Affinage

TBX4

T-box transcription factor TBX4 · UniProt P57082

Length
545 aa
Mass
60.2 kDa
Annotated
2026-04-28
76 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBX4 is a T-box transcription factor that functions as a master regulator of hindlimb bud outgrowth and lung mesenchymal development by directly activating target genes including FGF10 and SHOX2 through binding to T-box elements in their promoters (PMID:35914404, PMID:24347445). In the hindlimb, TBX4 operates downstream of PITX1 and cooperates with ISL1 to initiate limb bud outgrowth and early chondroprogenitor differentiation during a brief developmental window, though it does not specify hindlimb-type morphology (PMID:10073939, PMID:15621531, PMID:34423345, PMID:17164415). In the lung, TBX4 drives mesenchymal FGF10-dependent branching morphogenesis and is required for postnatal alveologenesis, vascular development, and suppression of smooth muscle differentiation; TBX4-expressing mesenchymal progenitors are the predominant source of myofibroblasts, and TBX4 regulates hyaluronan synthase 2 to enable fibroblast matrix invasion during fibrosis (PMID:22876201, PMID:40106779, PMID:27400124). In the allantois, TBX4 is essential for vascular remodeling through regulation of Wnt2 and extracellular matrix genes, acting in peri-vascular mesenchyme rather than endothelium (PMID:12736212, PMID:22952711, PMID:21932311).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 High

    The question of what drives hindlimb-specific outgrowth was answered when misexpression and loss-of-function experiments established TBX4 as an essential regulator of hindlimb bud outgrowth linked to FGF, BMP, and Wnt signaling, and placed TBX4 downstream of PITX1 in a regulatory hierarchy.

    Evidence In ovo misexpression in chick wing buds, loss-of-function experiments, and Pitx1 misexpression inducing Tbx4

    PMID:10073939 PMID:10235263 PMID:10235264

    Open questions at the time
    • Whether TBX4 directly binds target gene promoters or acts indirectly was not resolved
    • The temporal window of TBX4 requirement was not defined
    • Whether TBX4 specifies limb identity versus outgrowth was debated
  2. 2003 High

    Mouse knockout studies resolved that TBX4 is required to maintain (not initiate) hindlimb bud outgrowth by sustaining FGF10 expression, and separately demonstrated that TBX4 activates FGF10 in lung visceral mesoderm to control lung bud formation and tracheo-esophageal septation.

    Evidence Targeted gene knockout in mouse (hindlimb, allantois phenotypes) and gain/loss-of-function electroporation in chick (lung)

    PMID:12588840 PMID:12736212

    Open questions at the time
    • Whether TBX4 directly binds the FGF10 promoter was not tested
    • Redundancy with TBX5 in lung was not addressed
    • The downstream effectors in allantoic vascular remodeling were unknown
  3. 2005 High

    Genetic deletion experiments clarified that TBX4 drives limb outgrowth but does not determine hindlimb-specific morphology, separating outgrowth from identity specification and attributing identity to PITX1.

    Evidence Conditional and constitutive gene deletion in mouse with morphological and molecular analysis

    PMID:15621531

    Open questions at the time
    • Whether TBX4 has any residual identity-related function was not fully excluded
    • Mechanism by which outgrowth is controlled at the molecular level remained unclear
  4. 2007 High

    Temporally controlled conditional deletion revealed that TBX4 is required only during a brief early window for hindlimb initiation; post-initiation loss causes proximal skeletal hypoplasia without halting outgrowth or affecting Fgf10 expression.

    Evidence Stage-specific Cre-lox conditional deletion in mouse with in situ hybridization and skeletal analysis

    PMID:17164415

    Open questions at the time
    • The mechanism linking TBX4 to proximal skeletal patterning was unexplained
    • Whether compensatory factors sustain Fgf10 after TBX4 loss was not tested
  5. 2011 High

    Lineage tracing and genetic rescue experiments established that TBX4-expressing allantois cells give rise to peri-vascular but not endothelial tissue, and confirmed that PITX1's outgrowth function operates through TBX4 regulation while its identity function is TBX4-independent.

