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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000785 chromatin | IBA GO_REF:0000033 | ACCEPT | Summary: Active in chromatin (IBA). 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. Supporting Evidence: PMID:18347092 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 |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Sequence-specific binding of RNA polymerase II cis-regulatory DNA through the T-box domain (IBA). 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. Supporting Evidence: PMID:18347092 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 PMID:18347092 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. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: Sequence-specific binding of RNA polymerase II cis-regulatory DNA through the T-box domain (IEA, InterPro T-box). 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. Supporting Evidence: PMID:18347092 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 PMID:18347092 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. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-specific binding of RNA polymerase II cis-regulatory DNA through the T-box domain (ISS from human TBX5). 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. Supporting Evidence: PMID:18347092 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 PMID:18347092 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. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: RNA polymerase II-specific DNA-binding transcription factor activity (IBA). 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). Supporting Evidence: PMID:18347092 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 PMID:19895804 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. PMID:24430697 We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: RNA polymerase II-specific DNA-binding transcription factor activity (ISS from human TBX5). 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). Supporting Evidence: PMID:18347092 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 PMID:19895804 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. PMID:24430697 We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. |
| GO:0001708 cell fate specification | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cell fate specification (IBA, T-box family node). 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. Supporting Evidence: PMID:20413782 We further show that tbx5a mutants also have severe defects in PE specification. PMID:33482174 our present data also implicate tbx5a function in cell specification, establishment and maintenance of cardiac left-right asymmetry. |
| GO:0001947 heart looping | IGI PMID:19895804 Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart a... | ACCEPT | Summary: Heart looping (IGI with pdlim7). 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). Supporting Evidence: PMID:19895804 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. PMID:12223419 However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. |
| GO:0001947 heart looping | IGI PMID:24430697 Kctd10 regulates heart morphogenesis by repressing the trans... | ACCEPT | Summary: Heart looping (IGI with kctd10). 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). Supporting Evidence: PMID:24430697 The knockdown of tbx5 rescues the ectopic expression of has2, and knockdown of either tbx5a or has2 alleviates the heart defects. PMID:12223419 However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. |
| GO:0001947 heart looping | IGI PMID:24759614 Distinct tissue-specific requirements for the zebrafish tbx5... | ACCEPT | Summary: Heart looping (IGI, tbx5a + tbx5b double morphants). 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. Supporting Evidence: PMID:24759614 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 PMID:24759614 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). |
| GO:0001947 heart looping | IMP PMID:12399308 The limb identity gene Tbx5 promotes limb initiation by inte... | ACCEPT | Summary: Heart looping (IMP, PMID:12399308). 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. Supporting Evidence: PMID:12223419 However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. PMID:34372968 In such a screen we identified the oudegracht (oug) mutant in which cardiac jogging was unaffected while cardiac looping was compromised. |
| GO:0001947 heart looping | IMP PMID:20413782 Tbx5 and Bmp signaling are essential for proepicardium speci... | ACCEPT | Summary: Heart looping (IMP, heartstrings). 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. Supporting Evidence: PMID:20413782 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 PMID:12223419 However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. |
