Affinage

TBX6

T-box transcription factor TBX6 · UniProt O95947

Length
436 aa
Mass
47.0 kDa
Annotated
2026-04-28
85 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBX6 is a T-box transcription factor that serves as a master regulator of posterior paraxial mesoderm specification during vertebrate embryogenesis, acting at the binary fate decision between mesodermal and neural identity. TBX6 functions primarily as a transcriptional activator that directly drives expression of key somitogenesis genes—including Dll1, Mesp2, Msgn1, and Hes7—in cooperation with WNT/LEF-TCF and Notch signaling pathways, while simultaneously repressing neural fate by inactivating the Sox2 N1 enhancer in presomitic mesoderm (PMID:9490412, PMID:21331042, PMID:15545628, PMID:16505380, PMID:23326414). TBX6 protein abundance is tightly controlled through Ripply2-mediated proteasomal degradation and Smad6/Smurf1-dependent ubiquitination, establishing negative feedback loops that define segmental boundaries during somitogenesis (PMID:29761784, PMID:25641698, PMID:19561075). Compound inheritance of TBX6 loss-of-function alleles (null plus common hypomorphic) causes congenital scoliosis and spondylocostal dysostosis in humans, while increased TBX6 dosage from 16p11.2 duplication causes congenital cervical vertebral malformations, demonstrating exquisite dosage sensitivity (PMID:25564734, PMID:31888956, PMID:23335591).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    Before the function of Tbx6 was known, establishing its restricted expression in primitive streak and presomitic mesoderm—and its dependence on Brachyury—placed it within the paraxial mesoderm transcription factor hierarchy.

    Evidence In situ hybridization in wild-type and Brachyury-null mouse embryos

    PMID:8954725

    Open questions at the time
    • Whether Tbx6 is a direct or indirect target of Brachyury was not resolved
    • No downstream targets of Tbx6 were identified
  2. 1998 High

    The foundational loss-of-function study revealed that Tbx6 is not merely a mesoderm marker but an essential fate determinant: without it, posterior paraxial mesoderm cells adopt neural identity and form ectopic neural tubes, establishing the core binary fate-switch model.

    Evidence Targeted null mutation in mouse with histological and immunohistochemical phenotyping

    PMID:9490412

    Open questions at the time
    • The molecular targets through which Tbx6 specifies mesoderm were unknown
    • Whether the fate switch involves transcriptional activation, repression, or both was unresolved
  3. 2001 Medium

    Chimeric activator/repressor domain-swap experiments demonstrated that Tbx6 functions as a transcriptional activator rather than repressor, resolving whether it promotes mesoderm by activating mesodermal genes or repressing neural genes.

    Evidence Tbx6-VP16 and Tbx6-EnR chimeric constructs in Xenopus animal cap assays

    PMID:11737146

    Open questions at the time
    • Activator function was shown in Xenopus; direct confirmation in mammalian systems was pending
    • Direct transcriptional targets remained unidentified
  4. 2003 High

    Genetic rescue and epistasis experiments identified Dll1 as a downstream target of Tbx6, linking Tbx6 to Notch signaling and explaining how Tbx6 controls segmentation beyond initial fate specification.

    Evidence Hypomorphic Tbx6 allele rescue; genetic interaction with Dll1; expression analysis in mutant embryos

    PMID:12620991 PMID:12915233

    Open questions at the time
    • Whether Dll1 is a direct transcriptional target (vs. indirect) was not established
    • The mechanism of Tbx6 cooperation with other signaling pathways was unknown
  5. 2005 High

    Direct DNA binding of Tbx6 to the Dll1 mesoderm enhancer was demonstrated, and Notch signaling was shown to act upstream of Tbx6 itself via an RBP-Jκ site in the Tbx6 enhancer, establishing a reciprocal Tbx6–Notch regulatory circuit.

    Evidence EMSA defining Tbx6 consensus binding site on Dll1 enhancer; transgenic reporter mutagenesis of Tbx6 presomitic mesoderm enhancer in mouse embryos

    PMID:15864811 PMID:15986483 PMID:16343478

    Open questions at the time
    • In vivo ChIP confirmation of Tbx6 occupancy at Dll1 was not yet performed
    • Whether Tbx6 cooperates with cofactors at these enhancers was unknown
  6. 2004 High

    The cooperation between Tbx6 and WNT/LEF-TCF signaling at the Dll1 promoter was demonstrated, revealing a synergistic activation mechanism that depends on both T-box and LEF/TCF binding sites in vivo.

    Evidence In vitro transcriptional assays and transgenic reporter analysis with site-directed mutagenesis in mouse embryos

    PMID:15545628

    Open questions at the time
    • Whether Tbx6 and LEF/TCF physically interact or act independently at the promoter was unclear
    • Generalizability of this cooperation to other Tbx6 target genes was untested
  7. 2006 High

    ChIP confirmed direct Tbx6 occupancy at the Mesp2 regulatory region, establishing Mesp2 as a second major direct target and showing that Tbx6 integrates Notch signaling input to activate Mesp2 specifically in anterior presomitic mesoderm.

