Affinage

TBX5

T-box transcription factor TBX5 · UniProt Q99593

Length
518 aa
Mass
57.7 kDa
Annotated
2026-06-10
100 papers in source corpus 60 papers cited in narrative 56 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBX5 is a dosage-sensitive T-box transcription factor that orchestrates heart and limb development by binding T-box (Brachyury-type) DNA consensus sites through its T-box domain and activating chamber- and tissue-specific gene programs (PMID:8988165, PMID:11555635, PMID:20450920). Crystallographic analysis of the T-box domain in DNA-bound and unbound states defines an inducible C-terminal 3(10)-helix recognition element, and HOS-associated T-box mutations reduce thermal stability and DNA-binding affinity (PMID:20450920); the protein carries a discrete transactivation domain (aa 339–379) and a KRK nuclear localization signal at aa 325–327 (PMID:15087119). TBX5 functions combinatorially, physically partnering with NKX2-5, GATA4, MEF2C, TBX20, and myocardin to synergistically activate cardiac targets such as NPPA, MYH6, and SCN5A, and disease mutations selectively dissociate DNA binding from these protein–protein synergies (PMID:11431700, PMID:12845333, PMID:12499378, PMID:19204083, PMID:21897873). In the second heart field it drives atrial septation through a Hedgehog–Foxf–RA–Wnt regulatory cascade and Osr1-dependent progenitor cell-cycle control (PMID:22898775, PMID:25356765, PMID:34643182, PMID:25986147), and in conducting and working myocardium it directly activates Scn5a/Nav1.5, Cx40, and SERCA2a/Atp2a2 to govern fast conduction and calcium handling (PMID:17604724, PMID:22728936, PMID:18378906). In the mature atrium TBX5 maintains atrial identity by binding and preserving the chromatin architecture of atrial-specific enhancers and loops (PMID:38344303), and operates in an incoherent feed-forward loop with PITX2 to set membrane-effector gene dosage (PMID:27582060). TBX5 nuclear availability is restrained by the PDLIM7/LMP4 cytoskeletal anchor (PMID:16880269, PMID:15302601), and its transcript dosage is tuned by autoregulation and miR-10-mediated repression (PMID:15095414, PMID:24714979). Heterozygous loss-of-function mutations cause Holt-Oram syndrome, while distinct adult loss- and gain-of-function alleles drive atrial fibrillation and arrhythmia syndromes through opposing effects on SERCA2a-dependent SR calcium uptake and atrial electrophysiology (PMID:8988165, PMID:18451335, PMID:27582060, PMID:30896405, PMID:35113653).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 High

    Established TBX5 as a disease gene, linking a single T-box transcription factor to coordinated heart and limb development through haploinsufficiency.

    Evidence Positional cloning and mutation identification in Holt-Oram syndrome pedigrees

    PMID:8988165

    Open questions at the time
    • Did not define molecular targets or partners
    • Did not explain dosage sensitivity mechanism
  2. 1999 High

    Showed TBX5 expression is graded and chamber-restricted, providing a spatial basis for the left-sided and septal cardiac defects of HOS.

    Evidence In situ hybridization in mouse and chick hearts correlated with human phenotype

    PMID:10373308

    Open questions at the time
    • Correlative, not functional
    • Mechanism establishing the gradient not defined
  3. 2000 Medium

    Demonstrated TBX5 directly specifies chamber-specific gene programs and global cardiac identity, beyond a role in septation alone.

    Evidence Dominant-negative Tbx5 in Xenopus and beta-MHC-driven ectopic ventricular expression in transgenic mice

    PMID:10079235 PMID:10864469

    Open questions at the time
    • Direct target genes not yet identified
    • Single-organism dominant-negative caveats
  4. 2001 High

    Defined the DNA-binding determinants and the first transcription-factor partner, explaining why distinct HOS mutations cause organ-selective phenotypes.

    Evidence Binding-site selection, EMSA, reporter assays, yeast two-hybrid and co-IP with NKX2-5; structural mapping to the Xbra T-box

    PMID:10077612 PMID:11431700 PMID:11555635

    Open questions at the time
    • Did not resolve whether DNA-binding and partner-interaction defects are separable
    • Structural inference based on Xbra not TBX5
  5. 2002 High

    Systematic mutational analysis separated two failure modes — loss of DNA binding versus loss of NKX2-5 synergy — and showed mutants mislocalize partly to cytoplasm.

    Evidence EMSA, co-IP, reporter assays, and immunofluorescence localization across seven HOS missense mutations

    PMID:12499378

    Open questions at the time
    • Mislocalization mechanism not yet linked to an NLS or anchor
    • Did not test all partner complexes
  6. 2002 High

    Defined TBX5 as essential for limb initiation and outgrowth, operating in a WNT→Tbx5→Fgf10 feedback circuit acting on mesodermal cell migration.

    Evidence Zebrafish heartstrings mutant, morpholino knockdown, and gain/loss-of-function epistasis in chick and zebrafish

    PMID:12066188 PMID:12223419 PMID:12399308

    Open questions at the time
    • Direct limb transcriptional targets not fully mapped
    • Cross-species relevance to mammalian forelimb assumed
  7. 2003 High

    Confirmed mammalian requirement for forelimb initiation and identified GATA4 as a second cooperative cardiac partner whose disease mutation disrupts the TBX5 interaction.

    Evidence Conditional mouse forelimb KO with chick misexpression; reciprocal co-IP/pull-down and reporter assays for GATA4

    PMID:12736217 PMID:12845333

    Open questions at the time
    • Did not define genome-wide GATA4-TBX5 cobound targets
    • Quantitative dosage contribution of each partner unclear
  8. 2004 High

    Mapped functional protein domains (transactivation aa339-379, KRK NLS aa325-327) and identified PDLIM7/LMP4 as a cytoskeletal anchor restraining nuclear TBX5 activity, plus MEF2C as a further partner.

    Evidence Deletion/point mutagenesis, GAL4 fusions, Y2H, co-IP, FRET, live-cell imaging, and reporter assays

    PMID:15087119 PMID:15302601 PMID:16880269 PMID:19204083

    Open questions at the time
    • Physiological signals controlling LMP4-mediated shuttling not defined
    • Whether anchoring is regulated developmentally unknown
  9. 2007 High

    Established a TBX5-NKX2-5-Id2 pathway required for ventricular conduction system specification, linking combinatorial transcription to a defined lineage.

