Affinage

TBX18

T-box transcription factor TBX18 · UniProt O95935

Length
607 aa
Mass
64.8 kDa
Annotated
2026-06-10
63 papers in source corpus 28 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBX18 is a T-box transcription factor that acts predominantly as a transcriptional repressor to control the differentiation and lineage specification of mesenchymal progenitors across multiple organ systems, including somites, the venous pole and pacemaker myocardium of the heart, ureteric mesenchyme, otic fibrocytes, prostate stroma, and aortic smooth muscle (PMID:15155583, PMID:17584735, PMID:19096026, PMID:18353863, PMID:27120339, PMID:41263385). Biochemically, TBX18 homo- and heterodimerizes (with TBX15), binds combinations of T half-sites, and represses transcription in a Groucho-corepressor-dependent manner, competing with activating T-box proteins such as TBX5 at shared promoters (PMID:17584735); its repressive activity is tuned by cofactors, being enhanced by CBFB, CHD7, and IKZF2 and relieved by NCOA5 and SBNO2, and it associates with the CoREST-complex component ZMYM2 (PMID:30071041, PMID:34935912). In the heart, TBX18 marks an Nkx2-5-negative progenitor lineage that builds the sinus horns and the sinoatrial node head, acting upstream of TBX3 in the pacemaker specification hierarchy, and it directly represses the Cx43 promoter to uncouple cells electrically while reprogramming working cardiomyocytes toward a pacemaker phenotype with altered HCN-channel expression (PMID:16709898, PMID:19096026, PMID:21205823, PMID:23242162, PMID:30259525). In the urogenital tract it is required cell-autonomously within the ureteric mesenchymal lineage to suppress a renal stromal fate and drive smooth muscle differentiation, partnering with SIX1 (PMID:16511601, PMID:20110314, PMID:23685333); dominant-negative TBX18 mutations that impair DNA binding or repression cause human congenital anomalies of the kidney and urinary tract (CAKUT) (PMID:26235987). TBX18 also genetically and physically cooperates with PAX3 to maintain anterior somite identity and bidirectionally controls epicardial epithelial-mesenchymal transition through direct regulation of the Slug promoter alongside WT1 (PMID:18644785, PMID:23469079).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 Medium

    Establishing TBX18 as a distinct human T-box family member and mapping its locus provided the molecular identity needed for all subsequent functional work.

    Evidence Radiation hybrid mapping and phylogenomic analysis placing TBX18 in the Tbx1 subfamily at 6q14-q15

    PMID:9888994

    Open questions at the time
    • No functional or expression data established
    • Family assignment did not predict molecular activity
  2. 2001 Medium

    Defining the embryonic expression domains of Tbx18 (proepicardium/epicardium, paraxial/presomitic mesoderm, anterior somite, genital ridge, limb bud) framed where the factor might act developmentally.

    Evidence Expression cloning and in situ hybridization in mouse embryos

    PMID:11118889

    Open questions at the time
    • Expression does not establish requirement
    • No molecular mechanism or targets defined
  3. 2004 High

    Loss-of-function genetics showed Tbx18 maintains anterior-posterior somite polarity downstream of Mesp2/Notch, giving the first in vivo requirement and placing it in a patterning hierarchy.

    Evidence Tbx18 knockout mouse with histological/molecular analysis and ectopic expression

    PMID:15155583

    Open questions at the time
    • Direct transcriptional targets in somites not identified
    • Antiapoptotic mechanism not molecularly resolved
  4. 2006 High

    Knockouts revealed parallel roles for Tbx18 in building sinus horn myocardium from an Nkx2-5-negative progenitor lineage and in ureteric mesenchyme smooth muscle differentiation, defining its function as a driver of mesenchymal cell fate.

    Evidence Tbx18-null mice with lineage tracing, histology, and smooth muscle marker immunostaining

    PMID:16511601 PMID:16709898

    Open questions at the time
    • Direct target genes in these tissues not yet identified
    • Cell-autonomy versus signaling dependence unresolved at this stage
  5. 2007 High

    Biochemistry established the core molecular activity: Tbx18 dimerizes, binds T half-sites, represses transcription via Groucho, antagonizes activating T-box proteins, and physically binds Gata4 and Nkx2-5.

    Evidence Reporter assays, GST pull-down, co-IP, dimerization assays, and in vivo misexpression

    PMID:17584735

    Open questions at the time
    • Endogenous direct target promoters not mapped genome-wide
    • Relative contributions of Groucho versus other corepressors unknown
  6. 2008 High

    Reciprocal genetics ordered the pacemaker hierarchy (Tbx18 upstream of Tbx3) and identified physical/genetic partners Pax3 (somites) and tissue-specific roles in otic fibrocyte/stria vascularis formation, broadening the partner and organ repertoire.