    Evidence Chromatin immunoprecipitation; reporter assays; analysis in Tbx6-null embryos

    PMID:16505380

    Open questions at the time
    • How Tbx6 restricts Mesp2 to the anterior PSM compartment was not mechanistically resolved
    • The identity of Notch-dependent cofactors cooperating with Tbx6 at Mesp2 was unknown
  8. 2007 Medium

    The Tbx6 target network was expanded to include Msgn1 (via WNT synergy) and Hes7 (an oscillatory segmentation clock gene), and feedback loops involving the Xenopus corepressor Bowline were identified, demonstrating that Tbx6 can also participate in transcriptional repression through co-repressor recruitment.

    Evidence Transgenic reporters, epistasis analysis, and morpholino knockdown in mouse and Xenopus; Co-IP of Tbx6–Bowline–XGrg-4 complex

    PMID:17577580 PMID:17668009 PMID:18035347

    Open questions at the time
    • Whether the Bowline/Groucho co-repressor mechanism operates in mammals was not tested
    • Direct binding of Tbx6 to Msgn1 regulatory elements was not confirmed by ChIP
  9. 2008 High

    A post-translational negative feedback loop was discovered: Mesp2 triggers rapid proteasomal degradation of Tbx6 protein, which progressively defines the anterior boundary of the next somite; additionally, Tbx6 was shown to control left-right asymmetry via Dll1-dependent Notch signaling and nodal cilia function.

    Evidence FISH/IHC with proteasome inhibitors in mouse embryos; live cilia imaging and calcium signaling assays; knock-in enhancer mutagenesis phenocopying Mesp2-null

    PMID:18575602 PMID:18579680 PMID:18849530

    Open questions at the time
    • The E3 ubiquitin ligase mediating Mesp2-triggered Tbx6 degradation was not identified
    • Whether Tbx6 directly regulates cilia genes or acts solely through Dll1 was unclear
  10. 2009 High

    A second degradation pathway was characterized: Smad6 directly binds Tbx6 (residues 90–180) via its MH2 domain and recruits the E3 ubiquitin ligase Smurf1, providing a BMP-signaling-dependent mechanism for Tbx6 protein turnover.

    Evidence Co-immunoprecipitation; deletion mutant mapping; siRNA knockdown; transcriptional assays

    PMID:19561075

    Open questions at the time
    • In vivo relevance of Smad6/Smurf1-mediated Tbx6 degradation in presomitic mesoderm was not demonstrated
    • Relationship between Smurf1-mediated and Mesp2/Ripply-mediated degradation pathways was unclear
  11. 2011 High

    The mechanism of Tbx6-mediated neural fate repression was solved: Tbx6 inactivates the Sox2 N1 enhancer in paraxial mesoderm, and in its absence this enhancer remains active, driving ectopic Sox2 expression and the neural tube phenotype observed in Tbx6-null mice.

    Evidence N1 enhancer deletion in Tbx6-null background; transgenic Sox2 misexpression in paraxial mesoderm; in vivo enhancer activity assays

    PMID:21331042

    Open questions at the time
    • Whether Tbx6 directly binds and represses the N1 enhancer or acts indirectly was not resolved
    • Identity of cofactors mediating N1 inactivation was unknown
  12. 2015 High

    Compound inheritance of TBX6 loss-of-function alleles (rare null plus common hypomorphic haplotype) was identified as the genetic mechanism underlying human congenital scoliosis, and Ripply2 was shown to degrade Tbx6 protein independently of Mesp2, clarifying the segmental boundary-setting mechanism.

    Evidence Large human cohort with CGH and sequencing plus in vitro transcriptional assays; transgenic Ripply2 overexpression and knock-in mice with mRNA/protein distinction

    PMID:25564734 PMID:25641698

    Open questions at the time
    • The structural basis of Ripply2–Tbx6 interaction was unknown
    • Whether the common hypomorphic haplotype affects Tbx6 protein stability or solely transcription was unclear
  13. 2018 High

    The Ripply2-mediated degradation mechanism was molecularly dissected: Ripply2 directly binds Tbx6 and recruits the proteasome complex, and a specific motif in the T-box domain is required for degradation independently of Ripply2 binding; separately, temporal dynamics of Tbx6 expression were shown to determine cardiovascular versus somite lineage choice from pluripotent stem cells.

    Evidence Co-IP, mass spectrometry of Ripply2 complex, domain mutagenesis in ES cell PSM system; scRNA-seq, CRISPR-KO, directed differentiation of mouse and human PSCs

    PMID:29761784 PMID:30100166

    Open questions at the time
    • Whether Ripply2 acts as a direct adaptor for a specific proteasome subunit or uses an intermediary E3 ligase was not fully resolved
    • The chromatin targets through which transient vs. prolonged Tbx6 expression diverge into cardiac vs. somite fates were not mapped genome-wide
  14. 2019 High

    TBX6 dosage sensitivity was established bidirectionally: increased dosage from 16p11.2 duplication causes cervical vertebral malformations, Tbx6 autoregulates its own transcription via a proximal cis-regulatory module, and mouse models with engineered null/hypomorphic compound alleles recapitulated human congenital vertebral malformations.