    Evidence SAGE profiling, Id2-null mice, reporter assays, compound haploinsufficiency, and electrophysiology

    PMID:17604724

    Open questions at the time
    • Direct genomic Id2 enhancer occupancy in vivo not shown
    • Downstream conduction effectors not enumerated
  10. 2008 High

    Revealed that TBX5 gain-of-function (p.G125R) with enhanced DNA binding and target activation causes atrial fibrillation, establishing bidirectional dosage sensitivity, and that alternative splicing modulates GATA4 interaction.

    Evidence Reporter assays, EMSA, co-IP, localization, and clinical family analysis; RT-PCR and transgenic isoform studies

    PMID:18391012 PMID:18451335

    Open questions at the time
    • In vivo electrophysiological mechanism of G125R not yet defined (resolved later)
    • Isoform functional consequences only partially characterized
  11. 2010 High

    Solved the T-box domain crystal structures and connected direct transcriptional targets (Atp2a2/SERCA2a, Shox2-Bmp4) to TBX5 control of calcium handling and pacemaker development.

    Evidence X-ray crystallography, CD, ITC; Tbx5 haploinsufficient mice with promoter assays, calcium imaging, and ChIP

    PMID:18378906 PMID:20450920 PMID:20522556 PMID:20858598

    Open questions at the time
    • Structure lacked partner-bound complexes
    • Did not show how single targets integrate into network-level dosage effects
  12. 2012 High

    Defined direct, enhancer-level control of conduction (Scn5a/Cx40) and progenitor-pathway architecture for atrial septation (Hedgehog parallel role), and a requirement in lung specification.

    Evidence Mature-VCS and second-heart-field conditional KOs, ChIP, enhancer reporter mutagenesis, Hh rescue; conditional Tbx4/Tbx5 lung KO and enhancer-mutation CHD modeling

    PMID:22543974 PMID:22728936 PMID:22876201 PMID:22898775

    Open questions at the time
    • Full set of progenitor cell-cycle effectors incomplete
    • Tissue-specific cofactors at conduction enhancers not enumerated
  13. 2014 High

    Connected TBX5 directly to Hedgehog output (Foxf1a via GLI cooperativity) and to proepicardial/coronary vasculogenesis, integrating septation signaling with vascular development.

    Evidence TBX5 and GLI ChIP, reporter synergy, compound haploinsufficiency; proepicardial-specific KO with vascular and exercise phenotypes

    PMID:25245104 PMID:25356765

    Open questions at the time
    • Quantitative GLI-TBX5 cooperativity at single enhancers not resolved
    • Coronary defect's transcriptional targets in epicardium not mapped
  14. 2016 High

    Defined the incoherent feed-forward loop between TBX5 and its direct target PITX2 that sets atrial membrane-effector dosage, establishing the transcriptional logic underlying atrial fibrillation.

    Evidence Adult conditional Tbx5 KO, ECG, action potential and calcium-chelation rescue, compound Tbx5/Pitx2 epistasis; pSHF ChIP for Pcsk6

    PMID:26744331 PMID:27582060

    Open questions at the time
    • Precise stoichiometry of TBX5/PITX2 antagonism at each target unclear
    • Did not isolate the dominant arrhythmogenic effector
  15. 2018 High

    Placed TBX5 at the apex of a mesoderm-to-endoderm Wnt2/Wnt2b-RA-Shh signaling cascade required for pulmonary specification and downstream atrial septation.

    Evidence TBX5 ChIP-seq, conditional mouse KO, Xenopus knockdown, enhancer-reporter rescue in zebrafish; RA/Shh enhancer ChIP and epistasis

    PMID:30352852 PMID:34643182

    Open questions at the time
    • Feedback between Wnt/RA/Shh loops not fully ordered
    • Cell-population specificity of each enhancer not resolved
  16. 2019 High

    Identified the specific cellular mechanism of TBX5-deficient atrial fibrillation: reduced SERCA2a-mediated SR calcium uptake balanced by trans-sarcolemmal flux, generating triggered activity, rescuable by restoring SERCA function.

    Evidence Adult conditional KO with patch clamp, calcium imaging, optical mapping, and phospholamban-removal genetic rescue

    PMID:30896405

    Open questions at the time
    • Did not resolve which transcriptional targets dominate the SR/sarcolemmal imbalance
    • Translational reversibility window not defined here
  17. 2020 High

    Resolved TBX5 dosage effects to discrete cardiomyocyte subpopulations and validated MEF2C as a dosage-sensitive network node for ventricular septation using human and mouse genetics.

    Evidence TBX5-heterozygous human iPSC-CMs with single-cell RNA-seq and spatial transcriptomics, GRN analysis, and compound Tbx5/Mef2c mouse validation

    PMID:33321106

    Open questions at the time
    • Subpopulation-specific direct targets not exhaustively mapped
    • Human-mouse network conservation only partially tested
  18. 2021 High

    Demonstrated reversibility of TBX5-dependent disease: restoring TBX5 protein after arrhythmia onset re-establishes its direct transcriptome and ameliorates dysfunction, defining ongoing transcriptional maintenance roles.

    Evidence Ventricular conditional KO, RNA-seq, ChIP-validated targets, and AAV9-mediated TBX5 rescue with ECG monitoring

    PMID:32777030

    Open questions at the time
    • Durability and dosage precision of AAV rescue not fully characterized
    • Mechanism of transcriptome re-establishment at chromatin level not shown here
  19. 2022 High

    Showed TBX5 maintains adult atrial identity and arrhythmia susceptibility through enhancer chromatin architecture, and that distinct missense variants produce mechanistically separable channelopathies (Brugada, Long QT) via differential SCN5A/CAMK2D control.

    Evidence Atrial- and variant-knockin mouse models, snRNA/ATAC-seq, H3K27ac HiChIP/CUT&RUN, hiPSC-CM and HL-1 electrophysiology, and pharmacological (ranolazine) rescue

    PMID:33576403 PMID:35113653 PMID:38344303

    Open questions at the time
    • How TBX5 dosage sets specific loop anchors mechanistically unresolved
    • Generalizability of variant-specific channel mechanisms to other alleles unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TBX5 mechanistically reads dosage to selectively reconfigure enhancer cooperativity and chromatin looping in a partner- and tissue-specific manner remains unresolved.
  • No structure of TBX5 bound with partner transcription factors on composite enhancers
  • Mechanism converting small dosage changes into discrete chromatin-architecture shifts not defined
  • Signals controlling TBX5 nuclear availability in vivo not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-397014 Muscle contraction 3 R-HSA-4839726 Chromatin organization 2
Partners
GATA4MEF2CMYOCDNKX2-5PAX6PDLIM7PITX2TBX20

