP, morpholino). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:18661250 supporting_text: >- injection of tbx5 morpholino antisense RNA caused changes of heart conformation, defect of heart looping, pericardium effusion, dropsy of ventral position and decreased heart rate. - term: id: GO:0007507 label: heart development evidence_type: IMP original_reference_id: PMID:18661250 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-090227-1 review: summary: Heart development (IMP, second tbx5a morpholino). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:18661250 supporting_text: >- Our data suggests that the heart failure caused by the knockdown of tbx5 gene might result from the down-regulation of cardiac myogenesis genes. - term: id: GO:0007507 label: heart development evidence_type: IMP original_reference_id: PMID:22776023 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Heart development (IMP, morpholino; growth hormone rescue). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:22776023 supporting_text: >- Perturbations of cardiac development (Figure 1B) were exhibited in tbx5-MO treated (MO) zebrafish embryos, along with curved trunks and abnormal “U-shaped” somites (Figure 1G), and pectoral fin growth (Figure 1L) was either truncated or even atretic. - term: id: GO:0007507 label: heart development evidence_type: IMP original_reference_id: PMID:23441045 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-080813-1 review: summary: Heart development (IMP, heartstrings). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:23441045 supporting_text: >- Homozygous mutation of zebrafish tbx5a leads to lethal defects in cardiac looping morphogenesis, blocks pectoral fin initiation, and impairs outgrowth. - reference_id: PMID:23441045 supporting_text: >- Because tbx5a hypomorphic mutations are embryonic lethal, tbx5a and tbx5b functions in the heart must not be completely redundant. - term: id: GO:0007507 label: heart development evidence_type: IMP original_reference_id: PMID:23441045 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-090227-1 review: summary: Heart development (IMP, morpholino). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:23441045 supporting_text: >- Homozygous mutation of zebrafish tbx5a leads to lethal defects in cardiac looping morphogenesis, blocks pectoral fin initiation, and impairs outgrowth. - term: id: GO:0007507 label: heart development evidence_type: IMP original_reference_id: PMID:28761722 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Heart development (IMP, morpholino). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:28761722 supporting_text: >- tbx5 loss-of-function in zebrafish caused heart developmental defects, including different degrees of heart looping arrested, heart edematous, string-like heart, and so on, which were confirmed in our results - term: id: GO:0007507 label: heart development evidence_type: IMP original_reference_id: PMID:29922649 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Heart development (IMP, morpholino). action: ACCEPT reason: >- tbx5a is required for zebrafish heart development. heartstrings (tbx5a nonsense) mutants form a heart tube that fails to loop and then deteriorates (PMID:12223419), and T-box-truncating (oug) and gene-trap alleles confirm the requirement (PMID:34372968, PMID:29933372). The term is broad but correct, and is part of the core role. Many of these rows rest on morpholino data alone, but the genetic alleles support the term. supported_by: - reference_id: PMID:29922649 supporting_text: >- The engagement of s1pr1 in the Tbx5 regulatory circuit is supported by data showing an increase of this receptor in zebrafish Tbx5a mutant embryos and by rescue experiments. - term: id: GO:0009653 label: anatomical structure morphogenesis evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00026583 review: summary: Anatomical structure morphogenesis (IEA, ARBA). action: ACCEPT reason: >- Very broad, but true: tbx5a is needed for heart and pectoral fin morphogenesis. It is implied by the more specific experimental terms. supported_by: - reference_id: PMID:12223419 supporting_text: >- Homozygous mutant embryos never develop pectoral fin buds and do not express several markers of early fin differentiation. - reference_id: PMID:12223419 supporting_text: >- However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. - term: id: GO:0009887 label: animal organ morphogenesis evidence_type: IMP original_reference_id: PMID:21982178 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Animal organ morphogenesis (IMP, morpholino). action: ACCEPT reason: >- tbx5 morphants show heart (string-like) and pectoral fin (hypoplasia or agenesis) dysmorphogenesis (PMID:21982178). Broad but correct. supported_by: - reference_id: PMID:21982178 supporting_text: >- Injection of the tbx5 morpholino (MO) directly into embryos at the 1-cell stage resulted in retardation of the looping process, and the most prominent cardiac finding in tbx5 morphants was a string-like heart (Figure 1B). - reference_id: PMID:21982178 supporting_text: >- For example, no ectopic fin was found in embryos, although hypogenesis or agenesis of the pectoral fin was frequently observed in tbx5 morphants, as was the string-like heart. - term: id: GO:0015629 label: actin cytoskeleton evidence_type: IPI original_reference_id: PMID:19895804 qualifier: located_in supporting_entities: - ZFIN:ZDB-GENE-040426-2092 review: summary: Actin cytoskeleton (IPI with