| GO:0001947 heart looping | IMP PMID:24759614 Distinct tissue-specific requirements for the zebrafish tbx5... | ACCEPT | Summary: Heart looping (IMP, tbx5a morpholino). 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. Supporting Evidence: PMID:24759614 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 |
| GO:0003007 heart morphogenesis | IGI PMID:21715426 Smarcd3b and Gata5 promote a cardiac progenitor fate in the ... | ACCEPT | Summary: Heart morphogenesis (IGI with smarcd3b/gata5). 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. Supporting Evidence: PMID:21715426 Overexpression of smarcd3b and gata5 in zebrafish results in an enlarged heart, whereas combinatorial loss of cBAF components inhibits cardiac differentiation. PMID:12223419 However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. |
| GO:0003007 heart morphogenesis | IMP PMID:23226307 MicroRNA 218 mediates the effects of Tbx5a over-expression o... | ACCEPT | Summary: Heart morphogenesis (IMP, morpholino). Reason: tbx5a morphants and embryos overexpressing tbx5a both show looping and chamber defects, and miR-218 interacts with tbx5a in heart morphogenesis (PMID:23226307). Supporting Evidence: PMID:23226307 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 PMID:23226307 However, the injection of both MO-Tbx5a and miR-218a mimic at these doses dramatically increased the number of embryos with looping defects |
| GO:0003143 embryonic heart tube morphogenesis | IGI PMID:19895804 Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart a... | ACCEPT | Summary: Embryonic heart tube morphogenesis (IGI with pdlim7). Reason: Pdlim7 and Tbx5 interact genetically and physically to shape the heart tube and the AV boundary (PMID:19895804). Supporting Evidence: PMID:19895804 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. |
| GO:0003143 embryonic heart tube morphogenesis | IMP PMID:19895804 Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart a... | ACCEPT | Summary: Embryonic heart tube morphogenesis (IMP, heartstrings). Reason: heartstrings mutants lose tbx2b at the AV boundary and fail to loop (PMID:19895804). Supporting Evidence: PMID:19895804 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. PMID:19895804 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. |
| GO:0003146 heart jogging | IGI PMID:24759614 Distinct tissue-specific requirements for the zebrafish tbx5... | UNDECIDED | Summary: Heart jogging (IGI, tbx5a + tbx5b double morphants). 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). Supporting Evidence: PMID:24759614 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 PMID:24759614 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). PMID:34372968 In such a screen we identified the oudegracht (oug) mutant in which cardiac jogging was unaffected while cardiac looping was compromised. PMID:34372968 Indeed, in oug approximately 75% of the gene product is lost, including a large portion of the DNA-binding T-box domain. |
| GO:0003146 heart jogging | IMP PMID:24759614 Distinct tissue-specific requirements for the zebrafish tbx5... | UNDECIDED | Summary: Heart jogging (IMP, tbx5a morpholino). 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). Supporting Evidence: PMID:24759614 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. PMID:34372968 In such a screen we identified the oudegracht (oug) mutant in which cardiac jogging was unaffected while cardiac looping was compromised. |
| GO:0003190 atrioventricular valve formation | IMP PMID:19895804 Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart a... | KEEP AS NON CORE | Summary: Atrioventricular valve formation (IMP, heartstrings). 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. Supporting Evidence: PMID:19895804 Knock-down of Pdlim7 results in loss of detectable valve structures while lack of Tbx5 function leads to increased amounts of valve tissue. PMID:19895804 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. |
| GO:0003206 cardiac chamber morphogenesis | IMP PMID:34372968 Twisting of the zebrafish heart tube during cardiac looping ... | ACCEPT | Summary: Cardiac chamber morphogenesis (IMP, oug mutant). 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. Supporting Evidence: PMID:34372968 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. PMID:34372968 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 |
| GO:0003218 cardiac left ventricle formation | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Cardiac left ventricle formation (IBA). 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. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: LINEAGE OR TAXON MISMATCH Sources checked: PANTHER:PTN002601200 SUPPORTS SOURCE BUT NOT TARGET 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. MGI:MGI:102541 SUPPORTS SOURCE BUT NOT TARGET Mouse experimental evidence for left ventricle formation; the anatomy is absent in zebrafish. Supporting Evidence: PMID:12223419 However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. PMID:29382818 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. |