    Evidence Lineage tracing, reciprocal knockouts, explant assays, co-IP, double-mutant epistasis, and transgenic rescue with auditory phenotyping

    PMID:18353863 PMID:18644785 PMID:19096026

    Open questions at the time
    • Molecular basis of the Tbx18-to-Tbx3 handoff not defined
    • Direct otic and SAN target genes not identified
  7. 2009 Medium

    Demonstrating myocardial Tbx18 expression cautioned against interpreting Tbx18-Cre lineage tracing as proof of an exclusive epicardial cardiomyocyte origin, refining how the gene's lineage tools are read.

    Evidence In situ hybridization and immunostaining in mouse embryonic myocardium

    PMID:19369973

    Open questions at the time
    • Does not address Tbx18 function in myocardium
    • No mechanistic claim
  8. 2011 High

    Identifying Cx43 as a direct repressed target connected TBX18 transcriptional repression to a physiological output—electrical uncoupling that mimics the sinoatrial node.

    Evidence Adenoviral overexpression in cardiomyocytes, promoter-reporter, dye transfer, Ca2+ imaging, and conduction velocity measurement

    PMID:21205823

    Open questions at the time
    • Direct promoter occupancy at endogenous Cx43 locus not shown by ChIP here
    • Selectivity for Cx43 over Cx40/Cx45 mechanism unexplained
  9. 2012 High

    Forced Tbx18 expression reprogrammed ventricular myocytes into functional pacemaker cells in vitro and in vivo, establishing Tbx18 as a master regulator sufficient to impose pacemaker identity in this context, while a separate study showed it is dispensable for normal epicardium yet represses premature SMC differentiation via Notch/TGFβ.

    Evidence Adenoviral gene transfer with patch-clamp, epigenetic and morphological analysis, telemetry; plus conditional KO and Tbx18VP16 misexpression with pharmacological rescue

    PMID:22926762 PMID:23242162

    Open questions at the time
    • Direct targets mediating automaticity not fully enumerated
    • Degree of reprogramming versus partial phenotype debated by later studies
  10. 2013 High

    Mechanistic dissection refined TBX18 as a context-dependent repressor controlling coronary plexus remodeling (SRF/CArG-dependent repression), epicardial EMT (direct Slug promoter regulation opposing Wt1), and ureteric mesenchyme prepatterning for epithelial signal responsiveness.

    Evidence Knockouts, ChIP, promoter-reporter assays, tissue recombination, and DiI labeling

    PMID:23469079 PMID:23685333 PMID:24016759

    Open questions at the time
    • Integration of repressor and direct-activation activities not unified
    • Signals prepatterning ureteric mesenchyme not molecularly identified
  11. 2015 High

    Patient mutation analysis proved that intact TBX18 DNA binding and repression are required for human ureter development, linking the gene causally to CAKUT through dominant-negative alleles.

    Evidence Whole exome sequencing with dimerization, stability, repression, and DNA-binding assays

    PMID:26235987

    Open questions at the time
    • Full spectrum of disease-relevant target genes not defined
    • Mechanism of mutant protein stabilization unresolved
  12. 2016 High

    Chamber misexpression studies established the limit of TBX18 sufficiency: it suppresses working myocardial genes and represses Pitx2 but cannot impose the full SAN gene signature in fetal chamber cardiomyocytes, and it is also required for prostate periductal smooth muscle differentiation.

    Evidence Conditional chamber-specific misexpression and prostate knockout/hypomorph models with molecular phenotyping

    PMID:27120339 PMID:27180262

    Open questions at the time
    • Cofactors needed beyond TBX18 for full SAN program unknown
    • Direct prostate stromal targets not mapped
  13. 2018 High

    Unbiased proteomics and gene transfer defined the TBX18 cofactor network (CBFB, CHD7, IKZF2, NCOA5, SBNO2, homeobox proteins) tuning its repression and identified an HCN2-isoform switch as the molecular basis of TBX18-driven pacemaker rate.

    Evidence Tandem affinity purification/LC-MS with reporter assays; gene transfer with electrophysiology and computational modeling

    PMID:30071041 PMID:30259525

    Open questions at the time
    • Which cofactors operate in which tissues not resolved
    • Whether HCN2 switch is a direct transcriptional effect unclear
  14. 2022 High

    Endogenous interactome and omics work linked TBX18 to the CoREST corepressor via ZMYM2 and showed reprogramming entails genome-wide proteome remodeling driven partly by induction of EMT transcription factors, deepening the mechanistic picture of pacemaker conversion.