    Evidence Tbx4-Cre lineage tracing in mouse and transgenic gene replacement in Pitx1 mutant background

    PMID:21932311 PMID:22071103

    Open questions at the time
    • The signals by which TBX4+ peri-vascular cells promote endothelial remodeling were not identified
    • The Tbx4 regulatory elements active in allantois were not mapped
  6. 2012 High

    Double conditional mutagenesis demonstrated that TBX4 and TBX5 are jointly required for lung branching morphogenesis through regulation of Wnt2, Fgf10, Bmp4, and Spry2, and that TBX4 controls allantoic vascular formation upstream of canonical Wnt signaling via Wnt2.

    Evidence Conditional double KO in mouse lung mesenchyme, organ culture rescue, genetic interaction with Fgf10 and Wnt2

    PMID:22876201 PMID:22952711

    Open questions at the time
    • Whether TBX4 and TBX5 have distinct or fully redundant roles in lung was not resolved
    • Direct binding of TBX4 to Wnt2 or Bmp4 regulatory regions was not shown
  7. 2014 Medium

    EMSA demonstrated that TBX4 directly binds T-box binding sites in the SHOX2 promoter and transcriptionally activates it, with SHOX2 in turn inhibiting TBX4 in forelimbs, establishing a direct transcriptional feedback loop.

    Evidence EMSA for direct DNA binding, expression analysis in Shox2-/- limbs

    PMID:24347445

    Open questions at the time
    • ChIP confirmation of TBX4 binding at endogenous Shox2 locus was not performed
    • Functional consequence of disrupting this feedback loop in vivo was not tested
  8. 2016 High

    Lineage tracing and cell ablation in adult lung revealed that TBX4-expressing mesenchymal progenitors are the predominant source of myofibroblasts in fibrosis, and that TBX4 enables fibroblast matrix invasion by regulating hyaluronan synthase 2 (HAS2).

    Evidence In vivo lineage tracing, cell ablation, conditional disruption in bleomycin fibrosis model, invasion assays in murine and human fibroblasts

    PMID:27400124

    Open questions at the time
    • Whether TBX4 directly binds the HAS2 promoter was not shown
    • The full spectrum of TBX4 targets in fibrotic fibroblasts was not defined
  9. 2021 High

    Triple mutant analysis established that TBX4, PITX1, and ISL1 cooperate in a gene regulatory network for hindlimb bud establishment, and live imaging revealed that TBX4 is required for early chondroprogenitor-to-chondrocyte differentiation, explaining proximal limb defects.

    Evidence Genetic epistasis with triple mutant analysis, live imaging of chondrogenesis in micromass culture

    PMID:34423345

    Open questions at the time
    • Direct transcriptional targets of TBX4 in chondroprogenitors were not identified
    • Whether ISL1 directly regulates TBX4 transcription was not resolved
  10. 2022 High

    Direct TBX4 binding to the FGF10 promoter was confirmed by ChIP and luciferase assays, and domain mutagenesis showed that nuclear localization and DNA-binding domains are essential for FGF10 transactivation; systematic variant analysis revealed that TBX4 missense mutations can produce either loss- or gain-of-function effects with distinct clinical correlates.

    Evidence ChIP, luciferase reporter assays with wild-type and mutant TBX4, genotype-phenotype correlation in multicenter cohort of 42 missense variants

    PMID:35216193 PMID:35852389 PMID:35914404

    Open questions at the time
    • Structural basis for gain-of-function variants was not determined
    • Whether gain-of-function variants alter target gene selectivity was not tested
  11. 2025 High

    Lung mesenchyme-specific TBX4 loss was shown to cause postnatal alveolar simplification, decreased vessel density, pulmonary hypertension, and excessive smooth muscle differentiation, establishing TBX4 as a critical suppressor of smooth muscle fate in lung mesenchyme with genome-wide identification of 555 direct target genes.

    Evidence Conditional KO in mouse lung mesenchyme with hemodynamic measurements, 3D whole-mount analysis, integrated RNA-seq and ChIP-seq in fibroblasts and pericytes

    PMID:39980707 PMID:40106779

    Open questions at the time
    • The direct TBX4 target(s) mediating smooth muscle suppression are not identified
    • Whether TBX4's vascular and smooth muscle phenotypes are cell-autonomous in pericytes versus fibroblasts is unresolved
    • The preprint finding on smooth muscle differentiation awaits peer review