Pdlim7). action: KEEP_AS_NON_CORE reason: >- In transfected cells, full-length Tbx5 co-localizes with Pdlim7 on actin filaments. This sequesters it from the nucleus, and the hst truncation removes the ability (PMID:19895804). A regulatory location, not where Tbx5a acts. supported_by: - reference_id: PMID:19895804 supporting_text: >- As expected, comparable to the chicken protein, full-length Tbx5 was detected in the nucleus but also in the cytoplasm colocalized with Pdlim7 along the actin cytoskeleton - reference_id: PMID:19895804 supporting_text: >- Regulated by yet unknown signals, Tbx5 exits the nucleus and binds to Pdlim7 along cytoplasmic actin filaments. - term: id: GO:0021554 label: optic nerve development evidence_type: IGI original_reference_id: PMID:24759614 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 - ZFIN:ZDB-MRPHLNO-130123-3 review: summary: Optic nerve development (IGI, tbx5a + tbx5b double morphants). action: KEEP_AS_NON_CORE reason: >- Only double morphants have a thinner optic nerve; single morphants are normal (PMID:24759614). This is morpholino-only evidence of a shared, additive retinal role, the same for both copies. supported_by: - reference_id: PMID:24759614 supporting_text: >- Moreover, and in agreement with both tbx5 genes acting redundantly to ensure proper optic nerve formation, double-morphant embryos showed a significantly thinner optic nerve (figure 4n). - term: id: GO:0032991 label: protein-containing complex evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: part_of supporting_entities: - UniProtKB:Q99593 review: summary: Protein-containing complex (ISS). action: MARK_AS_OVER_ANNOTATED reason: >- An uninformative location. Tbx5 does form complexes (for example with Mef2c, PMID:19204083), but this generic term adds nothing to nucleus and chromatin. supported_by: - reference_id: PMID:19204083 supporting_text: >- Morpholino-mediated knockdowns of Tbx5 and Mef2c in zebrafish suggest that the genetic interaction of these proteins is not only required for MYH6 expression but also essential for the early stages of heart development and survival. - term: id: GO:0032993 label: protein-DNA complex evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: part_of supporting_entities: - UniProtKB:Q99593 review: summary: Protein-DNA complex (ISS from human TBX5). action: KEEP_AS_NON_CORE reason: >- T-box factors bind DNA as monomers or dimers (UniProt, by similarity to human TBX5). Consistent with the EMSA data (PMID:18347092), but inferred. supported_by: - reference_id: PMID:18347092 supporting_text: >- In electromobility shift assays (EMSA) to test DNA-binding affinity, Foxn4 and Tbx5 bound efficiently to their labeled putative binding sites, and binding was efficiently competed with excess unlabeled cognate competitors, but not with mutated oligonucleotides - term: id: GO:0033339 label: pectoral fin development evidence_type: IMP original_reference_id: PMID:12066188 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-3 review: summary: Pectoral fin development (IMP, morpholino). action: ACCEPT reason: >- Core, copy-defining role. Every tbx5a loss-of-function reagent abolishes the pectoral fin: heartstrings nonsense mutants never form fin buds (PMID:12223419), morphants fail to initiate fin buds (PMID:12066188), and 100% of CRISPR F0 knockouts lack fins (PMID:33416493). tbx5b is also needed, but later and for shape and outgrowth rather than initiation (PMID:24759614, PMID:34756968). supported_by: - reference_id: PMID:12066188 supporting_text: >- Functional knockdown of zebrafish tbx5 through the use of an antisense oligonucleotide resulted in a failure to initiate fin bud formation, leading to the complete loss of pectoral fins. - term: id: GO:0033339 label: pectoral fin development evidence_type: IMP original_reference_id: PMID:12223419 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-030627-1 review: summary: Pectoral fin development (IMP, heartstrings). action: ACCEPT reason: >- Core, copy-defining role. Every tbx5a loss-of-function reagent abolishes the pectoral fin: heartstrings nonsense mutants never form fin buds (PMID:12223419), morphants fail to initiate fin buds (PMID:12066188), and 100% of CRISPR F0 knockouts lack fins (PMID:33416493). tbx5b is also needed, but later and for shape and outgrowth rather than initiation (PMID:24759614, PMID:34756968). supported_by: - reference_id: PMID:12223419 supporting_text: >- Homozygous mutant embryos never develop pectoral fin buds and do not express several markers of early fin differentiation. - term: id: GO:0033339 label: pectoral fin development evidence_type: IMP original_reference_id: PMID:12223419 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Pectoral fin development (IMP, morpholino). action: ACCEPT reason: >- Core, copy-defining role. Every tbx5a loss-of-function reagent abolishes the pectoral fin: heartstrings nonsense mutants never form fin buds (PMID:12223419), morphants fail to initiate fin buds (PMID:12066188), and 100% of CRISPR F0 knockouts lack fins (PMID:33416493). tbx5b is also needed, but later and for shape and outgrowth rather than initiation (PMID:24759614, PMID:34756968). supported_by: - reference_id: PMID:12223419 supporting_text: >- Moderate reduction of Tbx5 by morpholino causes fin malformations, revealing an additional early requirement for Tbx5 in coordinating the axes of fin outgrowth. - term: id: GO:0033339 label: pectoral fin development evidence_type: IMP original_reference_id: PMID:23441045 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-080813-1 review: summary: Pectoral fin development (IMP, heartstrings). action: ACCEPT reason: >- Core, copy-defining role. Every tbx5a loss-of-function reagent abolishes the pectoral fin: heartstrings nonsense mutants never form fin buds (PMID:12223419), morphants fail to initiate fin buds (PMID:12066188), and 100% of CRISPR F0 knockouts lack fins (PMID:33416493). tbx5b is also needed, but later and for shape and outgrowth rather than initiation (PMID:24759614, PMID:34756968). supported_by: - reference_id: PMID:23441045 supporting_text: >- Homozygous mutation of zebrafish tbx5a leads to lethal defects in cardiac looping morphogenesis, blocks pectoral fin initiation, and impairs outgrowth. - term: id: GO:0033339 label: pectoral fin development evidence_type: IMP original_reference_id: PMID:23441045 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-090227-1 review: summary: Pectoral fin development (IMP, morpholino). action: ACCEPT reason: >- Core, copy-defining role. Every tbx5a loss-of-function reagent abolishes the pectoral fin: heartstrings nonsense mutants never form fin buds (PMID:12223419), morphants fail to initiate fin buds (PMID:12066188), and 100% of CRISPR F0 knockouts lack fins (PMID:33416493). tbx5b is also needed, but later and for shape and outgrowth rather than initiation (PMID:24759614, PMID:34756968). supported_by: - reference_id: PMID:23441045 supporting_text: >- Homozygous mutation of zebrafish tbx5a leads to lethal defects in cardiac looping morphogenesis, blocks pectoral fin initiation, and impairs outgrowth. - term: id: GO:0033339 label: pectoral fin development evidence_type: IMP original_reference_id: PMID:24759614 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Pectoral fin development (IMP, morpholino). action: ACCEPT reason: >- Core, copy-defining role. Every tbx5a loss-of-function reagent abolishes the pectoral fin: heartstrings nonsense mutants never form fin buds (PMID:12223419), morphants fail to initiate fin buds (PMID:12066188), and 100% of CRISPR F0 knockouts lack fins (PMID:33416493). tbx5b is also needed, but later and for shape and outgrowth rather than initiation (PMID:24759614, PMID:34756968). supported_by: - reference_id: PMID:24759614 supporting_text: >- Taken together, we show that pectoral fin development has a different requirement for each of the tbx5 paralogues: tbx5a function is required for the earliest steps of initiation of fin outgrowth, whereas tbx5b functions later to ensure properly timed and sustained fin outgrowth. - term: id: GO:0033339 label: pectoral fin development evidence_type: IMP original_reference_id: PMID:33416493 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-CRISPR-181010-12 - ZFIN:ZDB-CRISPR-210903-14 - ZFIN:ZDB-CRISPR-210903-15 review: summary: Pectoral fin development (IMP, CRISPR F0 knockout). action: ACCEPT reason: >- Core, copy-defining role. Every tbx5a loss-of-function reagent abolishes the pectoral fin: heartstrings nonsense mutants never form fin buds (PMID:12223419), morphants fail to initiate fin buds (PMID:12066188), and 100% of CRISPR F0 knockouts lack fins (PMID:33416493). tbx5b is also needed, but later and for shape and outgrowth rather than initiation (PMID:24759614, PMID:34756968). supported_by: - reference_id: PMID:33416493 supporting_text: 100% (43/43) of the tbx5a F0 larvae did not develop pectoral fins (Figure 4A). - term: id: GO:0035050 label: embryonic heart tube development evidence_type: IMP original_reference_id: PMID:18407257 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-080813-1 review: summary: Embryonic heart tube development (IMP, heartstrings). action: ACCEPT reason: >- ndrg4 expression drops in tbx5 mutant hearts, and not merely because of a general myocardial defect (PMID:18407257). supported_by: - reference_id: PMID:18407257 supporting_text: >- Therefore, reduction of ndrg4 expression in tbx5 mutant hearts is not just due to a general myocardial differentiation defect in tbx5 mutant myocardium. - term: id: GO:0035050 label: embryonic heart tube development evidence_type: IMP original_reference_id: PMID:18407257 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Embryonic heart tube development (IMP, morpholino). action: ACCEPT reason: >- Tbx5 regulates ndrg4 in the heart tube, and ndrg4 is needed for myocyte proliferation (PMID:18407257). supported_by: - reference_id: PMID:18407257 supporting_text: >- These data further suggest that Tbx5 acts to regulate the level of ndrg4 expression during the heart development, and that ndrg4 is potentially a novel downstream target of tbx5 activation - term: id: GO:0035118 label: embryonic pectoral fin morphogenesis evidence_type: IMP original_reference_id: PMID:12399308 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-030627-1 review: summary: Embryonic pectoral fin morphogenesis (IMP, heartstrings). action: ACCEPT reason: >- Tbx5 is needed downstream of Wnt2b to start and sustain fin/limb outgrowth through Fgf10 (PMID:12399308; abstract only). hst mutants have no fin buds (PMID:12223419). supported_by: - reference_id: PMID:12399308 supporting_text: >- We find that Tbx5 functions downstream of WNT signaling to regulate Fgf10, which, in turn, maintains Tbx5 expression during limb outgrowth. - reference_id: PMID:12223419 supporting_text: >- Homozygous mutant embryos never develop pectoral fin buds and do not express several markers of early fin differentiation. - term: id: GO:0035118 label: embryonic pectoral fin morphogenesis evidence_type: IMP original_reference_id: PMID:12399308 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-070315-3 review: summary: Embryonic pectoral fin morphogenesis (IMP, morpholino). action: ACCEPT reason: Tbx5 is necessary and sufficient for limb/fin outgrowth (PMID:12399308). supported_by: - reference_id: PMID:12399308 supporting_text: >- we show that Tbx5, in addition to its role governing forelimb identity, is both necessary and sufficient for limb outgrowth. - term: id: GO:0035118 label: embryonic pectoral fin morphogenesis evidence_type: IMP original_reference_id: PMID:12810598 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Embryonic pectoral fin morphogenesis (IMP, morpholino, PMID:12810598). action: ACCEPT reason: >- fgf24 acts downstream of tbx5 to turn on fgf10 and to guide tbx5-expressing cells to the fin bud (PMID:12810598). supported_by: - reference_id: PMID:12810598 supporting_text: >- We show that the zebrafish fgf24 gene, which belongs to the Fgf8/17/18 subfamily of Fgf ligands, acts downstream of tbx5 to activate fgf10 expression in the lateral plate mesoderm. - term: id: GO:0035138 label: pectoral fin morphogenesis evidence_type: IMP original_reference_id: PMID:22776023 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Pectoral fin morphogenesis (IMP, morpholino; growth hormone rescue). action: ACCEPT reason: tbx5 morphants have truncated or absent pectoral fins (PMID:22776023). supported_by: - reference_id: PMID:22776023 supporting_text: >- Perturbations of cardiac development (Figure 1B) were exhibited in tbx5-MO treated (MO) zebrafish embryos, along with curved trunks and abnormal “U-shaped” somites (Figure 1G), and pectoral fin growth (Figure 1L) was either truncated or even atretic. - term: id: GO:0036302 label: atrioventricular canal development evidence_type: IGI original_reference_id: PMID:24430697 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENE-040426-2843 review: summary: Atrioventricular canal development (IGI with kctd10). action: ACCEPT reason: >- Tbx5a restricts the AV canal program. kctd10 mutants misexpress AV canal markers, and knocking down tbx5a rescues this (PMID:24430697). oug mutants expand the AV canal (PMID:34372968). supported_by: - reference_id: PMID:24430697 supporting_text: >- The knockdown of tbx5 rescues the ectopic expression of has2, and knockdown of either tbx5a or has2 alleviates the heart defects. - reference_id: PMID:34372968 supporting_text: >- In the zebrafish oug mutant, the absence of Tbx5a results in the expansion of the AV canal as illustrated by expanded domains of expression of tbx2b, bmp4, and has2 - term: id: GO:0043565 label: sequence-specific DNA binding evidence_type: IDA original_reference_id: PMID:18347092 qualifier: enables review: summary: Sequence-specific DNA binding (IDA, EMSA). action: ACCEPT reason: >- Tbx5 binds the tbx2b enhancer T-box site in EMSA, and mutant competitors do not compete (PMID:18347092). GO:0000978 is the more informative sibling. supported_by: - reference_id: PMID:18347092 supporting_text: >- In electromobility shift assays (EMSA) to test DNA-binding affinity, Foxn4 and Tbx5 bound efficiently to their labeled putative binding sites, and binding was efficiently competed with excess unlabeled cognate competitors, but not with mutated oligonucleotides - term: id: GO:0045893 label: positive regulation of DNA-templated transcription evidence_type: IDA original_reference_id: PMID:18347092 qualifier: acts_upstream_of_or_within review: summary: Positive regulation of DNA-templated transcription (IDA, tbx2b enhancer). action: ACCEPT reason: >- The Tbx5 site is needed for correct activity of the tbx2b enhancer in vivo (PMID:18347092). supported_by: - reference_id: PMID:18347092 supporting_text: >- Thus, the putative Foxn4 and Tbx5 DNA-binding sites are required for the precise control of this highly conserved tbx2b enhancer during AV canal development. - term: id: GO:0045893 label: positive regulation of DNA-templated transcription evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in supporting_entities: - InterPro:IPR046360 review: summary: Positive regulation of DNA-templated transcription (IEA, InterPro). action: ACCEPT reason: Tbx5 is a transcriptional activator of its targets (tbx2b, fgf24, ndrg4). supported_by: - reference_id: PMID:19895804 supporting_text: >- The presence of a Tbx5-binding-element in the promoter of tbx2b along with the reduction of expression in hst heterozygous mutants and complete loss in homozygotes reveals that Tbx5 regulates tbx2b at the AV boundary. - reference_id: PMID:12810598 supporting_text: >- We show that the zebrafish fgf24 gene, which belongs to the Fgf8/17/18 subfamily of Fgf ligands, acts downstream of tbx5 to activate fgf10 expression in the lateral plate mesoderm. - term: id: GO:0045893 label: positive regulation of DNA-templated transcription evidence_type: IMP original_reference_id: PMID:18407257 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-080813-1 review: summary: Positive regulation of DNA-templated transcription (IMP, heartstrings; ndrg4). action: ACCEPT reason: >- ndrg4 expression depends on tbx5 in the heart (PMID:18407257). Probably direct or indirect activation. supported_by: - reference_id: PMID:18407257 supporting_text: >- These data further suggest that Tbx5 acts to regulate the level of ndrg4 expression during the heart development, and that ndrg4 is potentially