    Evidence CRISPR endogenous tagging/affinity-MS with co-IP validation; tandem mass tag proteomics and RNAseq with network analysis

    PMID:34935912 PMID:36006872

    Open questions at the time
    • Functional requirement of ZMYM2/CoREST for TBX18 repression in vivo not tested
    • Causal hierarchy among induced EMT factors unresolved
  15. 2023 High

    In esophageal squamous carcinoma, TBX18 acts as a direct transcriptional activator of CHN1 to elevate RhoA activity and radiation-induced autophagy, showing a context-dependent activating role distinct from its developmental repressor function.

    Evidence Dual-luciferase reporter, ChIP, GST pull-down, and knockdown/overexpression in cells and xenografts

    PMID:37399907

    Open questions at the time
    • Why TBX18 activates rather than represses CHN1 not explained
    • Cofactor switch enabling activation not identified
  16. 2025 High

    ChIP-seq and staged conditional ablation established a direct role for TBX18 in aortic smooth muscle homeostasis, binding genes such as EGR1/FOS/JUNB, with adult loss exacerbating Marfan-driven aortic degeneration; a parallel preprint reported that non-fibrogenic TBX18 levels suppress working myocardial genes but fail to induce a pacemaker program.

    Evidence ChIP-seq in human aortic SMCs with embryonic and adult conditional KO and multiomics; AAV gene transfer with electrophysiology (preprint)

    PMID:41263385

    Open questions at the time
    • Direct versus indirect contribution of EGR1/FOS/JUNB to aortic phenotype not separated
    • Dose-dependence of pacemaker induction not reconciled with earlier sufficiency claims
  17. 2026 Medium

    Extending Cx43 repression to human atrial fibroblasts, miR-1 was shown to lower TBX18 protein via its 3'-UTR, de-repressing Cx43, integrating microRNA control with TBX18 transcriptional output.

    Evidence Luciferase 3'-UTR and promoter reporters, miR-1 overexpression/antagomiR, and Tbx18 siRNA in human atrial fibroblasts

    PMID:41608281

    Open questions at the time
    • Physiological relevance in intact tissue not established
    • Whether Cx43 repression is direct in fibroblasts not confirmed by ChIP

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved why TBX18 functions as a repressor in development yet a direct activator in cancer, and what determines the cofactor and dosage thresholds that govern full versus partial pacemaker reprogramming.
  • No unified model of repressor-to-activator switching
  • Tissue-specific cofactor requirements not systematically mapped
  • Dose thresholds for pacemaker conversion in vivo unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 7 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1643685 Disease 2
Partners
CBFBCHD7GATA4NKX2-5PAX3SIX1TBX15ZMYM2
Complex memberships
CoREST complex (via ZMYM2)