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the direct TBX4 targets that suppress smooth muscle differentiation, whether TBX4 and TBX5 have fully redundant versus unique functions in lung mesenchyme, the structural basis for gain-of-function TBX4 variants, and how TBX4 integrates with SHH-FOXF1 signaling during lung development.
  • No structural model of TBX4 bound to target DNA exists
  • Genome-wide target overlap between TBX4 and TBX5 in lung has not been compared
  • The direct mechanism linking TBX4 to smooth muscle suppression is not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 8 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 3
Partners
FGF10ISL1LMP4PITX1SHOX2TBX5WNT2

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Tbx4 is an essential regulator of hindlimb outgrowth whose function is linked to FGF, BMP, and Wnt signaling proteins required for limb outgrowth and patterning; misexpression of Tbx4 in chick wing buds and loss-of-function experiments demonstrated its role in both limb outgrowth and limb identity specification. In ovo misexpression (chick), loss-of-function genetic experiments, molecular marker analysis Nature High 10235263 10235264
1999 Pitx1 acts upstream of Tbx4 in hindlimb specification; misexpression of Pitx1 in chick wing buds induced distal expression of Tbx4 as well as HoxC10 and HoxC11, establishing a Pitx1→Tbx4 regulatory hierarchy. In ovo misexpression of Pitx1 in chick wing buds, molecular marker analysis (in situ hybridization) Science High 10073939
2003 Loss of Tbx4 in mice causes failure of chorioallantoic fusion and endothelial vascular remodeling in the allantois, and failure to maintain Fgf10 expression in hindlimb mesenchyme, indicating Tbx4 regulates Fgf10 and Tbx2 in hindlimb and allantois. Hindlimb bud induction occurs normally without Tbx4, but outgrowth fails. Targeted gene knockout (null allele) in mouse, in vivo and in vitro analysis of hindlimb bud development, in situ hybridization for Fgf10 and Tbx2 Development High 12736212
2003 Tbx4 in the visceral mesoderm of the lung primordium controls lung bud formation by activating Fgf10 expression; ectopic Tbx4 induced ectopic bud formation in the esophagus by inducing Fgf10, and interference with Tbx4 suppressed Fgf10 and prevented lung bud formation. Tbx4 also regulates Nkx2.1 in respiratory endoderm and controls tracheo-esophageal septum formation. In ovo electroporation (gain- and loss-of-function) in chick embryos, in situ hybridization for Fgf10 and Nkx2.1 Development High 12588840
2004 TBX4 and TBX5 interact with a PDZ-LIM protein (chicken LMP-4) via distinct LIM domains; LMP-4 tethers TBX4 (and TBX5) to the cytoskeleton, interfering with their nuclear localization. The interaction is specific to the Tbx2/3/4/5 subfamily members Tbx4 and Tbx5, not Tbx2 or Tbx3. Yeast two-hybrid screen, domain mapping of LIM interactions, subcellular co-localization (immunofluorescence), co-expression analysis in chick limb and heart Developmental biology Medium 15302601
2005 Genetic deletion experiments in mouse show that Tbx4 (and Tbx5) are required for initiation of limb outgrowth but do not determine limb-specific morphologies; Pitx1, not Tbx4, specifies hindlimb-specific morphology. Conditional and constitutive gene deletion in mouse, morphological and molecular marker analysis Developmental cell High 15621531
2007 Conditional ablation of Tbx4 before limb bud initiation blocks hindlimb outgrowth, but ablation shortly after limb bud onset does not affect outgrowth or Fgf10 expression, revealing a brief early developmental window for Tbx4 function. Post-initiation loss of Tbx4 causes reduction of limb core tissue and proximal skeletal hypoplasia without altering hindlimb identity. Conditional gene deletion (Cre-lox) in mouse at different developmental stages, in situ hybridization, skeletal analysis Development High 17164415
2008 Two independent hindlimb enhancers (HLEA and HLEB) control Tbx4 expression in the hindlimb bud; deletion of HLEA reduces Tbx4 hindlimb expression and produces viable mice with hindlimb-specific bone size changes, demonstrating separable cis-regulatory control of Tbx4 levels and downstream bone size specification. Comparative genomics, transgenic reporter assays in mice, targeted HLEA deletion from endogenous mouse locus Development High 18579682