a novel downstream target of tbx5 activation - reference_id: PMID:18407257 supporting_text: >- Therefore, reduction of ndrg4 expression in tbx5 mutant hearts is not just due to a general myocardial differentiation defect in tbx5 mutant myocardium. - term: id: GO:0045893 label: positive regulation of DNA-templated transcription evidence_type: IMP original_reference_id: PMID:18407257 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 review: summary: Positive regulation of DNA-templated transcription (IMP, morpholino; ndrg4). action: ACCEPT reason: As for the heartstrings row (PMID:18407257). supported_by: - reference_id: PMID:18407257 supporting_text: >- These data further suggest that Tbx5 acts to regulate the level of ndrg4 expression during the heart development, and that ndrg4 is potentially a novel downstream target of tbx5 activation - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: IDA original_reference_id: PMID:24430697 qualifier: acts_upstream_of_or_within review: summary: Positive regulation of transcription by RNA polymerase II (IDA, PMID:24430697). action: ACCEPT reason: >- Tbx5a transcriptional activity is repressed by Kctd10 (PMID:24430697; abstract only). This is consistent with the activator role shown on tbx2b (PMID:18347092). supported_by: - reference_id: PMID:24430697 supporting_text: >- We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. - reference_id: PMID:18347092 supporting_text: >- Thus, the putative Foxn4 and Tbx5 DNA-binding sites are required for the precise control of this highly conserved tbx2b enhancer during AV canal development. - term: id: GO:0048794 label: swim bladder development evidence_type: IGI original_reference_id: PMID:30352852 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-3 - ZFIN:ZDB-MRPHLNO-130123-3 negated: true review: summary: NOT swim bladder development (negated). action: ACCEPT reason: >- This NOT annotation asserts that tbx5a (with tbx5b) is not required to form the swim bladder. hst mutants and tbx5a/tbx5b single and double morphants form swim bladders, unlike the Tbx5 requirement for lung specification in mouse and Xenopus (PMID:30352852). Accepted as a negative result. tbx5b mutants fail to inflate the swim bladder, but that is a later event, likely secondary to heart failure (PMID:30532148). It does not contradict this NOT. supported_by: - reference_id: PMID:30352852 supporting_text: >- However, we find that although Tbx5 is required for lung formation, tbx5a / b is not required for SB formation in the zebrafish. - reference_id: PMID:30352852 supporting_text: >- To address potential redundancy, we utilized published MOs designed to target tbx5a , tbx5b , or tbx5a and tbx5b ( 47 , 48 ). - term: id: GO:0048794 label: swim bladder development evidence_type: IMP original_reference_id: PMID:30352852 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-080813-1 negated: true review: summary: NOT swim bladder development (negated). action: ACCEPT reason: >- This NOT annotation asserts that tbx5a (with tbx5b) is not required to form the swim bladder. hst mutants and tbx5a/tbx5b single and double morphants form swim bladders, unlike the Tbx5 requirement for lung specification in mouse and Xenopus (PMID:30352852). Accepted as a negative result. tbx5b mutants fail to inflate the swim bladder, but that is a later event, likely secondary to heart failure (PMID:30532148). It does not contradict this NOT. supported_by: - reference_id: PMID:30352852 supporting_text: >- However, we find that although Tbx5 is required for lung formation, tbx5a / b is not required for SB formation in the zebrafish. - reference_id: PMID:30352852 supporting_text: >- To address potential redundancy, we utilized published MOs designed to target tbx5a , tbx5b , or tbx5a and tbx5b ( 47 , 48 ). - term: id: GO:0048794 label: swim bladder development evidence_type: IMP original_reference_id: PMID:30352852 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-3 negated: true review: summary: NOT swim bladder development (negated). action: ACCEPT reason: >- This NOT annotation asserts that tbx5a (with tbx5b) is not required to form the swim bladder. hst mutants and tbx5a/tbx5b single and double morphants form swim bladders, unlike the Tbx5 requirement for lung specification in mouse and Xenopus (PMID:30352852). Accepted as a negative result. tbx5b mutants fail to inflate the swim bladder, but that is a later event, likely secondary to heart failure (PMID:30532148). It does not contradict this NOT. supported_by: - reference_id: PMID:30352852 supporting_text: >- However, we find that although Tbx5 is required for lung formation, tbx5a / b is not required for SB formation in the zebrafish. - reference_id: PMID:30352852 supporting_text: >- To address potential redundancy, we utilized published MOs designed to target tbx5a , tbx5b , or tbx5a and tbx5b ( 47 , 48 ). - term: id: GO:0055007 label: cardiac muscle cell differentiation evidence_type: IGI original_reference_id: PMID:21715426 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 - ZFIN:ZDB-MRPHLNO-060522-2 - ZFIN:ZDB-MRPHLNO-070409-1 review: summary: Cardiac muscle cell differentiation (IGI with smarcd3b/gata5). action: KEEP_AS_NON_CORE reason: >- Combined loss of cBAF components (gata5, smarcd3b, tbx5a) inhibits cardiac differentiation (PMID:21715426; abstract only). tbx5a alone is not needed to form cardiomyocytes: hst hearts form and beat (PMID:12223419). Kept as a cooperative, non-core role. supported_by: - reference_id: PMID:21715426 supporting_text: >- Overexpression of smarcd3b and gata5 in zebrafish results in an enlarged heart, whereas combinatorial loss of cBAF components inhibits cardiac differentiation. - reference_id: PMID:12223419 supporting_text: >- However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. - term: id: GO:0060042 label: retina morphogenesis in camera-type eye evidence_type: IGI original_reference_id: PMID:24759614 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-2 - ZFIN:ZDB-MRPHLNO-130123-3 review: summary: Retina morphogenesis in camera-type eye (IGI, tbx5a + tbx5b double morphants). action: KEEP_AS_NON_CORE reason: >- Dorsal efnb2a expression shrinks significantly only when both tbx5 genes are knocked down, and ventral ephB2 expands (PMID:24759614). This is dorsoventral patterning of the retina, shared by the two copies, and so far shown only with morpholinos. supported_by: - reference_id: PMID:24759614 supporting_text: >- suggesting that tbx5 paralogues act redundantly in the dorsal retina to ensure efnb2a expression in this territory. - term: id: GO:0060174 label: limb bud formation evidence_type: IMP original_reference_id: PMID:12066188 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-MRPHLNO-060328-3 review: summary: Limb bud formation (IMP, morpholino). action: ACCEPT reason: >- tbx5 knockdown stops pectoral fin (forelimb-homologous) bud initiation by blocking directed migration of LPM cells into the fin field (PMID:12066188). hst mutants and CRISPR F0 knockouts agree (PMID:12223419, PMID:33416493). This is the copy-specific core role of tbx5a. supported_by: - reference_id: PMID:12066188 supporting_text: >- Functional knockdown of zebrafish tbx5 through the use of an antisense oligonucleotide resulted in a failure to initiate fin bud formation, leading to the complete loss of pectoral fins. - reference_id: PMID:12066188 supporting_text: >- The function of the tbx5 gene in the development of zebrafish forelimbs seems to involve the directed migration of individual lateral-plate mesodermal cells into the future limb-bud-producing region. - reference_id: PMID:33416493 supporting_text: 100% (43/43) of the tbx5a F0 larvae did not develop pectoral fins (Figure 4A). - term: id: GO:0060429 label: epithelium development evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00027680 review: summary: Epithelium development (IEA, ARBA). action: MARK_AS_OVER_ANNOTATED reason: >- No zebrafish evidence that tbx5a acts in epithelium development as such. It is an ARBA machine-learning generalization from family members. - term: id: GO:0061026 label: cardiac muscle tissue regeneration evidence_type: IMP original_reference_id: PMID:29933372 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-190912-10 review: summary: Cardiac muscle tissue regeneration (IMP, conditional gene trap). action: KEEP_AS_NON_CORE reason: >- Hearts homozygous for a conditionally re-inverted tbx5a gene-trap allele fail to regenerate (PMID:29933372). Strong conditional-mutant evidence of an adult role, kept as non-core relative to the developmental roles. supported_by: - reference_id: PMID:29933372 supporting_text: while all tbx5atpl58R/tpl58R fish failed to regenerate their hearts (n = 8) - term: id: GO:0061026 label: cardiac muscle tissue regeneration evidence_type: IMP original_reference_id: PMID:29933372 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-190912-9 review: summary: Cardiac muscle tissue regeneration (IMP, conditional gene trap). action: KEEP_AS_NON_CORE reason: >- Hearts homozygous for a conditionally re-inverted tbx5a gene-trap allele fail to regenerate (PMID:29933372). Strong conditional-mutant evidence of an adult role, kept as non-core relative to the developmental roles. supported_by: - reference_id: PMID:29933372 supporting_text: while all tbx5atpl58R/tpl58R fish failed to regenerate their hearts (n = 8) - term: id: GO:0061629 label: RNA polymerase II-specific DNA-binding transcription factor binding evidence_type: IPI original_reference_id: PMID:24430697 qualifier: enables supporting_entities: - ZFIN:ZDB-GENE-040426-2843 review: summary: >- RNA polymerase II-specific DNA-binding transcription factor binding (IPI with Kctd10). action: UNDECIDED reason: >- The partner named in WITH/FROM is Kctd10, and the cached abstract says Kctd10 binds Tbx5 to repress it (PMID:24430697). The term asserts that tbx5a binds a DNA-binding transcription factor. Kctd10 is a BTB/KCTD-domain protein, not a DNA-binding TF, so the term seems to belong on kctd10 (which binds the TF Tbx5a) rather than on tbx5a. Only the abstract is cached, so this is left undecided, not removed. supported_by: - reference_id: PMID:24430697 supporting_text: >- We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: >- Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: >- Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt 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:12066188 title: T-box gene tbx5 is essential for formation of the pectoral limb bud. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only; morpholino abolishes fin bud initiation. - id: PMID:12223419 title: >- The heartstrings mutation in zebrafish causes heart/fin Tbx5 deficiency syndrome. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only; heartstrings = tbx5a nonsense at aa 316. - id: PMID:12399308 title: >- The limb identity gene Tbx5 promotes limb initiation by interacting with Wnt2b and Fgf10. findings: [] - id: PMID:12810598 title: >- The zebrafish fgf24 mutant identifies an additional level of Fgf signaling involved in vertebrate forelimb initiation. findings: [] - id: PMID:16501170 title: sall4 acts downstream of tbx5 and is required for pectoral fin outgrowth. findings: [] - id: PMID:18347092 title: Foxn4 directly regulates tbx2b expression and atrioventricular canal formation. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Full text; EMSA of Tbx5 on tbx2b enhancer (source species of Tbx5 construct not stated in extracted text). - id: PMID:18407257 title: >- Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish. findings: [] - id: PMID:18661250 title: >- Cascade effect of cardiac myogenesis gene expression during cardiac looping in tbx5 knockdown zebrafish embryos. findings: [] - id: PMID:19204083 title: >- Physical interaction between TBX5 and MEF2C is required for early heart development. findings: [] - id: PMID:19895804 title: >- Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart atrio-ventricular boundary and valve formation. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text; Pdlim7-Tbx5 interaction, AV boundary, localization. - id: PMID:20413782 title: >- Tbx5 and Bmp signaling are essential for proepicardium specification in zebrafish. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text; tbx5a mutants lack proepicardium. - id: PMID:21715426 title: Smarcd3b and Gata5 promote a cardiac progenitor fate in the zebrafish embryo. findings: [] - id: PMID:21982178 title: >- Induction of apoptosis and inhibition of cell growth by tbx5 knockdown contribute to dysmorphogenesis in Zebrafish embryos. findings: [] - id: PMID:22776023 title: >- The paracrine effect of exogenous growth hormone alleviates dysmorphogenesis caused by tbx5 deficiency in zebrafish (Danio rerio) embryos. findings: [] - id: PMID:23226307 title: >- MicroRNA 218 mediates the effects of Tbx5a over-expression on zebrafish heart development. findings: [] - id: PMID:23441045 title: >- Zebrafish tbx5 paralogs demonstrate independent essential requirements in cardiac and pectoral fin development. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Abstract only; key pair paper (tbx5b morphants, no cross-rescue). - id: PMID:24430697 title: >- Kctd10 regulates heart morphogenesis by repressing the transcriptional activity of Tbx5a in zebrafish. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract only; Kctd10 binds and represses Tbx5a. - id: PMID:24759614 title: >- Distinct tissue-specific requirements for the zebrafish tbx5 genes during heart, retina and pectoral fin development. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text; single/double morphants of both paralogs; hst hypomorph argument. - id: PMID:26657204 title: >- MicroRNA 19a replacement partially rescues fin and cardiac defects in zebrafish model of Holt Oram syndrome. findings: [] - id: PMID:28761722 title: >- A TBX5 3'UTR variant increases the risk of congenital heart disease in the Han Chinese population. findings: [] - id: PMID:29922649 title: >- Post-transcriptional Modulation of Sphingosine-1-Phosphate Receptor 1 by miR-19a Affects Cardiovascular Development in Zebrafish. findings: [] - id: PMID:29933372 title: >- Analysis of a conditional gene trap reveals that tbx5a is required for heart regeneration in zebrafish. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Full text; conditional gene trap, regeneration; discusses allele-dependent compensation. - id: PMID:30352852 title: >- Evolutionarily conserved Tbx5-Wnt2/2b pathway orchestrates cardiopulmonary development. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text; tbx5a/b not required for swim bladder formation. - id: PMID:33416493 title: >- A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes. findings: [] - id: PMID:34372968 title: >- Twisting of the zebrafish heart tube during cardiac looping is a tbx5-dependent and tissue-intrinsic process. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Full text; oug allele truncates Tbx5a in the T-box; jogging normal, looping defective. - id: PMID:19925885 title: >- Identification and characterisation of the developmental expression pattern of tbx5b, a novel tbx5 gene in zebrafish. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Abstract only. Identifies tbx5b as a TGD paralog; fin expression not detected in this study. - id: PMID:30532148 title: A transcriptomics analysis of the Tbx5 paralogues in zebrafish. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Full text. tbx5b CRISPR mutant (intron-1 insertion, frameshift, PTC) phenocopies morphants; comparative RNA-seq. - id: PMID:34756968 title: >- Tbx5a and Tbx5b paralogues act in combination to control separate vectors of migration in the fin field of zebrafish. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Full text. tbx5a: AP convergence; tbx5b: ML migration of fin field cells.' - id: PMID:33482174 title: >- Anterior lateral plate mesoderm gives rise to multiple tissues and requires tbx5a function in left-right asymmetry, migration dynamics, and cell specification of late-addition cardiac cells. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text; morpholino-based fate mapping. - id: PMID:29382818 title: >- Tbx5a lineage tracing shows cardiomyocyte plasticity during zebrafish heart regeneration. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text; tbx5a lineage and expression in adult heart. - id: PMID:27503876 title: Regulatory evolution of Tbx5 and the origin of paired appendages. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text; CNS12 fin enhancer conserved in gar/zebrafish/mouse rescues hst fin. - id: PMID:39079985 title: 'Zebrafish: unraveling genetic complexity through duplicated genes.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Review; states 83% T-box identity between Tbx5a and Tbx5b. core_functions: - description: >- Sequence-specific DNA-binding transcription factor (T-box) that activates target genes such as tbx2b, fgf24/fgf10 and ndrg4. 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:18347092 supporting_text: >- In electromobility shift assays (EMSA) to test DNA-binding affinity, Foxn4 and Tbx5 bound efficiently to their labeled putative binding sites, and binding was efficiently competed with excess unlabeled cognate competitors, but not with mutated oligonucleotides - reference_id: PMID:18347092 supporting_text: >- Thus, the putative Foxn4 and Tbx5 DNA-binding sites are required for the precise control of this highly conserved tbx2b enhancer during AV canal development. - reference_id: PMID:19895804 supporting_text: >- The presence of a Tbx5-binding-element in the promoter of tbx2b along with the reduction of expression in hst heterozygous mutants and complete loss in homozygotes reveals that Tbx5 regulates tbx2b at the AV boundary. - description: >- Initiation of the pectoral fin bud: the tbx5a-specific role. It drives fgf24 in fin-field mesenchyme and the antero-posterior convergence of lateral plate mesoderm cells. Loss abolishes the fin. molecular_function: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific directly_involved_in: - id: GO:0060174 label: limb bud formation - id: GO:0033339 label: pectoral fin development locations: - id: GO:0005634 label: nucleus supported_by: - reference_id: PMID:12223419 supporting_text: >- Homozygous mutant embryos never develop pectoral fin buds and do not express several markers of early fin differentiation. - reference_id: PMID:12066188 supporting_text: >- Functional knockdown of zebrafish tbx5 through the use of an antisense oligonucleotide resulted in a failure to initiate fin bud formation, leading to the complete loss of pectoral fins. - reference_id: PMID:33416493 supporting_text: 100% (43/43) of the tbx5a F0 larvae did not develop pectoral fins (Figure 4A). - reference_id: PMID:34756968 supporting_text: >- In both tbx5a −/− mutants and Tbx5a knock-down embryos, AP convergence of the fin field cells fails to occur; however these same precursors exhibit a robust ML movement that is similar in migration dynamics to that of wt embryos. - reference_id: PMID:24759614 supporting_text: >- Taken together, we show that pectoral fin development has a different requirement for each of the tbx5 paralogues: tbx5a function is required for the earliest steps of initiation of fin outgrowth, whereas tbx5b functions later to ensure properly timed and sustained fin outgrowth. - description: >- Cardiac looping and chamber/AV-canal patterning (with tbx5b, non-redundantly), including restriction of tbx2b to the AV boundary and specification of the proepicardium. molecular_function: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific directly_involved_in: - id: GO:0001947 label: heart looping - id: GO:0003206 label: cardiac chamber morphogenesis - id: GO:0003342 label: proepicardium development locations: - id: GO:0005634 label: nucleus supported_by: - reference_id: PMID:12223419 supporting_text: >- However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. - reference_id: PMID:34372968 supporting_text: >- Hence, the ventricle and the atrium undergo asymmetric rotational movements around the atrioventricular canal, effectively transmitting a twisting transformation to the heart tube, a process which we show to be defective in tbx5a-/- zebrafish mutants. - reference_id: PMID:34372968 supporting_text: >- In the zebrafish oug mutant, the absence of Tbx5a results in the expansion of the AV canal as illustrated by expanded domains of expression of tbx2b, bmp4, and has2 - reference_id: PMID:20413782 supporting_text: We further show that tbx5a mutants also have severe defects in PE specification. - reference_id: PMID:23441045 supporting_text: >- Because tbx5a hypomorphic mutations are embryonic lethal, tbx5a and tbx5b functions in the heart must not be completely redundant. suggested_questions: - question: >- Does heart jogging need tbx5a? Morphants show jogging defects, but hst and the T-box-truncating oug allele jog normally. Is this a morpholino artefact, or transcriptional adaptation in PTC alleles? - question: >- Why can tbx5b mRNA not rescue tbx5a loss (and the reverse)? Is the block in the divergent C-terminal region, in the T-box (83% identity), or in dose and timing? - question: >- Should the ZFIN IPI annotation to GO:0061629 (TF binding, partner Kctd10) move to kctd10, which binds the transcription factor? suggested_experiments: - hypothesis: The paralogs differ at the protein level, not only in expression. description: >- Swap the tbx5b coding sequence into the tbx5a locus (knock-in) and score fin bud initiation and heart looping. Compare with a tbx5a-into-tbx5a knock-in control. experiment_type: cross-rescue by coding-sequence swap - hypothesis: Normal jogging in tbx5a nonsense alleles reflects genetic compensation. description: >- Make a promoter-less (RNA-less) tbx5a allele, score jogging, and measure tbx5b and tbx3/tbx2 expression in hst, oug and RNA-less mutants. experiment_type: genetic compensation test