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Tbx18 is expressed most prominently in the proepicardial organ and epicardium during mouse development, as well as in cranial paraxial mesoderm, presomitic mesoderm, anterior somite half, genital ridge, and developing limb buds, establishing its tissue-specific expression pattern. Expression cloning and in situ hybridization Mechanisms of development Medium 11118889
1999 Human TBX18 was identified as a novel member of the Tbx1 subfamily of T-box transcription factors and mapped to chromosome 6q14-q15 by radiation hybrid mapping. Radiation hybrid mapping, phylogenomic analysis Genomics Medium 9888994
2004 Tbx18 is required to maintain anterior-posterior somite polarity: Tbx18-deficient mice show expansion of posterior lateral sclerotome derivatives (pedicles, transverse processes, proximal ribs), with posterior cells invading the anterior somite half during maturation. Tbx18 acts downstream of Mesp2 and Delta/Notch signaling as an antiapoptotic factor in anterior lateral sclerotome. Loss-of-function mouse genetics (Tbx18 knockout), histological and molecular analysis, ectopic expression experiments Genes & development High 15155583
2006 Tbx18 is required for formation of the myocardial sinus horns at the venous pole of the heart. In Tbx18-deficient mice, mesenchymal cells of the septum transversum/pericardial mesenchyme fail to differentiate into sinus horn myocardium. This precursor population is Nkx2-5-negative, defining a novel Nkx2-5-negative heart progenitor lineage. Tbx18 knockout mouse genetics, genetic lineage analysis, in situ hybridization, histology Circulation research High 16709898
2006 Tbx18 is required for development of the ureteral mesenchyme: in Tbx18-null mice, prospective ureteral mesenchymal cells mis-localize to the kidney surface, show reduced proliferation, and fail to differentiate into smooth muscle cells, instead becoming fibrous/ligamentous tissue, resulting in hydroureter and hydronephrosis. Tbx18 knockout mouse genetics, histology, immunostaining for smooth muscle markers The Journal of clinical investigation High 16511601
2007 Tbx18 and Tbx15 proteins (1) homo- and heterodimerize, (2) bind to various combinations of T half-sites on DNA, (3) repress transcription in a Groucho corepressor-dependent manner, (4) interact physically with Gata4 and Nkx2-5, and (5) compete with activating T-box protein Tbx5 for activation of the Natriuretic peptide precursor type a (Nppa) promoter. Ectopic Tbx18 in vivo down-regulates Tbx6-activated Delta-like 1 expression in somitic mesoderm. Reporter assays, GST pull-down, co-immunoprecipitation, dimerization assays, in vivo misexpression The Journal of biological chemistry High 17584735
2008 Tbx18-expressing mesenchymal progenitors in the inflow tract differentiate into pacemaker myocardium to form the sinoatrial node (SAN) head. Tbx18 is required to establish the large SAN head structure from mesenchymal precursors, whereas Tbx3 subsequently imposes the pacemaker gene program (including suppression of Cx40 and atrial genes) on the formed structure, defining a functional epistatic order: Tbx18 acts upstream of Tbx3 in SAN formation. Genetic lineage tracing, Tbx18 and Tbx3 knockout mouse genetics, explant assays, immunostaining, electrophysiology Circulation research High 19096026
2008 Tbx18 protein physically interacts with the paired box transcription factor Pax3, and loss of Pax3 function enhances the vertebral defects seen in Tbx18 mutant mice (gain of posterior somite-derived vertebral elements), demonstrating cooperative genetic interaction in maintaining anterior somite half identity. Pax3 and Tbx18 are co-expressed in the anterior presomitic mesoderm and early somites. Co-immunoprecipitation, genetic epistasis (Tbx18/Pax3 double mutants), in situ hybridization The Journal of biological chemistry High 18644785
2008 Tbx18 expression in the developing inner ear is restricted to otic mesenchyme fated to become fibrocytes. Tbx18-deficient mice exhibit profound deafness due to loss of endocochlear potential, failure of otic fibrocytes to form the basal cell layer of the stria vascularis (by defective mesenchymal-epithelial transition), and disrupted lineage restriction/boundary formation in otic mesenchyme. Transgenic rescue of perinatal lethality, auditory brainstem response, histology, lineage tracing Development (Cambridge, England) High 18353863
2009 Tbx18 is itself expressed in the myocardium (not exclusively epicardium), demonstrating that genetic lineage tracing systems using Tbx18-Cre do not permit conclusions about an exclusive epicardial origin of cardiomyocytes in vivo. In situ hybridization and immunostaining in mouse embryos Nature Medium 19369973
2010 Six1 and Tbx18 genetically interact synergistically to regulate ureteral smooth muscle cell development. Six1 and Tbx18 gene products form a physical protein complex in cultured cells and in the developing ureter. Two missense mutations in SIX1 from BOR syndrome patients reduced or abolished SIX1-TBX18 complex formation. Co-immunoprecipitation, genetic epistasis (Six1/Tbx18 double mutants), rescue experiments, analysis of patient mutations Development (Cambridge, England) High 20110314