| GO:0003294 atrial ventricular junction remodeling | IMP PMID:19895804 Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart a... | KEEP AS NON CORE | Summary: Atrial ventricular junction remodeling (IMP, heartstrings). Reason: AV boundary defects in hst: loss of tbx2b and excess valve tissue (PMID:19895804). Supporting Evidence: PMID:19895804 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. PMID:19895804 Knock-down of Pdlim7 results in loss of detectable valve structures while lack of Tbx5 function leads to increased amounts of valve tissue. |
| GO:0003342 proepicardium development | IMP PMID:20413782 Tbx5 and Bmp signaling are essential for proepicardium speci... | ACCEPT | Summary: Proepicardium development (IMP, tbx5a mutants and dominant negative). 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. Supporting Evidence: PMID:20413782 We further show that tbx5a mutants also have severe defects in PE specification. |
| GO:0003344 pericardium morphogenesis | IMP PMID:12399308 The limb identity gene Tbx5 promotes limb initiation by inte... | KEEP AS NON CORE | Summary: Pericardium morphogenesis (IMP, PMID:12399308). 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. Supporting Evidence: PMID:33482174 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. PMID:18661250 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. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:18347092 Foxn4 directly regulates tbx2b expression and atrioventricul... | ACCEPT | Summary: DNA-binding transcription factor activity (IDA, EMSA on the tbx2b enhancer). 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. Supporting Evidence: PMID:18347092 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 PMID:18347092 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. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:24430697 Kctd10 regulates heart morphogenesis by repressing the trans... | ACCEPT | Summary: DNA-binding transcription factor activity (IDA, PMID:24430697). Reason: Kctd10 represses Tbx5a transcriptional activity, which implies reporter activation by Tbx5a (PMID:24430697; abstract only). Consistent with the core function. Supporting Evidence: PMID:24430697 We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: DNA-binding transcription factor activity (IEA, InterPro T-box). 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). Supporting Evidence: PMID:18347092 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 PMID:19895804 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. PMID:24430697 We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. |
| GO:0005515 protein binding | IPI PMID:24430697 Kctd10 regulates heart morphogenesis by repressing the trans... | REMOVE | Summary: Protein binding (IPI with Kctd10). 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. Supporting Evidence: PMID:24430697 We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization (IBA). 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). Supporting Evidence: PMID:19895804 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 |
| GO:0005634 nucleus | IDA PMID:19895804 Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart a... | ACCEPT | Summary: Nucleus (IDA, transfected Tbx5 and hst-like Tbx5). Reason: Full-length Tbx5 is nuclear, with a cytoplasmic pool on actin with Pdlim7. The hst-truncated protein is strictly nuclear (PMID:19895804). Supporting Evidence: PMID:19895804 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 |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization (IEA). 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). Supporting Evidence: PMID:19895804 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 |
| GO:0005634 nucleus | IEP PMID:24430697 Kctd10 regulates heart morphogenesis by repressing the trans... | ACCEPT | Summary: Nucleus (IEP, PMID:24430697). Reason: Nuclear localization is correct for Tbx5a (PMID:19895804), although IEP is an unusual evidence code for a location. Supporting Evidence: PMID:19895804 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 |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: Nuclear localization (ISS). 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). Supporting Evidence: PMID:19895804 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 |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasmic localization (IEA). 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. Supporting Evidence: PMID:19895804 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 PMID:19895804 Regulated by yet unknown signals, Tbx5 exits the nucleus and binds to Pdlim7 along cytoplasmic actin filaments. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cytoplasmic localization (ISS). 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. Supporting Evidence: PMID:19895804 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 PMID:19895804 Regulated by yet unknown signals, Tbx5 exits the nucleus and binds to Pdlim7 along cytoplasmic actin filaments. |