    Evidence CRISPR-edited regulatory regions with micro-CT phenotyping; ChIP showing direct Tbx6 binding to its own TR1 element in zebrafish; CRISPR-engineered mouse alleles mimicking human variants

    PMID:30307510 PMID:31015262 PMID:31444219 PMID:31888956

    Open questions at the time
    • How autoregulation is integrated with Ripply-mediated protein degradation to achieve sharp transcriptional shutoff was not modeled quantitatively
    • The full spectrum of TBX6 dosage-sensitive phenotypes in humans remains incompletely catalogued
  15. 2025 Medium

    An epigenetic input to Tbx6 expression was identified: Dot1L-catalyzed H3K79me2 at the Tbx6 locus promotes its expression in stressed cardiomyocytes, and Tbx6 upregulation mediates Dot1L-driven cardiac hypertrophy, revealing a non-developmental pathological role for TBX6.

    Evidence ChIP-seq and RNA-seq in cardiomyocyte-specific Dot1L knockout/transgenic mice; transverse aortic constriction model; Tbx6 knockdown rescue

    PMID:40583756

    Open questions at the time
    • Whether Tbx6 directly activates hypertrophic gene programs or acts through its canonical targets (Dll1, Mesp2) in cardiomyocytes is unknown
    • Relevance to human cardiac hypertrophy has not been demonstrated
    • Single-lab finding awaiting independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the genome-wide direct target repertoire of TBX6 in human presomitic mesoderm, the structural basis of Tbx6–Ripply2 interaction and proteasome recruitment, how Tbx6 mechanistically inactivates the Sox2 N1 enhancer (direct binding vs. indirect chromatin remodeling), and the full pathogenic spectrum of TBX6 dosage variation in non-skeletal tissues.
  • No genome-wide ChIP-seq map of TBX6 binding in human PSM cells exists
  • No crystal structure of TBX6 alone or in complex with Ripply2
  • Mechanism of Sox2 N1 enhancer inactivation (direct vs. indirect) unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 3
Partners
DLL1LEF1MESP2RIPPLY2SMAD6SMURF1