2011 TBX18 directly represses the Cx43 (connexin 43) promoter, specifically down-regulating Cx43 transcript and protein in cardiomyocytes while leaving Cx45 and Cx40 levels unchanged. This Cx43 suppression leads to electrical uncoupling (slowed dye transfer, asynchronous Ca2+ oscillations, >50% reduction in conduction velocity), recapitulating a key phenotypic hallmark of the sinoatrial node. Adenoviral overexpression in neonatal rat cardiomyocytes, promoter-reporter assay, western blot, calcein dye transfer assay, Ca2+ imaging, conduction velocity measurement, in vivo injection The Journal of biological chemistry High 21205823
2012 Forced expression of Tbx18 in rodent ventricular cardiomyocytes (in vitro and in vivo) converts them to induced sinoatrial node (iSAN) pacemaker cells, acquiring spontaneous electrical firing, tapering morphology, epigenetic changes characteristic of SAN cells, and functional automaticity. In vivo Tbx18 gene transfer in guinea-pig ventricle yields ectopic pacemaker activity correcting bradycardia. Adenoviral gene transfer in neonatal rat cardiomyocytes and guinea-pig hearts, patch-clamp electrophysiology, morphological and epigenetic analysis, telemetry Nature biotechnology High 23242162
2012 Tbx18 is dispensable for normal epicardial development (epicardium forms, undergoes EMT, differentiates into smooth muscle cells and fibroblasts, forms normal coronary vasculature in Tbx18-null mice). However, expression of a transcriptional activator version (Tbx18VP16) in epicardium causes premature smooth muscle differentiation, which is reversed by inhibition of Notch and TGFβ receptor signaling, suggesting a repressive T-box function prevents premature SMC differentiation by repressing these pathways. Tbx18 conditional knockout, transgenic misexpression (Tbx18VP16), explant cultures with Notch/TGFβ inhibitors, molecular analysis Cardiovascular research High 22926762
2013 Tbx18 controls critical early steps in coronary development including epicardial integrity and coronary vascular plexus remodeling. Tbx18-deficient epicardium contains cyst-like protrusions overlying a disorganized vascular plexus. Tbx18 possesses SRF/CArG box-dependent repressor activity capable of inhibiting progenitor cell differentiation into smooth muscle cells. Tbx18 knockout mouse genetics, PECAM-1 immunostaining, vascular casts, gene expression profiling, reporter assays for repressor activity Developmental biology High 24016759
2013 Tbx18 and Wt1 bi-directionally control epicardial EMT through their opposing effects on Slug expression. Tbx18 knockdown inhibits EMT and reduces Slug expression, while Wt1 knockdown induces EMT and increases Slug. Both factors directly bind the Slug promoter as shown by ChIP and promoter assays. siRNA knockdown, ChIP, promoter-reporter assay, migration assay, immunostaining in murine primary epicardial cells PloS one High 23469079
2013 In the urogenital system, Tbx18 is required exclusively within the ureteric mesenchymal lineage to suppress a renal stromal fate. Tbx18-deficient ureteric mesenchymal cells adopt a stromal rather than smooth muscle fate. Restriction of Tbx18 expression to prospective ureteric mesenchyme is due to loss of Tbx18 expression out of range of ureteric epithelial signals, and Tbx18 is required to prepattern the ureteric mesenchyme for responsiveness to these signals. Conditional KO, genetic lineage tracing, DiI labeling, tissue recombination experiments Developmental biology High 23685333
2015 Dominant-negative TBX18 mutations (c.1010delG, c.1570C>T, c.487A>G) cause human CAKUT. Mutant proteins still dimerize with wild-type TBX18 but have prolonged half-life and reduced transcriptional repression activity. The p.Lys163Glu substitution impairs TBX18-DNA binding, demonstrating that TBX18 function in ureter smooth muscle development requires intact DNA binding and transcriptional repression. Whole exome sequencing, dimerization assays, protein stability assays, transcriptional repression reporter assays, DNA binding assays American journal of human genetics High 26235987
2016 Tbx18 misexpression in fetal mouse cardiac chambers inhibits the working myocardial gene program in atria and ventricles but does not induce the full SAN pacemaker gene signature (SAN gap junction and ion channel profile not ectopically induced). Left atrial Pitx2 expression is strongly repressed. Tbx18 is therefore not sufficient to induce full SAN differentiation of chamber cardiomyocytes in fetal mice. Conditional misexpression using chamber-specific Cre drivers (Myh6-Cre, Tagln-Cre) with Hprt(Tbx18) allele, molecular analyses Journal of molecular and cellular cardiology High 27180262
2016 Tbx18 is required for differentiation of periductal smooth muscle stromal cells in the prostate. Tbx18-deficient cells fail to condense into smooth muscle cells and instead adopt a hypertrophic myofibroblastic state, with adjacent epithelium becoming disorganized. Genes regulating cell proliferation, smooth muscle differentiation, prostate epithelium development, and inflammatory response are dysregulated in the Tbx18-null urogenital sinus. Tbx18 null and conditional knockout mice, hypomorphic allele, gene expression analysis, histology PloS one High 27120339