| GO:0006351 DNA-templated transcription | IMP PMID:16501170 sall4 acts downstream of tbx5 and is required for pectoral f... | MODIFY | Summary: DNA-templated transcription (IMP, sall4 expression depends on tbx5). 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 replacements: regulation of transcription by RNA polymerase II Supporting Evidence: PMID:16501170 We demonstrate that sall4 and a related gene sall1 act downstream of tbx5 and are required for pectoral fin development. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: Regulation of transcription (IEA, InterPro). Reason: Tbx5a is a DNA-binding transcription factor. Target genes in zebrafish include tbx2b, fgf24/fgf10 and ndrg4 (PMID:19895804, PMID:12810598, PMID:18407257). Supporting Evidence: PMID:19895804 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. PMID:12810598 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. |
| GO:0006355 regulation of DNA-templated transcription | IMP PMID:18661250 Cascade effect of cardiac myogenesis gene expression during ... | ACCEPT | Summary: Regulation of DNA-templated transcription (IMP, morpholino). 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. Supporting Evidence: PMID:18661250 Our data suggests that the heart failure caused by the knockdown of tbx5 gene might result from the down-regulation of cardiac myogenesis genes. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Regulation of transcription (IBA). Reason: Tbx5a is a DNA-binding transcription factor. Target genes in zebrafish include tbx2b, fgf24/fgf10 and ndrg4 (PMID:19895804, PMID:12810598, PMID:18407257). Supporting Evidence: PMID:19895804 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. PMID:12810598 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. |
| GO:0007389 pattern specification process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Pattern specification process (IBA). Reason: Tbx5a contributes to axis patterning in the fin field and to dorsoventral patterning of the retina (PMID:24759614, PMID:34756968). Broad but correct. Supporting Evidence: PMID:24759614 suggesting that tbx5 paralogues act redundantly in the dorsal retina to ensure efnb2a expression in this territory. PMID:34756968 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. |
| GO:0007507 heart development | IGI PMID:19204083 Physical interaction between TBX5 and MEF2C is required for ... | ACCEPT | Summary: Heart development (IGI with mef2c). Tbx5 and Mef2c cooperate on myh6 and on early heart development. 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. Supporting Evidence: PMID:19204083 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. |
| GO:0007507 heart development | IGI PMID:23226307 MicroRNA 218 mediates the effects of Tbx5a over-expression o... | ACCEPT | Summary: Heart development (IGI with miR-218). 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. Supporting Evidence: PMID:23226307 However, the injection of both MO-Tbx5a and miR-218a mimic at these doses dramatically increased the number of embryos with looping defects |
| GO:0007507 heart development | IGI PMID:26657204 MicroRNA 19a replacement partially rescues fin and cardiac d... | ACCEPT | Summary: Heart development (IGI with miR-19a). 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. Supporting Evidence: PMID:26657204 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. |
| GO:0007507 heart development | IGI PMID:26657204 MicroRNA 19a replacement partially rescues fin and cardiac d... | ACCEPT | Summary: Heart development (IGI with miR-19a morpholino). 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. Supporting Evidence: PMID:26657204 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. |
| GO:0007507 heart development | IGI PMID:29922649 Post-transcriptional Modulation of Sphingosine-1-Phosphate R... | ACCEPT | Summary: Heart development (IGI with s1pr1). 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. Supporting Evidence: PMID:29922649 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. |
| GO:0007507 heart development | IMP PMID:12223419 The heartstrings mutation in zebrafish causes heart/fin Tbx5... | ACCEPT | Summary: Heart development (IMP, heartstrings). 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. Supporting Evidence: PMID:12223419 However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. PMID:12223419 we isolated the recessive lethal mutant heartstrings, which lacks pectoral fins and exhibits severe cardiac dysfunction |