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Tbx6 is essential for specification of posterior paraxial mesoderm; in its absence, cells destined to form posterior somites instead differentiate along a neuronal pathway, forming ectopic neural-tube-like structures with dorsal/ventral patterning and differentiated motor neurons. Targeted knockout (null mutation) in mouse with histological and immunohistochemical analysis of ectopic neural tubes Nature High 9490412
1996 Tbx6 is expressed exclusively in the primitive streak and presomitic/paraxial mesoderm during gastrulation and somitogenesis, and its continued expression in presomitic mesoderm is directly or indirectly dependent on Brachyury (T) expression. In situ hybridization in wild-type and homozygous Brachyury null mutant embryos; temporal expression analysis Developmental biology High 8954725
2011 Tbx6 represses Sox2 by inactivating its neural enhancer N1, thereby preventing axial stem cells from adopting a neural fate and specifying them toward paraxial mesoderm; in Tbx6 mutant embryos, enhancer N1 remains active in paraxial mesoderm, driving ectopic Sox2 expression and neural tube formation. Enhancer-N1-specific deletion knockin in Tbx6 mutant embryos; transgenic misexpression of Sox2 in paraxial mesoderm; in vivo enhancer activity assays Nature High 21331042
2004 TBX6 cooperates with LEF/TCF transcription factors downstream of WNT signaling to activate transcription of the Notch ligand Dll1 in the presomitic mesoderm; mutating either T-box or LEF/TCF binding sites in the Dll1 promoter abolishes expression in vivo. In vitro transcriptional assays; transgenic reporter analysis in mouse embryos; site-directed mutagenesis of promoter elements Genes & development High 15545628
2006 Tbx6 directly binds to the Mesp2 upstream regulatory region and mediates Notch signaling to drive Mesp2 transcription specifically in the anterior presomitic mesoderm. Chromatin immunoprecipitation; reporter assays; genetic analysis in Tbx6 mutant embryos Proceedings of the National Academy of Sciences of the United States of America High 16505380
2008 Tbx6 binding to two conserved sites in the Mesp2 enhancer is indispensable for Mesp2 expression in the presomitic mesoderm in vivo; knock-in mice with mutations at these Tbx6 binding sites phenocopy Mesp2-null mice with impaired skeletal segmentation. Enhancer knock-in mouse with mutated Tbx6 binding sites; chromatin immunoprecipitation; in vivo enhancer analysis Development (Cambridge, England) High 18849530
2008 Mesp2 protein leads to rapid post-translational degradation of Tbx6 protein via the ubiquitin-proteasome pathway, establishing a reciprocal feedback loop that successively defines the anterior border of Mesp2 expression during somitogenesis. High-resolution fluorescent in situ hybridization combined with immunohistochemistry; proteasome inhibitor experiments Development (Cambridge, England) High 18579680
2005 Tbx6 directly binds to two T-box consensus sites within the Dll1 paraxial mesoderm enhancer in vitro, establishing Dll1 as a direct transcriptional target of Tbx6. Electrophoretic mobility shift assay (EMSA); identification of Tbx6 consensus binding site; analysis of Tbx6-null embryos Genesis (New York, N.Y. : 2000) High 15986483
2005 Notch signaling (via RBP-Jkappa binding site) is upstream of Tbx6 in the presomitic mesoderm; a RBP-Jkappa binding site in the Tbx6 presomitic mesoderm enhancer is necessary for its activity, separable from the primitive streak enhancer element. Transgenic reporter analysis; site-directed mutagenesis of Tbx6 enhancer in transgenic mouse embryos Genesis (New York, N.Y. : 2000) High 15864811
2003 Tbx6 null ES cells fail to populate posterior somites in chimeric embryos, and there is a combinatorial (but not epistatic) interaction between Tbx6 and T (Brachyury) at the phenotypic level in genetic crosses. Chimeric embryo analysis; ES cell differentiation assays; genetic crosses between Tbx6 null and T mutant alleles Mechanisms of development Medium 12915233
2003 Partial restoration of Tbx6 expression in null mutants rescues somite development but not rostrocaudal patterning; Tbx6 genetically interacts with the Notch ligand Dll1, and Dll1 expression is a target of Tbx6 in the paraxial mesoderm. Genetic rescue with hypomorphic allele; expression analysis of Notch pathway components; genetic interaction analysis Development (Cambridge, England) High 12620991
2007 WNT signaling synergizes with Tbx6 (via a feed-forward mechanism) to control expression of Msgn1, a bHLH transcription factor essential for presomitic mesoderm maturation. Transgenic reporter assays; expression analysis in mutant embryos; epistasis analysis EMBO reports Medium 17668009
2008 Tbx6 is required for correct left/right axis determination; it acts through Notch signaling (via Dll1) around the node and through effects on nodal cilia morphology and motility, resulting in loss of asymmetric calcium signaling at the node periphery. Analysis of Tbx6-null embryos; live imaging of cilia with fluorescent tubulin fusion; calcium signaling assays; Dll1 expression analysis PloS one High 18575602