2018 Unbiased proteomic analysis identified multiple TBX18 binding proteins including transcriptional cofactors (CBFB, GAR1, IKZF2, NCOA5, SBNO2, CHD7) and homeobox transcription factors that interact with the T-box domain of TBX18. CBFB, CHD7, and IKZF2 enhanced TBX18-mediated transcriptional repression, while NCOA5 and SBNO2 dose-dependently relieved it. Pbx and Prrx homeobox subfamily members are coexpressed with Tbx18 in the developing ureter. Tandem affinity purification, LC-MS, nuclear recruitment assays, GST pull-downs, transcriptional reporter assays PloS one High 30071041
2018 TBX18 overexpression in subsidiary atrial pacemaker tissue restores normal sinoatrial node function (increased rate, improved heart rate stability, restored isoprenaline response) via a TBX18-induced switch in dominant HCN isoform, with significant upregulation of HCN2. Biophysical modeling confirmed that measured changes in HCN abundance account for observed beating rate changes. Gene transfer in rat subsidiary atrial pacemaker tissue, electrophysiology, RT-PCR, computational modeling The Journal of physiology High 30259525
2022 ZMYM2, a component of the CoREST transcriptional corepressor complex, is an endogenous binding partner of TBX18 in both 293 and A549 cells, identified by CRISPR/Cas9-mediated endogenous tagging and affinity purification. Tbx18 is coexpressed with Zmym2 in the mesenchymal compartment of the developing mouse ureter, consistent with in vivo relevance. CRISPR/Cas9 endogenous epitope tagging, anti-FLAG affinity purification, LC-MS, co-immunoprecipitation validation The Biochemical journal High 34935912
2022 Tbx18-mediated reprogramming of ventricular cardiomyocytes to pacemaker cells entails massive proteome remodeling: upregulation of pacemaker ion channels Hcn4, Cx45, mechanosensitive channels Piezo1, Trpp2, TrpM7; downregulation of metabolic pathways and ventricular excitation-contraction coupling channels; and extensive cytoskeletal/ECM remodeling involving 96 EMT-associated proteins. RNAseq revealed upregulation of EMT-inducing transcription factors Snai1, Snai2, Twist1, Twist2, Zeb2 downstream of Tbx18. Tandem mass tag proteomics, RNAseq, network diffusion mapping in TBX18-transduced neonatal rat ventricular myocytes Journal of proteome research High 36006872
2022 Chemically modified mRNA encoding TBX18 is suppressed by upregulation of miR-1-3p and miR-1b in transfected cells. Co-administration of antagomiRs against these miRNAs prolongs TBX18 expression in vitro and in vivo, enabling electrical pacing of the heart, demonstrating that microRNA-dependent suppression limits TBX18 CMmRNA translation. CMmRNA transfection, small RNA sequencing, antagomiR co-administration, patch-clamp, in vivo pacing experiments in rats with AV block Cell reports. Medicine High 36543116
2023 TBX18 transcriptionally activates CHN1 by binding to the CHN1 promoter region, thereby elevating RhoA activity. TBX18 knockdown reduces CHN1 transcription, decreases RhoA activity, and sensitizes esophageal squamous cell carcinoma cells to radiotherapy. TBX18 overexpression increases autophagy after radiation, partially reversed by RhoA knockdown. Dual-luciferase reporter assay, ChIP, GST pull-down (CHN1-RhoA interaction), ectopic expression/knockdown in cells and nude mouse xenograft model Radiotherapy and oncology High 37399907
2025 TBX18 in smooth muscle cells directly regulates genes controlling aortic homeostasis: ChIP-seq in primary human aortic SMCs showed TBX18 directly binds genes misexpressed in mutant aortae (including EGR1, FOS, JUNB). Embryonic conditional ablation of Tbx18 in SMCs causes severe aortic malformations and lethality; adult ablation combined with a Marfan-causing mutation promotes aortic structural degradation, root dilation, and lethality. Conditional knockout mouse models (embryonic and adult SMC-specific), ChIP-seq in human aortic SMCs, multiomics (transcriptomic and translatomic analyses), histological quantitative imaging Cardiovascular research High 41263385
2025 AAV-mediated long-term TBX18 expression at non-fibrogenic levels suppresses key working myocardial genes but does not induce a pacemaker gene program or hyperpolarization-activated funny current in mouse hearts. TBX18 is therefore not sufficient to induce pacemaker activity at functional non-fibrogenic levels, and does not augment Hcn2-mediated pacing in a rat AV-block model. AAV gene transfer in mice and rats, electrophysiological studies, gene expression analysis, complete AV-block rat model bioRxivpreprint Medium
2026 In human atrial fibroblasts under rapid electrical stimulation, miR-1 overexpression reduces Tbx18 protein levels (via 3'-UTR targeting demonstrated by luciferase reporter), which in turn upregulates Cx43 expression; Tbx18 siRNA also upregulates Cx43, confirming that Tbx18 transcriptionally represses Cx43 in this cellular context. Luciferase 3'-UTR reporter assay, miR-1 overexpression and antagomiR, Tbx18 siRNA knockdown, immunohistochemistry, promoter-reporter assay in human atrial fibroblasts Acta Cardiologica Sinica Medium 41608281