Evidence

Reading pass · 56 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 TBX5 is a T-box transcription factor whose mutations (including nonsense and missense mutations) cause Holt-Oram syndrome, establishing TBX5 as critical for limb and heart development; haploinsufficiency of TBX5 is sufficient to cause the syndrome. Genetic cloning, mutation identification in affected pedigrees, positional mapping to chromosome 12q24.1 Nature genetics High 8988165
2001 TBX5 physically interacts with NKX2-5 (cardiac homeobox protein); the interaction requires the N-terminal domain and N-terminal T-box of TBX5 and the homeodomain of NKX2-5. TBX5 and NKX2-5 together synergistically activate the NPPA (ANF) promoter. The HOS-causing cardiac missense mutation G80R abolishes this synergy, while the limb-predominant R237Q mutation does not. Yeast two-hybrid, GST pull-down, co-immunoprecipitation in COS-7 cells, co-transfection/luciferase reporter assays, overexpression in P19CL6 cells with functional differentiation readout Nature genetics High 11431700
2003 GATA4 physically interacts with TBX5; a HOS-associated GATA4 G296S missense mutation abrogates this interaction. Specific HOS-causing TBX5 missense mutations similarly disrupt the GATA4-TBX5 physical interaction, indicating cooperative transcriptional activation through this complex. Co-immunoprecipitation, GST pull-down, luciferase transcriptional assays, genetic linkage and sequencing Nature High 12845333
1999 TBX5 is expressed in a graded fashion in the developing heart: strong posteriorly and in the left ventricle but absent from the right ventricle and outflow tract. This chamber-specific expression pattern correlates with the cardiac defects observed in HOS (atrial septal defects, left-sided malformations). In situ hybridization in developing mouse and chick hearts; correlation with human HOS cardiac phenotype Developmental biology High 10373308
1999 HOS missense mutations at residue 80 (Gly80Arg) primarily cause cardiac malformations whereas mutations at residue 237 (Arg237Gln/Trp) primarily cause skeletal malformations; structural mapping to the Xbra T-box showed residue 80 contacts the major groove of target DNA while residue 237 contacts the minor groove, suggesting organ-specific TBX5 activity depends on biophysical interactions with different target DNA sequences. Clinical phenotype analysis of 10 HOS mutations correlated with structural modeling of TBX5 T-box based on Xbra crystal structure Proceedings of the National Academy of Sciences of the United States of America Medium 10077612
2001 TBX5 binds a specific 8 bp core DNA sequence (part of the Brachyury consensus binding site) including the full palindromic and half-palindrome Brachyury sites; amino acids 1-237 are required for DNA binding. HOS mutations G80R and R237Q eliminate binding to target DNA. TBX5 activates an ANF reporter construct in a T-box binding-site-dependent manner. In vitro binding site selection assay, EMSA, cell transfection/luciferase reporter, mutational analysis Human molecular genetics High 11555635
2002 Zebrafish tbx5 (heartstrings mutation, premature stop at aa316) is required for pectoral fin bud formation and for cardiac looping morphogenesis; homozygous mutants lack pectoral fins entirely and show progressive cardiac deterioration. Tbx5 functions very early in pectoral fin induction and coordinates fin outgrowth axes. Forward genetic screen, positional cloning, morpholino knockdown, in situ hybridization Development (Cambridge, England) High 12223419
2002 Tbx5 is required for formation of the pectoral fin bud in zebrafish; morpholino knockdown results in complete loss of pectoral fins through a defect in directed migration of lateral plate mesodermal cells into the limb-bud-producing region. Antisense morpholino knockdown, histological analysis of mesodermal cell migration in zebrafish Nature High 12066188
2003 Tbx5 is required for forelimb bud initiation in mouse (conditional knockout removes forelimb buds entirely). Additionally, dominant-negative and dominant-activated Tbx5 in chick demonstrate that Tbx5 is required at later stages for continued limb outgrowth. Limb outgrowth and limb identity specification are linked through Tbx5. Conditional knockout in mouse (forelimb mesenchyme), retroviral dominant-negative and dominant-activated Tbx5 misexpression in chick Development (Cambridge, England) High 12736217
2002 Tbx5 promotes limb initiation by functioning downstream of WNT signaling to regulate Fgf10; Fgf10 in turn maintains Tbx5 expression during limb outgrowth. Tbx5 and Wnt2b function together to initiate and specify forelimb outgrowth and identity. Gain- and loss-of-function experiments in zebrafish and chick; mutant analysis; pathway epistasis Development (Cambridge, England) High 12399308
2000 Tbx5 misexpression in chick induces dorsalization of the ventral eye and alters retinotectal projection topography, establishing Tbx5 as a topographic determinant for the visual projection between retina and tectum. Retroviral misexpression of Tbx5 in chick optic vesicle, retinal axon tracing Science (New York, N.Y.) Medium 10615048
2000 Dominant-negative Tbx5 in Xenopus embryos causes failure of heart development, establishing a global role for Tbx5 in cardiac specification beyond septation. Tbx5 is expressed in the early heart field posterior to Nkx2.5. Hormone-inducible dominant-negative Tbx5 in Xenopus embryos, in situ hybridization Development (Cambridge, England) Medium 10079235
2000 Ectopic Tbx5 expression in ventricular myocardium (driven by beta-MHC promoter in transgenic mice) suppresses ventricular-specific gene expression and retards ventricular chamber morphogenesis, demonstrating that Tbx5 directly controls chamber-specific gene programs. Transgenic mouse overexpression under beta-MHC promoter, molecular marker analysis, histology Developmental biology High 10864469
2001 TBX5 inhibits cardiomyocyte proliferation in vitro and in vivo; mutagenesis of the 5' T-box region (G80R) abolishes this anti-proliferative effect. This inhibition includes a non-cell-autonomous component in both cultured cells and transgenic chick hearts. In vitro overexpression in D17/MEQC cells, transgenic chick heart overexpression, PCNA analysis, co-culture assays Developmental biology Medium 11161571
2003 TBX5 misexpression throughout the ventricular myocardium prevents ventricular septum formation (single ventricle) and induces left ventricle-specific gene (ANF) in the right ventricle. A complementary right ventricular factor, chick Tbx20, is repressed by Tbx5 misexpression. Tbx5, Nkx2.5, and GATA4 synergistically activate the human ANF promoter; this is abrogated by Tbx20. Misexpression in chick and transient transgenic mouse, luciferase reporter assays, in situ hybridization Development (Cambridge, England) High 14573514