| GO:0007507 heart development | IMP PMID:12223419 The heartstrings mutation in zebrafish causes heart/fin Tbx5... | ACCEPT | Summary: Heart development (IMP, morpholino). 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. Supporting Evidence: PMID:12223419 However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. |
| GO:0007507 heart development | IMP PMID:18661250 Cascade effect of cardiac myogenesis gene expression during ... | ACCEPT | Summary: Heart development (IMP, morpholino). 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. Supporting Evidence: PMID:18661250 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. |
| GO:0007507 heart development | IMP PMID:18661250 Cascade effect of cardiac myogenesis gene expression during ... | ACCEPT | Summary: Heart development (IMP, second tbx5a morpholino). 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. Supporting Evidence: PMID:18661250 Our data suggests that the heart failure caused by the knockdown of tbx5 gene might result from the down-regulation of cardiac myogenesis genes. |
| GO:0007507 heart development | IMP PMID:22776023 The paracrine effect of exogenous growth hormone alleviates ... | ACCEPT | Summary: Heart development (IMP, morpholino; growth hormone rescue). 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. Supporting Evidence: PMID:22776023 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. |
| GO:0007507 heart development | IMP PMID:23441045 Zebrafish tbx5 paralogs demonstrate independent essential re... | ACCEPT | Summary: Heart development (IMP, heartstrings). 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. Supporting Evidence: PMID:23441045 Homozygous mutation of zebrafish tbx5a leads to lethal defects in cardiac looping morphogenesis, blocks pectoral fin initiation, and impairs outgrowth. PMID:23441045 Because tbx5a hypomorphic mutations are embryonic lethal, tbx5a and tbx5b functions in the heart must not be completely redundant. |
| GO:0007507 heart development | IMP PMID:23441045 Zebrafish tbx5 paralogs demonstrate independent essential re... | ACCEPT | Summary: Heart development (IMP, morpholino). 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. Supporting Evidence: PMID:23441045 Homozygous mutation of zebrafish tbx5a leads to lethal defects in cardiac looping morphogenesis, blocks pectoral fin initiation, and impairs outgrowth. |
| GO:0007507 heart development | IMP PMID:28761722 A TBX5 3'UTR variant increases the risk of congenital heart ... | ACCEPT | Summary: Heart development (IMP, morpholino). 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. Supporting Evidence: PMID:28761722 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 |
| GO:0007507 heart development | IMP PMID:29922649 Post-transcriptional Modulation of Sphingosine-1-Phosphate R... | ACCEPT | Summary: Heart development (IMP, morpholino). 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. Supporting Evidence: PMID:29922649 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. |
| GO:0009653 anatomical structure morphogenesis | IEA GO_REF:0000117 | ACCEPT | Summary: Anatomical structure morphogenesis (IEA, ARBA). Reason: Very broad, but true: tbx5a is needed for heart and pectoral fin morphogenesis. It is implied by the more specific experimental terms. Supporting Evidence: PMID:12223419 Homozygous mutant embryos never develop pectoral fin buds and do not express several markers of early fin differentiation. PMID:12223419 However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. |
| GO:0009887 animal organ morphogenesis | IMP PMID:21982178 Induction of apoptosis and inhibition of cell growth by tbx5... | ACCEPT | Summary: Animal organ morphogenesis (IMP, morpholino). Reason: tbx5 morphants show heart (string-like) and pectoral fin (hypoplasia or agenesis) dysmorphogenesis (PMID:21982178). Broad but correct. Supporting Evidence: PMID:21982178 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). PMID:21982178 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. |
| GO:0015629 actin cytoskeleton | IPI PMID:19895804 Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart a... | KEEP AS NON CORE | Summary: Actin cytoskeleton (IPI with Pdlim7). 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. Supporting Evidence: PMID:19895804 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 PMID:19895804 Regulated by yet unknown signals, Tbx5 exits the nucleus and binds to Pdlim7 along cytoplasmic actin filaments. |
| GO:0021554 optic nerve development | IGI PMID:24759614 Distinct tissue-specific requirements for the zebrafish tbx5... | KEEP AS NON CORE | Summary: Optic nerve development (IGI, tbx5a + tbx5b double morphants). 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. Supporting Evidence: PMID:24759614 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). |