2009 Smad6 (inhibitory Smad of BMP signaling) directly interacts with Tbx6 via its MH2 domain binding to residues 90-180 of Tbx6, recruits the E3 ubiquitin ligase Smurf1 to facilitate Tbx6 protein degradation, and consequently reduces Tbx6-mediated Myf-5 gene activation. Co-immunoprecipitation; pulldown with deletion mutants; siRNA knockdown; in vitro transcriptional assays The Journal of biological chemistry High 19561075
2009 In Ciona, Tbx6 and Lhx3 function synergistically as direct activators of Mesp expression to define the cardiac field; Tbx6 cannot account alone for restricted Mesp expression since it is expressed broadly in presumptive tail muscles, but the co-expression of Tbx6 and Lhx3 is unique to B7.5 (heart field) blastomeres. Morpholino knockdown; misexpression assays; enhancer mutagenesis of Tbx6/Lhx3 composite elements Developmental biology Medium 19389354
2013 Tbx6 and the Wnt pathway cooperatively regulate Hes7 promoter activity; a 400 bp region of the Hes7 promoter contains essential Tbx6 and Lef1 binding sites, and Tbx6 binding sites are required for normal Hes7 oscillatory expression in the presomitic mesoderm. Transgenic mouse reporter assays; site-directed mutagenesis of Hes7 promoter; cell culture transcriptional assays PloS one Medium 23326414
2015 Ripply2 represses Tbx6 protein in a Mesp2-independent manner through post-translational mechanism (protein degradation, not mRNA reduction) to define segmental borders in mouse somitogenesis; accelerated Tbx6 degradation occurs with Ripply2 overexpression, and ectopic Ripply2 in entire PSM causes ectopic neural tube formation resembling Tbx6-null phenotype. Transgenic overexpression, knock-in mice, ectopic expression constructs; in situ hybridization and immunostaining to distinguish mRNA vs. protein levels Developmental biology High 25641698
2018 Ripply2 directly binds to Tbx6 protein in cultured cells and recruits the proteasome complex (identified by mass spectrometry) to degrade Tbx6; a specific motif in the T-box domain of Tbx6 is required for its degradation independently of Ripply2 binding. Co-immunoprecipitation; mouse ES cell PSM induction system; mass spectrometry of Ripply2-binding complex; domain mutagenesis eLife High 29761784
2007 Bowline (a corepressor-associated protein) mediates interaction between Tbx6 and the transcriptional corepressor XGrg-4 in Xenopus, repressing Tbx6-dependent transcription of Thylacine1 in the anterior presomitic mesoderm; bowline-deficient embryos show anterior expansion of segmentation genes. Co-immunoprecipitation; morpholino knockdown; in situ hybridization; reporter assays Biochemical and biophysical research communications Medium 17577580
2007 Tbx6, Thylacine1, and E47 synergistically activate bowline expression in Xenopus, identifying a negative feedback loop in somite segmentation where Tbx6 induces its own repressor Bowline. Luciferase reporter assays; misexpression in Xenopus; promoter analysis Developmental biology Medium 18035347
2008 Tbx6 and mespb proteins physically interact, and this interaction is required for synergistic activation of bowline/Ripply2 expression during Xenopus somitogenesis; domain mapping identified the essential interaction regions. Pulldown assays with deletion mutants; dominant-negative mespb; in situ hybridization Biochemical and biophysical research communications Medium 18510946
1999 Human TBX6 protein binds to the same target DNA as T (Brachyury) protein but does not form a heterodimer with T; TBX6 maps to chromosome 16p11.2. DNA/protein-binding studies (EMSA); genomic mapping Genomics Medium 9933572
2001 Tbx6 functions as a transcriptional activator (not repressor) in Xenopus; overexpression of Tbx6 or Tbx6VP16 (but not Tbx6EnR) in animal caps drives ventral mesodermal differentiation. Animal cap assays; mRNA overexpression; chimeric activator/repressor constructs (Tbx6VP16, Tbx6EnR) Development, growth & differentiation Medium 11737146
2005 FGF8, Xwnt8, and XMyf5 are immediate early responsive target genes of Tbx6 in Xenopus, identified using a hormone-inducible Tbx6 construct; their induction is independent of Xbra and VegT. Hormone-inducible Tbx6 (glucocorticoid receptor fusion); cycloheximide chase to identify immediate-early targets; in situ hybridization Developmental biology Medium 16343478
2018 Tbx6 induces nascent mesoderm from pluripotent stem cells and determines cardiovascular versus somite lineage specification via temporal expression; transient Tbx6 expression drives mesoderm and cardiovascular specification via direct upregulation of Mesp1, repression of Sox2, and activation of BMP/Nodal/Wnt signaling, while prolonged Tbx6 expression suppresses cardiac differentiation and induces somite lineages. Direct reprogramming-based screening; single-cell RNA-seq; CRISPR/Cas9 Tbx6 knockout in mouse PSCs; directed cardiac differentiation; mouse and human PSC assays Cell stem cell High 30100166
2013 A stoploss mutation in TBX6 that segregates with autosomal dominant spondylocostal dysostosis has a deleterious effect on TBX6 transcriptional activation activity, likely through haploinsufficiency. Exome sequencing; in vitro transcriptional activation assays with mutant TBX6 Human molecular genetics Medium 23335591