2002 Functional analysis of 7 HOS missense mutations shows: G80R, R237Q, R237W dramatically reduce TBX5 DNA-binding activity; Q49K, I54T, G169R, S252I have little effect on DNA binding but abolish synergistic transcriptional activation with NKX2-5. All 7 mutations greatly reduce TBX5-NKX2-5 interaction in vivo and in vitro. Wild-type TBX5 localizes exclusively to nucleus; mutants localize to both nucleus and cytoplasm. EMSA, co-immunoprecipitation, luciferase reporter assays, immunofluorescent localization in transfected cells The Journal of biological chemistry High 12499378
2004 TBX5 transactivating domain maps to amino acids 339-379 (C-terminal); point mutagenesis shows amino acids 349-351 are critical for transactivation. The nuclear localization signal (NLS) is identified as the KRK sequence at amino acids 325-327; deletion mislocalizes TBX5 to the cytoplasm. GAL4-TBX5 fusion in yeast one-hybrid, deletion mutagenesis, mammalian cell luciferase assays, cellular localization studies Gene High 15087119
2007 Tbx5 and Nkx2-5 cooperatively regulate the Id2 promoter (1.2 kb fragment) in vitro, and compound haploinsufficiency of Tbx5/Nkx2-5 or Tbx5/Id2 prevents embryonic specification of the ventricular conduction system, defining a Tbx5-Nkx2-5-Id2 molecular pathway for cardiac conduction system development. SAGE transcriptional profiling, Id2-null mice analysis, luciferase reporter with Tbx5+Nkx2-5, compound heterozygous mouse crosses, cardiac electrophysiology Cell High 17604724
2005 Tbx5 and Sall4 interact in a positive and negative feed-forward circuit: Tbx5 regulates Sall4 expression in the developing forelimb and heart; Sall4 heterozygosity produces limb and heart defects. Cooperative and antagonistic interactions between Tbx5 and Sall4 finely regulate patterning and morphogenesis. Mouse genetics (Sall4 gene trap heterozygotes), gene expression analysis, epistasis experiments, co-expression studies Nature genetics High 16380715
2008 GATA4 and Tbx5 genetically interact in vivo; compound Gata4/Tbx5 heterozygous mice show near-complete lethality with AV septal defects and myocardial thinning. Gata6 also interacts genetically with Tbx5. The Gata4-Tbx5 genetic interaction operates specifically in the myocardium (not endocardium). Gata4 and Tbx5 directly regulate Cdk4 expression while only Tbx5 activates Cdk2; cardiomyocyte proliferation is defective in compound heterozygotes. Compound heterozygous mouse crosses, cell-lineage-specific conditional knockouts, co-immunoprecipitation, ChIP, luciferase reporter assays Developmental biology High 19084512 24858909
2005 TBX5 and TBX20 physically interact; their interaction domains were mapped. Co-expression of Tbx5 and Tbx20 is not mutually dependent but they act synergistically in early heart development. The C-terminal of Tbx5 is a transcriptional activator while Tbx20 can repress; Tbx20 represses ANF promoter activation by Tbx5. Morpholino knockdown in Xenopus, co-immunoprecipitation, domain mapping, luciferase reporter assays Development (Cambridge, England) High 14978031 15634698
2004 TBX5 physically interacts with MEF2C through their DNA-binding domains; this interaction leads to synergistic activation of the alpha-cardiac myosin heavy chain (MYH6) promoter. HOS mutations G80R and R279X impair this synergy. Morpholino knockdown of Tbx5 and Mef2c in zebrafish reveals their genetic interaction is required for MYH6 expression and early heart development. Co-immunoprecipitation, FRET in live cells, luciferase reporter assays, morpholino knockdown in zebrafish Molecular and cellular biology High 19204083
2004 The LMP4/PDLIM7 PDZ-LIM protein binds exclusively to TBX5 and TBX4 (not TBX2 or TBX3) through distinct LIM domains. LMP4 tethers Tbx5 to the actin cytoskeleton and causes Tbx5 to shuttle dynamically between nucleus and cytoplasm, reducing its nuclear transcriptional activity on Fgf10 and ANF promoters. LMP4 acts as a repressor of Tbx5 transcriptional activity. Yeast two-hybrid, co-immunoprecipitation, subcellular localization (confocal, live cell), luciferase reporter assays, retroviral misexpression in chick The Journal of cell biology High 15302601 16880269
2009 Pdlim7/LMP4 regulates TBX5 nuclear/cytoplasmic distribution; Pdlim7 knockdown in zebrafish produces a non-looped heart similar to tbx5 heartstrings mutant. Loss of Pdlim7 causes no valve tissue formation while loss of Tbx5 causes increased valve tissue—opposing defects at the AV boundary. Pdlim7/Tbx5 interactions affect expression of Tbx5 target genes nppa and tbx2b at the AV boundary. Zebrafish morpholino knockdown, in situ hybridization, histological analysis of valve development Developmental biology Medium 19895804
2006 TBX5 is required for embryonic cardiac cell cycle progression; TBX5 depletion causes cell cycle arrest in late G1/early S-phase, reduces cardiac cell number, alters timing of differentiation, impairs sarcomere formation, and causes cardiomyocyte apoptosis. TBX5 is sufficient to determine the length of the embryonic cardiac cell cycle. TBX5 depletion in Xenopus by morpholino/dominant-negative, flow cytometry cell cycle analysis, TUNEL, immunostaining Development (Cambridge, England) Medium 16728474
2012 Tbx5 is required in the second heart field (SHF) for atrial septation; conditional Tbx5 haploinsufficiency in the SHF (but not myocardium or endocardium) causes atrial septal defects. Tbx5 mutant SHF progenitors show cell-cycle progression defects; Tbx5 regulates Cdk6 expression. Activated Hedgehog signaling rescues ASDs in Tbx5 mutant embryos, placing Tbx5 upstream or parallel to Hh in cardiac progenitors. Tbx5 regulates SHF Gas1 and Osr1 expression. Conditional knockout in mouse (SHF-specific, myocardium-specific, endocardium-specific Cre lines), rescue experiments with activated Hh signaling, cell cycle analysis Developmental cell High 22898775
2012 TBX5 directly drives Scn5a (Nav1.5) expression in the ventricular conduction system (VCS) via a TBX5-responsive enhancer downstream of Scn5a dependent on canonical T-box binding sites. Deletion of Tbx5 from mature VCS causes severe conduction defects, arrhythmias, and sudden death without altering VCS fate. Tbx5 also maintains Cx40 expression in the VCS. Conditional knockout in mature VCS, cardiac electrophysiology, ChIP, enhancer-reporter assay in vivo, T-box binding site mutagenesis The Journal of clinical investigation High 22728936
2010 Tbx5 haploinsufficiency in mouse causes impaired ventricular relaxation and reduced SERCA2a (Atp2a2) expression; Tbx5 directly activates the Atp2a2 promoter. Ca2+ uptake dynamics are impaired in Tbx5+/- cardiomyocytes. HOS patients also have diastolic filling abnormalities, defining a direct Tbx5-Atp2a2 pathway regulating cardiac diastolic function. Tbx5 haploinsufficient mouse model, echocardiography, calcium imaging, luciferase reporter assay with Atp2a2 promoter, human clinical data Proceedings of the National Academy of Sciences of the United States of America High 18378906
2010 Tbx5 is expressed in a subpopulation of endocardial cells; endocardial-specific deletion of Tbx5 causes fully penetrant atrial septal defects via increased apoptosis of Tbx5-null endocardial cells and neighboring Tbx5-positive myocardial cells through activation of endocardial NOS (Nos3). Compound Tbx5/Nos3 haploinsufficiency worsens cardiac phenotype. Endocardium-specific conditional knockout in mouse, TUNEL apoptosis assay, compound heterozygous crosses, immunohistochemistry Proceedings of the National Academy of Sciences of the United States of America High 20974940