| GO:0032991 protein-containing complex | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Protein-containing complex (ISS). Reason: An uninformative location. Tbx5 does form complexes (for example with Mef2c, PMID:19204083), but this generic term adds nothing to nucleus and chromatin. Supporting Evidence: PMID:19204083 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. |
| GO:0032993 protein-DNA complex | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Protein-DNA complex (ISS from human TBX5). 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. Supporting Evidence: PMID:18347092 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 |
| GO:0033339 pectoral fin development | IMP PMID:12066188 T-box gene tbx5 is essential for formation of the pectoral l... | ACCEPT | Summary: Pectoral fin development (IMP, morpholino). 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). Supporting Evidence: PMID:12066188 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. |
| GO:0033339 pectoral fin development | IMP PMID:12223419 The heartstrings mutation in zebrafish causes heart/fin Tbx5... | ACCEPT | Summary: Pectoral fin development (IMP, heartstrings). 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). Supporting Evidence: PMID:12223419 Homozygous mutant embryos never develop pectoral fin buds and do not express several markers of early fin differentiation. |
| GO:0033339 pectoral fin development | IMP PMID:12223419 The heartstrings mutation in zebrafish causes heart/fin Tbx5... | ACCEPT | Summary: Pectoral fin development (IMP, morpholino). 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). Supporting Evidence: PMID:12223419 Moderate reduction of Tbx5 by morpholino causes fin malformations, revealing an additional early requirement for Tbx5 in coordinating the axes of fin outgrowth. |
| GO:0033339 pectoral fin development | IMP PMID:23441045 Zebrafish tbx5 paralogs demonstrate independent essential re... | ACCEPT | Summary: Pectoral fin development (IMP, heartstrings). 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). Supporting Evidence: PMID:23441045 Homozygous mutation of zebrafish tbx5a leads to lethal defects in cardiac looping morphogenesis, blocks pectoral fin initiation, and impairs outgrowth. |
| GO:0033339 pectoral fin development | IMP PMID:23441045 Zebrafish tbx5 paralogs demonstrate independent essential re... | ACCEPT | Summary: Pectoral fin development (IMP, morpholino). 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). Supporting Evidence: PMID:23441045 Homozygous mutation of zebrafish tbx5a leads to lethal defects in cardiac looping morphogenesis, blocks pectoral fin initiation, and impairs outgrowth. |
| GO:0033339 pectoral fin development | IMP PMID:24759614 Distinct tissue-specific requirements for the zebrafish tbx5... | ACCEPT | Summary: Pectoral fin development (IMP, morpholino). 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). Supporting Evidence: PMID:24759614 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. |
| GO:0033339 pectoral fin development | IMP PMID:33416493 A simple and effective F0 knockout method for rapid screenin... | ACCEPT | Summary: Pectoral fin development (IMP, CRISPR F0 knockout). 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). Supporting Evidence: PMID:33416493 100% (43/43) of the tbx5a F0 larvae did not develop pectoral fins (Figure 4A). |
| GO:0035050 embryonic heart tube development | IMP PMID:18407257 Ndrg4 is required for normal myocyte proliferation during ea... | ACCEPT | Summary: Embryonic heart tube development (IMP, heartstrings). Reason: ndrg4 expression drops in tbx5 mutant hearts, and not merely because of a general myocardial defect (PMID:18407257). Supporting Evidence: PMID:18407257 Therefore, reduction of ndrg4 expression in tbx5 mutant hearts is not just due to a general myocardial differentiation defect in tbx5 mutant myocardium. |
| GO:0035050 embryonic heart tube development | IMP PMID:18407257 Ndrg4 is required for normal myocyte proliferation during ea... | ACCEPT | Summary: Embryonic heart tube development (IMP, morpholino). Reason: Tbx5 regulates ndrg4 in the heart tube, and ndrg4 is needed for myocyte proliferation (PMID:18407257). Supporting Evidence: PMID:18407257 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 |
| GO:0035118 embryonic pectoral fin morphogenesis | IMP PMID:12399308 The limb identity gene Tbx5 promotes limb initiation by inte... | ACCEPT | Summary: Embryonic pectoral fin morphogenesis (IMP, heartstrings). 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). Supporting Evidence: PMID:12399308 We find that Tbx5 functions downstream of WNT signaling to regulate Fgf10, which, in turn, maintains Tbx5 expression during limb outgrowth. PMID:12223419 Homozygous mutant embryos never develop pectoral fin buds and do not express several markers of early fin differentiation. |