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 A myocardial lineage derives from Tbx18 epicardial cells. Nature 619 18480752
2008 Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3. Circulation research 248 19096026
2012 Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nature biotechnology 244 23242162
2006 Formation of the venous pole of the heart from an Nkx2-5-negative precursor population requires Tbx18. Circulation research 225 16709898
2009 Tbx18 and the fate of epicardial progenitors. Nature 217 19369973
2001 Cloning and expression analysis of the mouse T-box gene Tbx18. Mechanisms of development 183 11118889
2004 The T-box transcription factor Tbx18 maintains the separation of anterior and posterior somite compartments. Genes & development 142 15155583
2006 Tbx18 regulates the development of the ureteral mesenchyme. The Journal of clinical investigation 128 16511601
2013 Tbx18 regulates development of the epicardium and coronary vessels. Developmental biology 84 24016759
2007 Transcriptional repression by the T-box proteins Tbx18 and Tbx15 depends on Groucho corepressors. The Journal of biological chemistry 82 17584735
2013 Tbx18 expression demarcates multipotent precursor populations in the developing urogenital system but is exclusively required within the ureteric mesenchymal lineage to suppress a renal stromal fate. Developmental biology 76 23685333
2015 Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development. American journal of human genetics 68 26235987
2008 Deafness in mice lacking the T-box transcription factor Tbx18 in otic fibrocytes. Development (Cambridge, England) 59 18353863
2011 Transcriptional suppression of connexin43 by TBX18 undermines cell-cell electrical coupling in postnatal cardiomyocytes. The Journal of biological chemistry 57 21205823
2013 The transcription factors Tbx18 and Wt1 control the epicardial epithelial-mesenchymal transition through bi-directional regulation of Slug in murine primary epicardial cells. PloS one 56 23469079
1999 Identification, mapping, and phylogenomic analysis of four new human members of the T-box gene family: EOMES, TBX6, TBX18, and TBX19. Genomics 47 9888994
2002 Cloning of zebrafish T-box genes tbx15 and tbx18 and their expression during embryonic development. Mechanisms of development 46 12175500
2010 SIX1 acts synergistically with TBX18 in mediating ureteral smooth muscle formation. Development (Cambridge, England) 44 20110314
2016 Efficient Differentiation of TBX18+/WT1+ Epicardial-Like Cells from Human Pluripotent Stem Cells Using Small Molecular Compounds. Stem cells and development 40 27927069
2012 Tbx18 targets dermal condensates for labeling, isolation, and gene ablation during embryonic hair follicle formation. The Journal of investigative dermatology 39 22992803
2004 Analysis of TBX18 expression in chick embryos. Development genes and evolution 38 15257458
2012 Tbx18 function in epicardial development. Cardiovascular research 34 22926762
2008 T-box protein Tbx18 interacts with the paired box protein Pax3 in the development of the paraxial mesoderm. The Journal of biological chemistry 31 18644785
2018 TBX18 transcription factor overexpression in human-induced pluripotent stem cells increases their differentiation into pacemaker-like cells. Journal of cellular physiology 30 30078203
2011 Developmental patterns and characteristics of epicardial cell markers Tbx18 and Wt1 in murine embryonic heart. Journal of biomedical science 29 21871065
2004 Tbx18 and boundary formation in chick somite and wing development. Developmental biology 28 15063182
2014 Tbx18 is essential for normal development of vasculature network and glomerular mesangium in the mammalian kidney. Developmental biology 25 24727670
2018 TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome. The Journal of physiology 22 30259525
2016 TBX18 gene induces adipose-derived stem cells to differentiate into pacemaker-like cells in the myocardial microenvironment. International journal of molecular medicine 20 27632938
2016 Hypoxia induced the differentiation of Tbx18-positive epicardial cells to CoSMCs. Scientific reports 19 27456656
2019 Engineered Cardiac Pacemaker Nodes Created by TBX18 Gene Transfer Overcome Source-Sink Mismatch. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 31763140
2016 Misexpression of Tbx18 in cardiac chambers of fetal mice interferes with chamber-specific developmental programs but does not induce a pacemaker-like gene signature. Journal of molecular and cellular cardiology 16 27180262
2010 Tbx18 and Tbx15 null-like phenotypes in mouse embryos expressing Tbx6 in somitic and lateral plate mesoderm. Developmental biology 14 20832395
2019 Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells. Experimental and therapeutic medicine 13 30906456