2010 Shox2 directly activates Bmp4 gene transcription in the pacemaker region; Tbx5 regulates Shox2 expression in the inflow tract and cooperates with Nkx2.5 to regulate Shox2 and Bmp4, establishing a Tbx5-Shox2-Bmp4 molecular pathway in pacemaker development. ChIP, luciferase reporter assays, ectopic expression in Xenopus, siRNA knockdown in cardiomyocytes, Tbx5del/+ and Shox2-/- mouse models Human molecular genetics Medium 20858598
2008 A gain-of-function TBX5 p.G125R mutation shows enhanced DNA binding and significantly augmented activation of NPPA, Cx40, Kcnj2, and Tbx3 promoters; maintains normal Nkx2-5 interaction and correct nuclear targeting. This is associated with paroxysmal atrial fibrillation with mild skeletal phenotype, establishing that TBX5 gain-of-function can cause AF. Luciferase reporter assays, EMSA, co-immunoprecipitation, immunofluorescence localization, clinical family analysis Circulation research High 18451335
2010 TBX5 crystal structure of the T-box domain was solved in both DNA-unbound and DNA-bound forms. A 3(10)-helix at the C-terminus is an inducible recognition element that forms only upon DNA binding. Six HOS mutations in the T-box show reduced thermal stability and reduced DNA-binding affinity; G80R and W121G show the most severe destabilization. X-ray crystallography, circular dichroism, isothermal titration calorimetry Journal of molecular biology High 20450920
2008 Tbx5 generates alternatively spliced isoforms: a full-length 518-aa protein and a shorter C-terminally truncated isoform. The short isoform retains DNA binding but has altered GATA-4 interaction. The two isoforms are oppositely regulated and present in distinct DNA-binding complexes. The long isoform expression correlates with growth stimulation and promotes cardiac hypertrophy when re-expressed in postnatal transgenic mouse hearts. RT-PCR, co-immunoprecipitation, transgenic mouse overexpression, C2C12 cell overexpression with growth/death assays Molecular and cellular biology Medium 18391012
2009 Tbx5 directly induces expression of the beta2 CaMK-II (camk2b2) isoform; morpholino knockdown of camk2b2 phenocopies tbx5 morphant cardiac and fin defects (bradycardia, elongated heart, diminished pectoral fins). Ectopic cytosolic CaMK-II expression in tbx5 morphants rescues cardiac phenotype, establishing Tbx5-CaMK-II as a functional pathway in cardiac and fin morphogenesis. Zebrafish morpholino knockdown of camk2b2 and tbx5, ectopic CaMK-II rescue in tbx5 morphants, overexpression in mouse fibroblasts (CaMK-II quantification), expression analysis Developmental biology Medium 19345202
2010 Stat3 directly binds the Tbx5 promoter and activates Tbx5 expression in response to gp130 receptor activation; Tbx5 expression is dependent on Stat3 during P19CL6 cardiomyocyte differentiation, placing Stat3 upstream of Tbx5 in cardiac differentiation. ChIP, luciferase reporter assays, siRNA knockdown of Stat3, P19CL6 differentiation assay The Journal of biological chemistry Medium 20522556
2011 Myocardin physically interacts with TBX5 through the basic domain of myocardin and the coil domain of Tbx5; they synergistically activate cardiac-specific ANF and alpha-MHC (but not smooth muscle) gene expression in a TBE-binding-site-dependent manner. The HOS mutation Tbx5G80R fails to synergize with myocardin. Co-immunoprecipitation, luciferase reporter assays, domain mapping, mutagenesis in cell culture PloS one Medium 21897873
2014 Foxf1a and Foxf2 are TBX5 target genes in the second heart field: a Foxf1a cis-regulatory element binds TBX5 and GLI1/GLI3 in vivo; GLI1 and TBX5 synergistically activate this element in vitro. This molecular interaction explains the genetic interaction between Tbx5 and Hedgehog signaling for cardiac septation. Whole-genome transcriptional profiling, GLI-ChIP, TBX5 ChIP, luciferase reporter assays, compound haploinsufficiency mouse crosses PLoS genetics High 25356765
2016 Adult-specific deletion of Tbx5 causes spontaneous atrial fibrillation (AF) with action potential abnormalities rescued by calcium chelation. TBX5 directly activates PITX2, and TBX5 and PITX2 antagonistically regulate membrane effector genes Scn5a, Gja1, Ryr2, Dsp, and Atp2a2. Pitx2 haploinsufficiency rescues the AF and gene expression defects caused by Tbx5 haploinsufficiency, defining an incoherent feed-forward loop. Adult-specific conditional Tbx5 knockout, ECG, action potential recordings, calcium chelation rescue, compound Tbx5/Pitx2 haploinsufficiency, gene expression analysis Science translational medicine High 27582060
2018 TBX5 directly drives Wnt2 and Wnt2b expression in cardiopulmonary mesoderm via ChIP-identified cis-regulatory elements at Wnt2, initiating a mesoderm-to-endoderm Wnt signaling loop required for pulmonary endoderm specification and subsequent atrial septation. Tbx5 cooperates with Shh signaling to drive Wnt2b for lung morphogenesis. Conditional Tbx5 knockout in mice, Tbx5 knockdown in amphibians (Xenopus), TBX5 ChIP-sequencing, in vitro Wnt2 promoter assays, enhancer reporter rescue in zebrafish tbx5 mutants Proceedings of the National Academy of Sciences of the United States of America High 30352852
2019 TBX5 deficiency causes atrial fibrillation through decreased SERCA2a-mediated SR calcium uptake, balanced by enhanced trans-sarcolemmal calcium fluxes (Ica and NCX), creating triggered activity. Phospholamban removal (which normalizes SERCA function) rescues action potential defects, cardiomyocyte ectopy, and AF, directly linking TBX5 transcriptional control to SERCA2 activity and AF. Adult-specific conditional Tbx5 knockout, patch clamp electrophysiology, calcium imaging, genetic rescue (phospholamban removal), optical mapping eLife High 30896405
2020 TBX5 haploinsufficiency in human iPSC-derived cardiomyocytes causes dysregulation of TBX5-dependent pathways in discrete cardiomyocyte subpopulations. A genetic interaction between Tbx5 and Mef2c causing ventricular septation defects was validated in mice, establishing Mef2c as a TBX5 dosage-sensitive cardiac network node. Human iPSC cardiomyocyte differentiation with TBX5 heterozygous deletion, single-cell RNA-seq, spatial transcriptomics, GRN analysis, compound Tbx5/Mef2c heterozygous mouse validation Developmental cell High 33321106
2021 Tbx5 directly maintains expression of Aldh1a2 (RA-synthesizing enzyme) in the foregut lateral plate mesoderm via an evolutionarily conserved intronic enhancer. Tbx5/Aldh1a2-dependent RA signaling directly activates Shh transcription in the foregut endoderm through a conserved MACS1 enhancer, establishing a Tbx5-RA-Shh-Wnt signaling cascade for cardiopulmonary development. Xenopus and mouse conditional Tbx5 knockout, TBX5 ChIP on Aldh1a2 enhancer, shh enhancer ChIP, luciferase reporter assays, epistasis experiments eLife High 34643182