| GO:0035118 embryonic pectoral fin morphogenesis | IMP PMID:12399308 The limb identity gene Tbx5 promotes limb initiation by inte... | ACCEPT | Summary: Embryonic pectoral fin morphogenesis (IMP, morpholino). Reason: Tbx5 is necessary and sufficient for limb/fin outgrowth (PMID:12399308). Supporting Evidence: PMID:12399308 we show that Tbx5, in addition to its role governing forelimb identity, is both necessary and sufficient for limb outgrowth. |
| GO:0035118 embryonic pectoral fin morphogenesis | IMP PMID:12810598 The zebrafish fgf24 mutant identifies an additional level of... | ACCEPT | Summary: Embryonic pectoral fin morphogenesis (IMP, morpholino, PMID:12810598). Reason: fgf24 acts downstream of tbx5 to turn on fgf10 and to guide tbx5-expressing cells to the fin bud (PMID:12810598). Supporting Evidence: PMID:12810598 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. |
| GO:0035138 pectoral fin morphogenesis | IMP PMID:22776023 The paracrine effect of exogenous growth hormone alleviates ... | ACCEPT | Summary: Pectoral fin morphogenesis (IMP, morpholino; growth hormone rescue). Reason: tbx5 morphants have truncated or absent pectoral fins (PMID:22776023). Supporting Evidence: PMID:22776023 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. |
| GO:0036302 atrioventricular canal development | IGI PMID:24430697 Kctd10 regulates heart morphogenesis by repressing the trans... | ACCEPT | Summary: Atrioventricular canal development (IGI with kctd10). 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). Supporting Evidence: PMID:24430697 The knockdown of tbx5 rescues the ectopic expression of has2, and knockdown of either tbx5a or has2 alleviates the heart defects. PMID:34372968 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 |
| GO:0043565 sequence-specific DNA binding | IDA PMID:18347092 Foxn4 directly regulates tbx2b expression and atrioventricul... | ACCEPT | Summary: Sequence-specific DNA binding (IDA, EMSA). 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. Supporting Evidence: PMID:18347092 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 |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:18347092 Foxn4 directly regulates tbx2b expression and atrioventricul... | ACCEPT | Summary: Positive regulation of DNA-templated transcription (IDA, tbx2b enhancer). Reason: The Tbx5 site is needed for correct activity of the tbx2b enhancer in vivo (PMID:18347092). Supporting Evidence: PMID:18347092 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. |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: Positive regulation of DNA-templated transcription (IEA, InterPro). Reason: Tbx5 is a transcriptional activator of its targets (tbx2b, fgf24, ndrg4). Supporting Evidence: PMID:19895804 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. PMID:12810598 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. |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:18407257 Ndrg4 is required for normal myocyte proliferation during ea... | ACCEPT | Summary: Positive regulation of DNA-templated transcription (IMP, heartstrings; ndrg4). Reason: ndrg4 expression depends on tbx5 in the heart (PMID:18407257). Probably direct or indirect activation. Supporting Evidence: PMID:18407257 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 PMID:18407257 Therefore, reduction of ndrg4 expression in tbx5 mutant hearts is not just due to a general myocardial differentiation defect in tbx5 mutant myocardium. |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:18407257 Ndrg4 is required for normal myocyte proliferation during ea... | ACCEPT | Summary: Positive regulation of DNA-templated transcription (IMP, morpholino; ndrg4). Reason: As for the heartstrings row (PMID:18407257). Supporting Evidence: PMID:18407257 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 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:24430697 Kctd10 regulates heart morphogenesis by repressing the trans... | ACCEPT | Summary: Positive regulation of transcription by RNA polymerase II (IDA, PMID:24430697). Reason: Tbx5a transcriptional activity is repressed by Kctd10 (PMID:24430697; abstract only). This is consistent with the activator role shown on tbx2b (PMID:18347092). Supporting Evidence: PMID:24430697 We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. PMID:18347092 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. |
| GO:0048794 swim bladder development | IGI NOT PMID:30352852 Evolutionarily conserved Tbx5-Wnt2/2b pathway orchestrates c... | ACCEPT | Summary: NOT swim bladder development (negated). 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. Supporting Evidence: PMID:30352852 However, we find that although Tbx5 is required for lung formation, tbx5a / b is not required for SB formation in the zebrafish. PMID:30352852 To address potential redundancy, we utilized published MOs designed to target tbx5a , tbx5b , or tbx5a and tbx5b ( 47 , 48 ). |