2015 TBX6 compound inheritance (rare null allele + common hypomorphic allele) is causative for congenital scoliosis; the risk haplotype is a hypomorphic allele with reduced transcriptional activity demonstrated in vitro. Comparative genomic hybridization; DNA sequencing; in vitro transcriptional functional assays The New England journal of medicine High 25564734
2019 Tbx6 autoregulates its own expression by binding to a proximal cis-regulatory module (TR1) containing two T-box sites in the presomitic mesoderm; this autoregulatory loop facilitates Ripply-mediated removal of Tbx6 by terminating its own transcription. Cis-regulatory deletion in zebrafish; ChIP assay; in situ hybridization; genetic interaction with ripply mutants Development (Cambridge, England) High 31444219
2018 Tbx6 controls left/right asymmetry through regulation of Gdf1 (a Nodal co-ligand) expression around the node; Gdf1 is a downstream target of Tbx6, and a Gdf1 transgene partially rescues the laterality defect of Tbx6 homozygous mutants. Gene expression analysis in Tbx6 mutants; transgenic rescue with Gdf1 transgene; molecular cascade analysis Biology open Medium 29650695
2019 Tbx6 compound inheritance (null + hypomorphic alleles) causes congenital vertebral malformations in mice via a gene dosage-dependent mechanism, with high penetrance of vertebral phenotypes only in combined null/hypomorphic compound heterozygotes. CRISPR-Cas9 generation of null and hypomorphic Tbx6 alleles in mice; micro-CT analysis; genetic analysis across cohorts Human molecular genetics High 30307510
2019 Increased TBX6 dosage (from 16p11.2 duplication) causes congenital cervical vertebral malformations; mouse models with elevated Tbx6 expression (~160% of wild-type) show 60% penetrance of cervical vertebral malformations. CRISPR-Cas9 editing of Tbx6 upstream regulatory region; luciferase reporter assays; micro-CT analysis; human duplication carrier analysis Journal of medical genetics High 31888956
2019 TBX6 missense variants can cause loss-of-function through decreased transcriptional activity or abnormal cellular localization (mislocalisation), as demonstrated by in vitro functional assays and iPS cell-derived presomitic mesoderm cells from SCD patients showing decreased TBX6 and downstream gene mRNA expression. In vitro transcriptional activity assays; immunofluorescence for protein localization; iPS cell differentiation into PSM-fated cells; in situ hybridization for downstream genes Journal of medical genetics Medium 31015262
2019 Tbx6 overexpression in postnatal and adult mouse cardiomyocytes induces cell cycle entry and proliferation by upregulating cell cycle activators (Aurkb, Mki67, Ccna1, Ccnb2) and suppressing the tumor suppressor Rb1. AAV9-mediated Tbx6 overexpression in mouse hearts; primary neonatal rat cardiomyocyte culture; cell cycle marker analysis Biochemical and biophysical research communications Medium 31010673
2021 The nephric mesenchyme lineage develops as a subpopulation of Tbx6-expressing mesodermal precursors (derived from neuromesoderm progenitors) through BMP-signal-dependent Osr1 expression; in Tbx6 mutant embryos, nephric mesenchyme cells change fate to neural tissue. Genetic lineage tracing (Sox2-N1 enhancer-EGFP); analysis of Tbx6 and Osr1 mutant embryos; BMP signaling manipulation Developmental biology Medium 34256037
2020 T and Tbx6 have different binding affinities for sites in the Dll1 mesoderm enhancer; Tbx6 activates expression ~10-fold higher than T at target promoters in vitro; T and Tbx6 can compete at target gene enhancers in a DNA-binding-dependent manner. In vitro luciferase transcriptional assays; EMSA for binding affinity comparison; genetic crosses including knock-in approach Biology open Medium 32855167
2025 Dot1L-catalyzed H3K79 dimethylation promotes Tbx6 expression in stressed cardiomyocytes; Dot1L-driven Tbx6 upregulation facilitates pressure overload-induced cardiac hypertrophy, and Tbx6 knockdown abolishes Dot1L overexpression-exaggerated hypertrophy. ChIP-sequencing; RNA-sequencing; cardiomyocyte-specific Dot1L knockout and transgenic mice; transverse aortic constriction; neonatal rat ventricular myocytes Circulation research Medium 40583756
2024 TBX6 binds directly to the OR51B5 promoter (core region -153 to -111 bp) and regulates its transcriptional activity; TBX6 binding was validated by EMSA, site-directed mutagenesis, and ChIP-qPCR. Luciferase reporter assay; EMSA; site-directed mutagenesis; ChIP-qPCR American journal of physiology. Cell physiology Medium 39466177
2017 LTR sequences of ORR1A-D MaLR endogenous retroviruses contain (C/T)CACACCT motifs that serve as direct Tbx6 binding sites; at least four genes (Twist2, Pitx2, Oscp1, Nfxl1) are downregulated in Tbx6-deficient mice, suggesting ERV-derived elements expand Tbx6's regulatory network. Comparison of gene expression in Tbx6+/- vs Tbx6-/- mice; in silico identification of Tbx6 binding motifs in LTR sequences Frontiers in chemistry Low 28664156