2022 TBX5 increases SCN5A transcription and represses CAMK2D and SPTBN4; p.F206L TBX5 fails to transactivate SCN5A (loss-of-function causing Brugada syndrome with reduced INa); p.D111Y TBX5 increases SCN5A but fails to repress CAMK2D/SPTBN4, leading to increased late INa and AP prolongation (Long QT syndrome). Ranolazine rescues the QT prolongation in p.D111Y mice. hiPSC-CM electrophysiology, HL-1 cell assays, transgenic mouse cardiomyocytes, luciferase reporter, ECG, pharmacological rescue Cardiovascular research High 33576403
2022 The TBX5-p.G125R gain-of-function variant in mice causes atrial arrhythmias with prolonged action potentials, decreased systolic/diastolic Ca2+ concentrations, and profound transcriptional deregulation (>1000 differentially expressed transcripts in cardiomyocytes). Epigenetic profiling shows thousands of TBX5-p.G125R-sensitive regulatory elements with increased chromatin accessibility occupied by Tbx5, suggesting altered DNA binding and cooperativity changes the atrial transcriptional regulatory network. Mouse knockin of TBX5-G125R, ECG, optical mapping, patch clamp, calcium measurements, single-nucleus RNA-seq, ATAC-seq, H3K27ac CUT&RUN, HiChIP Circulation High 35113653
2023 TBX5 is required in post-natal atrial cardiomyocytes to maintain atrial identity by binding to and preserving the chromatin architecture of atrial-specific enhancers. Atrial-specific Tbx5 KO downregulates atrial cardiomyocyte gene expression; 69% of control-enriched open chromatin regions are TBX5-bound. TBX5 dosage influences 510 chromatin loops including atrial enhancer anchors. Atrial-specific conditional Tbx5 knockout, single-nucleus RNA-seq plus ATAC-seq, H3K27ac HiChIP chromatin looping Nature cardiovascular research High 38344303
2015 Tbx5 and Osr1 interact genetically in the posterior SHF to regulate cell cycle progression (specifically G2/M phase entry) for cardiac septation; compound Tbx5/Osr1 haploinsufficiency causes increased AVSDs with reduced Cdk6 expression; disruption of Pten in atrial septum progenitors rescues the AVSDs. Osr1 expression in the pSHF depends on Tbx5 level before E10.5. Conditional compound haploinsufficiency in mouse, cell cycle analysis, Pten genetic rescue, cell fate mapping, immunohistochemistry Journal of molecular and cellular cardiology Medium 25986147
2016 Tbx5 directly regulates Pcsk6 in the posterior SHF as established by ChIP-qPCR and luciferase reporter assay, as part of a gene network module with Osr1 required for atrial septation. RNA-seq in pSHF of multiple mouse genotypes, ChIP-qPCR, luciferase reporter assay, human genetic study Human molecular genetics Medium 26744331
2004 TBX5 is expressed throughout the embryonic epicardium and coronary vasculature. Retrovirus-mediated Tbx5 overexpression inhibits proepicardial cell incorporation into the nascent epicardium; antisense knockdown also prevents proepicardial cell migration. This bidirectional sensitivity indicates Tbx5 regulates proepicardial cell migration, and proepicardial cells downregulate Tbx5 during normal migration. Immunohistochemistry of human embryonic tissue, retroviral overexpression and antisense knockdown in chick PEO, PEO explant culture Physiological genomics Medium 15138308
2014 Proepicardial-specific deletion of Tbx5 in mouse impairs epicardial attachment, delays epicardial-derived cell migration, reduces vascular smooth muscle cell recruitment, and causes defective coronary vasculogenesis with myocardial hypoxia and reduced exercise capacity. Conditional Tbx5 knockout (proepicardial-specific Cre), histology, immunostaining for epicardial-derived cells, HIF-1alpha expression, exercise testing Circulation research High 25245104
2012 Loss of Tbx5 in mouse lung mesenchyme leads to unilateral absence of lung bud specification and absence of tracheal specification in organ culture. Double Tbx4/Tbx5 conditional mutants show severe lung branching arrest with downregulation of Wnt2, Fgf10, Bmp4, and Spry2. Tbx4 and Tbx5 interact genetically with Fgf10 during lung growth and branching but not tracheal cartilage development. Conditional Tbx4/Tbx5 knockout using two different Cre lines, ex vivo organ culture, in situ hybridization, genetic interaction analysis PLoS genetics High 22876201
2014 A TBX5 enhancer ~90 kb downstream of TBX5 drives heart-restricted expression; a homozygous single-base-pair mutation in this enhancer found in an isolated CHD patient abrogates its ability to drive cardiac expression in both mouse and zebrafish transgenic models, demonstrating that non-coding regulatory mutations in TBX5 enhancers can cause isolated congenital heart disease without limb defects. Genomic/bioinformatic enhancer scanning, transgenic mouse and zebrafish enhancer reporter assays, enhancer mutation functional testing in vivo Human molecular genetics High 22543974
2004 Pax6 physically interacts with Tbx5 and cVax; Pax6 overexpression in chick optic cup expands Tbx5 and Bmp4 domains while reducing cVax. cVax and Tbx5 oppositely modulate Pax6 alpha-enhancer activity; Pax6/cVax interaction inhibits Pax6 transactivation. Together, Pax6, cVax, and Tbx5 mediate dorsoventral patterning of the eye. In ovo electroporation in chick, co-immunoprecipitation, luciferase reporter assays, in situ hybridization The Journal of biological chemistry Medium 15322073
2004 TBX5 is autoregulated; ectopically expressed TBX5 increases activity of its own promoter through TBE-B, TBE-C, and NKX2.5 binding sites in the 5'-flanking region. A GC box and T-box-like elements are functionally required for TBX5 promoter activity, as shown by site-directed mutagenesis, DNase footprinting, and EMSA. Site-directed mutagenesis, DNase I footprinting, EMSA, luciferase reporter assays, transient transfection Journal of cellular biochemistry Medium 15095414
2021 Ventricular-specific Tbx5 deletion in adult mice causes mild cardiac dysfunction, arrhythmias, and high mortality (60%) from sudden cardiac death. RNA-seq and ChIP identify 47 TBX5-controlled transcripts including Gja1, Kcnj5, Kcng2, Cacna1g, Chrm2 (conduction/contraction), Fhl2 (cardioprotection), and cytoskeletal genes. AAV9-mediated TBX5 protein normalization after arrhythmia development re-establishes TBX5-dependent transcriptome, reduces arrhythmia propensity, and ameliorates cardiac dysfunction. Conditional ventricular Tbx5 KO, RNA-seq, TBX5 ChIP, AAV9 rescue experiment, ECG monitoring Cardiovascular research High 32777030
2014 miR-10a and miR-10b directly target the 3'-UTR of TBX5 to repress TBX5 protein expression, establishing post-transcriptional regulation of TBX5 dosage. Luciferase 3'-UTR reporter assay, RT-qPCR, Western blot after miRNA mimic/inhibitor transfection Pediatric cardiology Medium 24714979
2012 Hox genes directly regulate Tbx5 forelimb-specific expression; the minimal regulatory element sufficient for forelimb-restricted Tbx5 expression is Hox-responsive. Hoxc9 (expressed in caudal LPM) forms a repressive complex on the Tbx5 forelimb regulatory element through two protein domains, while Hox proteins in rostral LPM form activating complexes, achieving positional restriction of Tbx5. Transgenic mouse enhancer-reporter assays, electroporation, ChIP, mutagenesis of Hox binding sites, in vitro transcriptional assays Development (Cambridge, England) High 22872086 24651482