2018 Proteomic analysis identifies transcriptional cofactors and homeobox transcription factors as TBX18 binding proteins. PloS one 11 30071041
2017 Transcription factor TBX18 promotes adult rat bone mesenchymal stem cell differentiation to biological pacemaker cells. International journal of molecular medicine 11 29207072
2019 Genetically Modified Porcine Mesenchymal Stem Cells by Lentiviral Tbx18 Create a Biological Pacemaker. Stem cells international 10 31814832
2018 Comparison of mouse brown and white adipose‑derived stem cell differentiation into pacemaker‑like cells induced by TBX18 transduction. Molecular medicine reports 10 29568953
2022 MicroRNA-dependent suppression of biological pacemaker activity induced by TBX18. Cell reports. Medicine 9 36543116
2021 Tbx18 promoted the conversion of human-induced pluripotent stem cell-derived cardiomyocytes into sinoatrial node-like pacemaker cells. Cell biology international 9 34882885
2017 Tbx18-dependent differentiation of brown adipose tissue-derived stem cells toward cardiac pacemaker cells. Molecular and cellular biochemistry 9 28382491
2016 Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate. PloS one 9 27120339
2013 Novel and functional variants within the TBX18 gene promoter in ventricular septal defects. Molecular and cellular biochemistry 8 23749171
2022 Tbx18 Orchestrates Cytostructural Transdifferentiation of Cardiomyocytes to Pacemaker Cells by Recruiting the Epithelial-Mesenchymal Transition Program. Journal of proteome research 7 36006872
2019 Transcription Factor TBX18 Reprograms Vascular Smooth Muscle Cells of Ascending Aorta to Pacemaker-Like Cells. DNA and cell biology 7 31633376
2016 Lack of Genetic Interaction between Tbx18 and Tbx2/Tbx20 in Mouse Epicardial Development. PloS one 7 27253890
2022 Proteomic analysis identifies ZMYM2 as endogenous binding partner of TBX18 protein in 293 and A549 cells. The Biochemical journal 6 34935912
2017 Tbx18-positive cells differentiated from murine ES cells serve as proepicardial progenitors to give rise to vascular smooth muscle cells and fibroblasts. Biomedical research (Tokyo, Japan) 6 28794400
2018 Transcription factor Tbx18 induces the differentiation of c-kit+ canine mesenchymal stem cells (cMSCs) into SAN-like pacemaker cells in a co-culture model in vitro. American journal of translational research 5 30210689
2014 A distant downstream enhancer directs essential expression of Tbx18 in urogenital tissues. Developmental biology 5 24854998
2003 Allelic imbalance at intragenic markers of Tbx18 is a hallmark of murine osteosarcoma. Carcinogenesis 5 12663494
2018 In vitro study of the effects of reprogramming neonatal rat fibroblasts transfected with TBX18 on spontaneous beating in neonatal rat cardiomyocytes. Molecular medicine reports 4 30365101
2019 [Role of over-expression of TBX3 and TBX18 in the enrichment and differentiation of human induced pluripotent stem cells into sinoatrial node-like cells]. Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery 3 30983202
2024 Single-cell RNA sequencing reveals the transcriptional heterogeneity of Tbx18-positive cardiac cells during heart development. Functional & integrative genomics 2 38265516
2021 Tbx18-positive cells-derived myofibroblasts contribute to renal interstitial fibrosis via transforming growth factor-β signaling. Experimental cell research 2 34118250
2018 An extended regulatory landscape drives Tbx18 activity in a variety of prostate-associated cell lineages. Developmental biology 2 30594504
2025 Biological pacemaker induced by focal cardiac transduction with AAV-TBX18. Molecular therapy : the journal of the American Society of Gene Therapy 1 41108077
2025 Transcription regulation by TBX18 in smooth muscle cells is essential for normal aortic development and homeostasis. Cardiovascular research 1 41263385
2023 TBX18 knockdown sensitizes esophageal squamous cell carcinoma to radiotherapy by blocking the CHN1/RhoA axis. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 1 37399907
2022 Epicardium-Derived Tbx18+ CDCs Transplantation Improve Heart Function in Infarcted Mice. Frontiers in cardiovascular medicine 1 35141286
2026 Exosomal MicroRNA-1 Regulate Cx43 Expression via Tbx18 in Culture Atrial Fibroblasts under Rapid Electrical Stimulation. Acta Cardiologica Sinica 0 41608281
2022 Generation of a human embryonic stem cell line (WAe009-A-78) carrying homozygous TBX18 knockout. Stem cell research 0 35533514
2016 Sonic hedgehog, TBX18, and TSHZ3 proteins involved in pyeloureteral motility development are overexpressed in ureteropelvic junction obstruction. An immunohistochemical, histopathological, and clinical comparative study. Saudi medical journal 0 27381532

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