| GO:0048794 swim bladder development | IMP NOT PMID:30352852 Evolutionarily conserved Tbx5-Wnt2/2b pathway orchestrates c... | ACCEPT | Summary: NOT swim bladder development (negated). 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. Supporting Evidence: PMID:30352852 However, we find that although Tbx5 is required for lung formation, tbx5a / b is not required for SB formation in the zebrafish. PMID:30352852 To address potential redundancy, we utilized published MOs designed to target tbx5a , tbx5b , or tbx5a and tbx5b ( 47 , 48 ). |
| GO:0048794 swim bladder development | IMP NOT PMID:30352852 Evolutionarily conserved Tbx5-Wnt2/2b pathway orchestrates c... | ACCEPT | Summary: NOT swim bladder development (negated). 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. Supporting Evidence: PMID:30352852 However, we find that although Tbx5 is required for lung formation, tbx5a / b is not required for SB formation in the zebrafish. PMID:30352852 To address potential redundancy, we utilized published MOs designed to target tbx5a , tbx5b , or tbx5a and tbx5b ( 47 , 48 ). |
| GO:0055007 cardiac muscle cell differentiation | IGI PMID:21715426 Smarcd3b and Gata5 promote a cardiac progenitor fate in the ... | KEEP AS NON CORE | Summary: Cardiac muscle cell differentiation (IGI with smarcd3b/gata5). 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. Supporting Evidence: PMID:21715426 Overexpression of smarcd3b and gata5 in zebrafish results in an enlarged heart, whereas combinatorial loss of cBAF components inhibits cardiac differentiation. PMID:12223419 However, the heart fails to loop and then progressively deteriorates, a process affecting the ventricle as well as the atrium. |
| GO:0060042 retina morphogenesis in camera-type eye | IGI PMID:24759614 Distinct tissue-specific requirements for the zebrafish tbx5... | KEEP AS NON CORE | Summary: Retina morphogenesis in camera-type eye (IGI, tbx5a + tbx5b double morphants). 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. Supporting Evidence: PMID:24759614 suggesting that tbx5 paralogues act redundantly in the dorsal retina to ensure efnb2a expression in this territory. |
| GO:0060174 limb bud formation | IMP PMID:12066188 T-box gene tbx5 is essential for formation of the pectoral l... | ACCEPT | Summary: Limb bud formation (IMP, morpholino). 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. Supporting Evidence: PMID:12066188 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. PMID:12066188 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. PMID:33416493 100% (43/43) of the tbx5a F0 larvae did not develop pectoral fins (Figure 4A). |
| GO:0060429 epithelium development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Epithelium development (IEA, ARBA). Reason: No zebrafish evidence that tbx5a acts in epithelium development as such. It is an ARBA machine-learning generalization from family members. |
| GO:0061026 cardiac muscle tissue regeneration | IMP PMID:29933372 Analysis of a conditional gene trap reveals that tbx5a is re... | KEEP AS NON CORE | Summary: Cardiac muscle tissue regeneration (IMP, conditional gene trap). 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. Supporting Evidence: PMID:29933372 while all tbx5atpl58R/tpl58R fish failed to regenerate their hearts (n = 8) |
| GO:0061026 cardiac muscle tissue regeneration | IMP PMID:29933372 Analysis of a conditional gene trap reveals that tbx5a is re... | KEEP AS NON CORE | Summary: Cardiac muscle tissue regeneration (IMP, conditional gene trap). 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. Supporting Evidence: PMID:29933372 while all tbx5atpl58R/tpl58R fish failed to regenerate their hearts (n = 8) |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:24430697 Kctd10 regulates heart morphogenesis by repressing the trans... | UNDECIDED | Summary: RNA polymerase II-specific DNA-binding transcription factor binding (IPI with Kctd10). 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. Supporting Evidence: PMID:24430697 We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Q: Should the ZFIN IPI annotation to GO:0061629 (TF binding, partner Kctd10) move to kctd10, which binds the transcription factor?
Experiment: 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.
Hypothesis: The paralogs differ at the protein level, not only in expression.
Type: cross-rescue by coding-sequence swap
Experiment: Make a promoter-less (RNA-less) tbx5a allele, score jogging, and measure tbx5b and tbx3/tbx2 expression in hst, oug and RNA-less mutants.
Hypothesis: Normal jogging in tbx5a nonsense alleles reflects genetic compensation.
Type: genetic compensation test
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