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 922 12845333
1997 Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. Nature genetics 843 8988165
1996 Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Developmental dynamics : an official publication of the American Association of Anatomists 531 8853987
2001 Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nature genetics 455 11431700
1999 Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. Developmental biology 374 10373308
1999 Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proceedings of the National Academy of Sciences of the United States of America 282 10077612
2002 The heartstrings mutation in zebrafish causes heart/fin Tbx5 deficiency syndrome. Development (Cambridge, England) 237 12223419
1999 The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature 234 10235264
2007 A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development. Cell 223 17604724
2012 Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5. Circulation research 212 22931955
2000 Tbx5 and the retinotectum projection. Science (New York, N.Y.) 205 10615048
1999 Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds. Nature 205 10235263
2014 Stoichiometry of Gata4, Mef2c, and Tbx5 influences the efficiency and quality of induced cardiac myocyte reprogramming. Circulation research 194 25416133
2003 Tbx5 is required for forelimb bud formation and continued outgrowth. Development (Cambridge, England) 189 12736217
2002 The limb identity gene Tbx5 promotes limb initiation by interacting with Wnt2b and Fgf10. Development (Cambridge, England) 183 12399308
1999 Tbx5 is essential for heart development. Development (Cambridge, England) 183 10079235
2002 T-box gene tbx5 is essential for formation of the pectoral limb bud. Nature 179 12066188
2000 Expression of chick Tbx-2, Tbx-3, and Tbx-5 genes during early heart development: evidence for BMP2 induction of Tbx2. Developmental biology 171 11087629
2012 Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Human molecular genetics 170 22543974
2008 Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. Developmental biology 160 19084512
2012 Multiple roles and interactions of Tbx4 and Tbx5 in development of the respiratory system. PLoS genetics 158 22876201
2000 Ventricular expression of tbx5 inhibits normal heart chamber development. Developmental biology 154 10864469
2008 A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation. Circulation research 145 18451335
1998 Involvement of T-box genes Tbx2-Tbx5 in vertebrate limb specification and development. Development (Cambridge, England) 144 9609833
1998 Expression of T-box genes Tbx2-Tbx5 during chick organogenesis. Mechanisms of development 140 9651516
2005 Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Nature genetics 137 16380715
2003 Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis. Development (Cambridge, England) 133 14573514
2013 Transcription factors MYOCD, SRF, Mesp1 and SMARCD3 enhance the cardio-inducing effect of GATA4, TBX5, and MEF2C during direct cellular reprogramming. PloS one 127 23704920
2012 Tbx5-hedgehog molecular networks are essential in the second heart field for atrial septation. Developmental cell 125 22898775
2012 TBX5 drives Scn5a expression to regulate cardiac conduction system function. The Journal of clinical investigation 124 22728936
2016 Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm. Science translational medicine 123 27582060
2004 TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed. Current opinion in cardiology 123 15096952
2001 Characterization of the TBX5 binding site and analysis of mutations that cause Holt-Oram syndrome. Human molecular genetics 120 11555635
2005 Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth. Developmental cell 119 15621531
2005 Tbx5 and Tbx20 act synergistically to control vertebrate heart morphogenesis. Development (Cambridge, England) 114 15634698
2004 Differential expression and function of Tbx5 and Tbx20 in cardiac development. The Journal of biological chemistry 107 14978031
2005 TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatric research 101 16183809
2009 Physical interaction between TBX5 and MEF2C is required for early heart development. Molecular and cellular biology 97 19204083
1998 Correlation of wing-leg identity in ectopic FGF-induced chimeric limbs with the differential expression of chick Tbx5 and Tbx4. Development (Cambridge, England) 97 9389663
2001 TBX5 transcription factor regulates cell proliferation during cardiogenesis. Developmental biology 96 11161571
2014 Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus. Gastroenterology 92 25447851
2003 Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype. American journal of human genetics 92 12789647
2020 Modeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease. Developmental cell 91 33321106
2010 Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart. Human molecular genetics 91 20858598
2002 Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome. The Journal of biological chemistry 90 12499378
2004 A role for Tbx5 in proepicardial cell migration during cardiogenesis. Physiological genomics 76 15138308
2011 Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations. Congenital heart disease 75 22011241
2004 TBX5 mutations in non-Holt-Oram syndrome (HOS) malformed hearts. Human mutation 73 15221798
2014 Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation. PLoS genetics 72 25356765
2000 Identification and localization of TBX5 transcription factor during human cardiac morphogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 69 10974675
2000 Conserved and divergent expression of T-box genes Tbx2-Tbx5 in Xenopus. Mechanisms of development 68 10704879
2012 Hox genes regulate the onset of Tbx5 expression in the forelimb. Development (Cambridge, England) 65 22872086
2004 Tbx5 and Tbx4 transcription factors interact with a new chicken PDZ-LIM protein in limb and heart development. Developmental biology 62 15302601
2010 An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation. Proceedings of the National Academy of Sciences of the United States of America 60 20974940
2006 TBX5 is required for embryonic cardiac cell cycle progression. Development (Cambridge, England) 58 16728474