Source papers

Stage 0 corpus · 85 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Three neural tubes in mouse embryos with mutations in the T-box gene Tbx6. Nature 343 9490412
2015 TBX6 null variants and a common hypomorphic allele in congenital scoliosis. The New England journal of medicine 246 25564734
1996 Tbx6, a mouse T-Box gene implicated in paraxial mesoderm formation at gastrulation. Developmental biology 238 8954725
2011 Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells. Nature 219 21331042
2004 WNT signaling, in synergy with T/TBX6, controls Notch signaling by regulating Dll1 expression in the presomitic mesoderm of mouse embryos. Genes & development 147 15545628
2006 Tbx6-mediated Notch signaling controls somite-specific Mesp2 expression. Proceedings of the National Academy of Sciences of the United States of America 116 16505380
1997 tbx6, a Brachyury-related gene expressed by ventral mesendodermal precursors in the zebrafish embryo. Developmental biology 96 9119115
2003 Defective somite patterning in mouse embryos with reduced levels of Tbx6. Development (Cambridge, England) 95 12620991
2008 Mesp2 and Tbx6 cooperatively create periodic patterns coupled with the clock machinery during mouse somitogenesis. Development (Cambridge, England) 85 18579680
2007 Expression of Msgn1 in the presomitic mesoderm is controlled by synergism of WNT signalling and Tbx6. EMBO reports 80 17668009
2013 Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6. Human molecular genetics 72 23335591
2013 TBX6, LHX1 and copy number variations in the complex genetics of Müllerian aplasia. Orphanet journal of rare diseases 71 23954021
2008 Tbx6 regulates left/right patterning in mouse embryos through effects on nodal cilia and perinodal signaling. PloS one 68 18575602
2012 Interaction of Wnt3a, Msgn1 and Tbx6 in neural versus paraxial mesoderm lineage commitment and paraxial mesoderm differentiation in the mouse embryo. Developmental biology 66 22546692
2019 TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model. Genetics in medicine : official journal of the American College of Medical Genetics 61 30636772
2002 The mouse rib-vertebrae mutation is a hypomorphic Tbx6 allele. Mechanisms of development 61 12464437
2003 Critical role for Tbx6 in mesoderm specification in the mouse embryo. Mechanisms of development 53 12915233
2018 Tbx6 Induces Nascent Mesoderm from Pluripotent Stem Cells and Temporally Controls Cardiac versus Somite Lineage Diversification. Cell stem cell 51 30100166
2005 Dll1 is a downstream target of Tbx6 in the paraxial mesoderm. Genesis (New York, N.Y. : 2000) 50 15986483
2009 Spatio-temporal intersection of Lhx3 and Tbx6 defines the cardiac field through synergistic activation of Mesp. Developmental biology 47 19389354
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
2015 Tbx6, Mesp-b and Ripply1 regulate the onset of skeletal myogenesis in zebrafish. Development (Cambridge, England) 46 25725067
2017 Compound Heterozygosity for Null Mutations and a Common Hypomorphic Risk Haplotype in TBX6 Causes Congenital Scoliosis. Human mutation 45 28054739
2019 TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice. Human molecular genetics 42 30307510
2017 Autosomal recessive variations of TBX6, from congenital scoliosis to spondylocostal dysostosis. Clinical genetics 41 27861764
2001 Cloning and characterization of the T-box gene Tbx6 in Xenopus laevis. Development, growth & differentiation 40 11737146
2017 Co-expression of Tbx6 and Sox2 identifies a novel transient neuromesoderm progenitor cell state. Development (Cambridge, England) 39 29084802
2008 Functional importance of evolutionally conserved Tbx6 binding sites in the presomitic mesoderm-specific enhancer of Mesp2. Development (Cambridge, England) 34 18849530
2005 FGF8, Wnt8 and Myf5 are target genes of Tbx6 during anteroposterior specification in Xenopus embryo. Developmental biology 34 16343478
1999 An ascidian T-box gene As-T2 is related to the Tbx6 subfamily and is associated with embryonic muscle cell differentiation. Developmental dynamics : an official publication of the American Association of Anatomists 34 10340757
2010 The association analysis of TBX6 polymorphism with susceptibility to congenital scoliosis in a Chinese Han population. Spine 33 20228709
2004 Drosophila Tbx6-related gene, Dorsocross, mediates high levels of Dpp and Scw signal required for the development of amnioserosa and wing disc primordium. Developmental biology 33 14732398
2012 Fss/Tbx6 is required for central dermomyotome cell fate in zebrafish. Biology open 31 23213474
2020 Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome. Kidney international 29 32450157
2019 TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease. Human mutation 28 31471994
2010 Temporal regulation of the muscle gene cascade by Macho1 and Tbx6 transcription factors in Ciona intestinalis. Journal of cell science 28 20592183
2009 Smad6 inhibits the transcriptional activity of Tbx6 by mediating its degradation. The Journal of biological chemistry 26 19561075
2010 Paraxial T-box genes, Tbx6 and Tbx1, are required for cranial chondrogenesis and myogenesis. Developmental biology 25 20692252
2005 Regulation of Tbx6 expression by Notch signaling. Genesis (New York, N.Y. : 2000) 25 15864811
2019 Increased TBX6 gene dosages induce congenital cervical vertebral malformations in humans and mice. Journal of medical genetics 23 31888956
2015 Segmental border is defined by Ripply2-mediated Tbx6 repression independent of Mesp2. Developmental biology 23 25641698
2007 Bowline mediates association of the transcriptional corepressor XGrg-4 with Tbx6 during somitogenesis in Xenopus. Biochemical and biophysical research communications 22 17577580
2012 Evolution of the tbx6/16 subfamily genes in vertebrates: insights from zebrafish. Molecular biology and evolution 20 22915831
2006 Xenopus Tbx6 mediates posterior patterning via activation of Wnt and FGF signalling. Cell research 20 16953215
2017 Cell lineage of timed cohorts of Tbx6-expressing cells in wild-type and Tbx6 mutant embryos. Biology open 19 28606934
2013 Control of Hes7 expression by Tbx6, the Wnt pathway and the chemical Gsk3 inhibitor LiCl in the mouse segmentation clock. PloS one 19 23326414
2007 Tbx6, Thylacine1, and E47 synergistically activate bowline expression in Xenopus somitogenesis. Developmental biology 19 18035347
2016 Progress and perspective of TBX6 gene in congenital vertebral malformations. Oncotarget 18 27437870
2020 Genetic variants of TBX6 and TBXT identified in patients with congenital scoliosis in Southern China. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 17 32672867
2010 Amphioxus Tbx6/16 and Tbx20 embryonic expression patterns reveal ancestral functions in chordates. Gene expression patterns : GEP 16 21185952
2003 The evolutionary relationships of zebrafish genes tbx6, tbx16/spadetail and mga. Development genes and evolution 16 12908107
2021 The nephric mesenchyme lineage of intermediate mesoderm is derived from Tbx6-expressing derivatives of neuro-mesodermal progenitors via BMP-dependent Osr1 function. Developmental biology 15 34256037
2019 Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis. Journal of medical genetics 15 31015262
2010 Tbx18 and Tbx15 null-like phenotypes in mouse embryos expressing Tbx6 in somitic and lateral plate mesoderm. Developmental biology 14 20832395
2015 Sequencing of the TBX6 Gene in Families with Familial Idiopathic Scoliosis. Spine deformity 12 26120555
2022 Functional characteristics of a broad spectrum of TBX6 variants in Mayer-Rokitansky-Küster-Hauser syndrome. Genetics in medicine : official journal of the American College of Medical Genetics 11 36112137
2022 TBX6 as a cause of a combined skeletal-kidney dysplasia syndrome. American journal of medical genetics. Part A 11 36161696
2014 Transcription factor Tbx6 plays a central role in fate determination between mesenchyme and muscle in embryos of the ascidian, Halocynthia roretzi. Development, growth & differentiation 11 24720515
2010 A divergent Tbx6-related gene and Tbx6 are both required for neural crest and intermediate mesoderm development in Xenopus. Developmental biology 11 20083100
1999 The human TBX6 gene: cloning and assignment to chromosome 16p11.2. Genomics 11 9933572
2019 Sequence Variants in TBX6 Are Associated with Disorders of the Müllerian Ducts: An Update. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 10 30739119
2019 Tbx6 induces cardiomyocyte proliferation in postnatal and adult mouse hearts. Biochemical and biophysical research communications 10 31010673
2018 Ripply2 recruits proteasome complex for Tbx6 degradation to define segment border during murine somitogenesis. eLife 10 29761784
2015 Novel ENU-Induced Mutation in Tbx6 Causes Dominant Spondylocostal Dysostosis-Like Vertebral Malformations in the Rat. PloS one 10 26090680
2019 Whole-Exome Sequencing Identified a TBX6 Loss of Function Mutation in a Patient with Distal Vaginal Atresia. Journal of pediatric and adolescent gynecology 9 31233831
2019 Transcriptional autoregulation of zebrafish tbx6 is required for somite segmentation. Development (Cambridge, England) 9 31444219
2023 Ripply suppresses Tbx6 to induce dynamic-to-static conversion in somite segmentation. Nature communications 8 37055428
2018 Tbx6 controls left-right asymmetry through regulation of Gdf1. Biology open 8 29650695
2020 Mutational burden and potential oligogenic model of TBX6-mediated genes in congenital scoliosis. Molecular genetics & genomic medicine 7 32815649
2008 Physical interaction between Tbx6 and mespb is indispensable for the activation of bowline expression during Xenopus somitogenesis. Biochemical and biophysical research communications 7 18510946
2021 Tbx15/18/22 shares a binding site with Tbx6-r.b to maintain expression of a muscle structural gene in ascidian late embryos. Developmental biology 6 34963554
2020 Functionally distinct roles for T and Tbx6 during mouse development. Biology open 6 32855167
2019 Noncoding rare variants of TBX6 in congenital anomalies of the kidney and urinary tract. Molecular genetics and genomics : MGG 6 30604070
2012 Tbx6 is a determinant of cardiac and neural cell fate decisions in multipotent P19CL6 cells. Differentiation; research in biological diversity 6 22721678
2004 Multiple signaling pathways control Tbx6 expression during Xenopus myogenesis. Acta biochimica et biophysica Sinica 5 15188053
2017 Comparative analysis of serum proteome in congenital scoliosis patients with TBX6 haploinsufficiency - a first report pointing to lipid metabolism. Journal of cellular and molecular medicine 4 28944995
2011 A transgenic Tbx6;CreERT2 line for inducible gene manipulation in the presomitic mesoderm. Genesis (New York, N.Y. : 2000) 4 22121035
2022 The Tbx6 Transcription Factor Dorsocross Mediates Dpp Signaling to Regulate Drosophila Thorax Closure. International journal of molecular sciences 3 35562934
2025 Dot1L Promotes Stress-Induced Cardiac Hypertrophy in Mice via Tbx6. Circulation research 2 40583756
2024 Concurrent of compound heterozygous variant of a novel in-frame deletion and the common hypomorphic haplotype in TBX6 and inherited 17q12 microdeletion in a fetus. BMC pregnancy and childbirth 2 38951757
2024 miR-1458 is inhibited by low concentrations of Vitamin B6 and targets TBX6 to promote the formation of spermatogonial stem cells in Rugao Yellow Chicken. Poultry science 2 39616678
2016 Non-neural and cardiac differentiating properties of Tbx6-expressing mouse embryonic stem cells. Regenerative therapy 2 31245465
2017 LTRs of Endogenous Retroviruses as a Source of Tbx6 Binding Sites. Frontiers in chemistry 1 28664156
2025 Preliminary study assessing the long-term surgical outcomes of TBX6-associated congenital scoliosis (TACS) patients using the propensity score matching method: exploring the clinical implications of genetic discoveries in congenital scoliosis. Orphanet journal of rare diseases 0 39833922
2024 Transcriptional regulation of olfactory receptor OR51B5 by the TBX6. American journal of physiology. Cell physiology 0 39466177