2008 Tbx5-dependent pathway regulating diastolic function in congenital heart disease. Proceedings of the National Academy of Sciences of the United States of America 56 18378906
1999 Differential expression of Tbx4 and Tbx5 in Zebrafish fin buds. Mechanisms of development 55 10495283
2018 Evolutionarily conserved Tbx5-Wnt2/2b pathway orchestrates cardiopulmonary development. Proceedings of the National Academy of Sciences of the United States of America 54 30352852
2014 Disruption of myocardial Gata4 and Tbx5 results in defects in cardiomyocyte proliferation and atrioventricular septation. Human molecular genetics 52 24858909
2006 sall4 acts downstream of tbx5 and is required for pectoral fin outgrowth. Development (Cambridge, England) 52 16501170
2010 Stat3 directly controls the expression of Tbx5, Nkx2.5, and GATA4 and is essential for cardiomyocyte differentiation of P19CL6 cells. The Journal of biological chemistry 48 20522556
2009 Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart atrio-ventricular boundary and valve formation. Developmental biology 47 19895804
2017 Down-regulation of miR-10a-5p in synoviocytes contributes to TBX5-controlled joint inflammation. Journal of cellular and molecular medicine 46 28782180
2014 Identification of TBX5 mutations in a series of 94 patients with Tetralogy of Fallot. American journal of medical genetics. Part A 46 25263169
2015 TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy. Biochemical and biophysical research communications 45 25725155
2015 Molecular basis of the clinical features of Holt-Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications. Gene 44 25680289
2010 Structural basis of TBX5-DNA recognition: the T-box domain in its DNA-bound and -unbound form. Journal of molecular biology 43 20450920
2008 Distinct expression and function of alternatively spliced Tbx5 isoforms in cell growth and differentiation. Molecular and cellular biology 42 18391012
2002 Different regulation of T-box genes Tbx4 and Tbx5 during limb development and limb regeneration. Developmental biology 41 12376111
2014 A combination of activation and repression by a colinear Hox code controls forelimb-restricted expression of Tbx5 and reveals Hox protein specificity. PLoS genetics 40 24651482
2004 Identification of the TBX5 transactivating domain and the nuclear localization signal. Gene 40 15087119
2016 TBX5 mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians. Cardiovascular research 39 26762269
2014 Regulatory modulation of the T-box gene Tbx5 links development, evolution, and adaptation of the sternum. Proceedings of the National Academy of Sciences of the United States of America 38 25468972
2019 A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice. eLife 37 30896405
2018 Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants. European journal of human genetics : EJHG 37 30552424
2015 Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation. Journal of molecular and cellular cardiology 37 25986147
2004 Pax6 interacts with cVax and Tbx5 to establish the dorsoventral boundary of the developing eye. The Journal of biological chemistry 37 15322073
2000 Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome. American journal of medical genetics 37 10842287
2022 Patient-Specific TBX5-G125R Variant Induces Profound Transcriptional Deregulation and Atrial Dysfunction. Circulation 34 35113653
2016 Regulatory evolution of Tbx5 and the origin of paired appendages. Proceedings of the National Academy of Sciences of the United States of America 34 27503876
2009 Tbx5-mediated expression of Ca(2+)/calmodulin-dependent protein kinase II is necessary for zebrafish cardiac and pectoral fin morphogenesis. Developmental biology 33 19345202
2014 Tbx5 is required for avian and Mammalian epicardial formation and coronary vasculogenesis. Circulation research 32 25245104
2006 LMP4 regulates Tbx5 protein subcellular localization and activity. The Journal of cell biology 31 16880269
2021 Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis. Annals of the rheumatic diseases 30 34750102
2015 A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy. International journal of molecular medicine 30 25963046
2011 Synergistic activation of cardiac genes by myocardin and Tbx5. PloS one 30 21897873
2005 The human TBX5 gene mutation database. Human mutation 30 16134140
2020 Mutations Upstream of the TBX5 and PITX1 Transcription Factor Genes Are Associated with Feathered Legs in the Domestic Chicken. Molecular biology and evolution 29 32344431
2017 A HAND to TBX5 Explains the Link Between Thalidomide and Cardiac Diseases. Scientific reports 29 28469241
2013 Zebrafish tbx5 paralogs demonstrate independent essential requirements in cardiac and pectoral fin development. Developmental dynamics : an official publication of the American Association of Anatomists 29 23441045
2012 Cardiac gene activation analysis in mammalian non-myoblasic cells by Nkx2-5, Tbx5, Gata4 and Myocd. PloS one 29 23144723
2016 Gene network and familial analyses uncover a gene network involving Tbx5/Osr1/Pcsk6 interaction in the second heart field for atrial septation. Human molecular genetics 28 26744331
2006 Developmental expression patterns of Tbx1, Tbx2, Tbx5, and Tbx20 in Xenopus tropicalis. Developmental dynamics : an official publication of the American Association of Anatomists 28 16477648
2004 TBX5, a gene mutated in Holt-Oram syndrome, is regulated through a GC box and T-box binding elements (TBEs). Journal of cellular biochemistry 27 15095414
2022 Tbx5 variants disrupt Nav1.5 function differently in patients diagnosed with Brugada or Long QT Syndrome. Cardiovascular research 26 33576403
2009 Identification and characterisation of the developmental expression pattern of tbx5b, a novel tbx5 gene in zebrafish. Gene expression patterns : GEP 26 19925885
2023 Tbx5 maintains atrial identity in post-natal cardiomyocytes by regulating an atrial-specific enhancer network. Nature cardiovascular research 25 38344303
2021 Preclinical evidence for the therapeutic value of TBX5 normalization in arrhythmia control. Cardiovascular research 25 32777030
2014 miR-10a and miR-10b target the 3'-untranslated region of TBX5 to repress its expression. Pediatric cardiology 25 24714979
2021 Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development. eLife 24 34643182

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