2011 Pitx1 is necessary for normal Tbx4 expression levels in the hindlimb bud to support hindlimb outgrowth; using transgenic gene replacement, the outgrowth function of Pitx1 was shown to operate through Tbx4 regulation, while hindlimb morphology specification by Pitx1 is independent of Tbx4. Transgenic gene replacement strategy in Pitx1 mutant mouse, conditional expression, molecular marker and skeletal analysis Development High 22071103
2011 Tbx4-Cre lineage tracing reveals that Tbx4-expressing cells in the allantois give rise to peri-vascular tissue but not endothelial cells; despite Tbx4's requirement for allantoic vasculogenesis, the umbilical vasculature is never Tbx4-lineage, indicating endothelial and peri-vascular lineages are segregated before vasculogenesis onset. Tbx4-Cre lineage tracing in mouse, immunofluorescence, in situ hybridization Developmental dynamics High 21932311
2012 Tbx4 and Tbx5 are required in lung mesenchyme for lung branching morphogenesis; double conditional mutants show severely reduced branching with downregulation of Wnt2, Fgf10, Bmp4, and Spry2. Tbx4 and Tbx5 genetically interact with Fgf10 during lung growth/branching but not during tracheal cartilage development. Loss of Tbx5 alone causes loss of lung bud specification. Conditional mutagenesis (Cre-lox) in mouse, organ culture, in situ hybridization, genetic interaction analysis PLoS genetics High 22876201
2012 Tbx4 regulates multiple downstream genes in the allantois including extracellular matrix molecules (Vcan, Has2, Itgα5), transcription factors (Snai1, Twist), and signaling molecules (Bmp2, Bmp7, Notch2, Jag1, Wnt2). Tbx4 mutant allantois vascular phenotype can be rescued ex vivo by Wnt pathway agonists, and Tbx4;Wnt2 double heterozygotes show decreased placental vasculature, placing Tbx4 upstream of canonical Wnt signaling in allantoic vascular formation. Candidate gene expression analysis in Tbx4 mutant allantois, ex vivo rescue with Wnt agonists/inhibitors, double heterozygous genetic interaction in mouse PloS one Medium 22952711
2013 A Tbx4 lung enhancer element drives lung mesenchyme-specific expression; a Tbx4 enhancer-rtTA transgenic system enables temporal targeting of specific lung mesenchymal cell types (endothelial cells, vascular smooth muscle, airway smooth muscle, fibroblasts, pericytes) in a doxycycline-dependent manner. Transgenic mouse (Tbx4 lung enhancer-rtTA Tet-On), Cre reporter lineage tracing, immunostaining BMC biology Medium 24225400
2014 Tbx4 directly binds T-box binding sites within the Shox2/SHOX2 promoter (shown by EMSA) and transcriptionally activates Shox2 in fore- and hindlimbs; reciprocally, Shox2 inhibits Tbx4 specifically in forelimbs, establishing a feedback regulatory loop between Tbx4 and Shox2. EMSA (electrophoretic mobility shift assay), expression profiling in Shox2-/- limbs, in situ hybridization Developmental dynamics Medium 24347445
2016 TBX4 is expressed in lung mesenchymal progenitors that are the predominant source of myofibroblasts in injured adult lung; ablation of TBX4-expressing cells or disruption of TBX4 signaling attenuates bleomycin-induced lung fibrosis. TBX4 regulates hyaluronan synthase 2 (HAS2) production to enable fibroblast matrix invasion. In vivo lineage tracing, cell ablation, conditional disruption in mouse (bleomycin model), fibroblast invasion assays in murine and human cells Journal of Clinical Investigation High 27400124
2017 TBX4 is required for lung fibroblast proliferation and collagen gel contraction capacity; TBX4 is associated with super-enhancers in lung fibroblasts and broadly regulates fibroblast-related transcriptional programs including partly super-enhancer-mediated pathways. CAGE sequencing, TBX4 knockdown with functional assays (proliferation, collagen gel contraction), transcriptome analysis American journal of physiology. Lung cellular and molecular physiology Medium 28971975
2021 ChIP-seq in human fetal lung fibroblasts (IMR-90) identified 1,862 TBX4 genome-wide binding sites, with 18.79% in gene promoter regions; TBX4 binding sites are enriched near FOXF1 and its antisense lncRNA FENDRR, indicating TBX4-FGF10 signaling may directly interact with SHH-FOXF1 signaling during lung branching. ChIP-seq in human fetal lung fibroblasts, bioinformatic pathway enrichment and motif analysis Respiratory research Medium 33478486
2021 Tbx4, Pitx1, and Isl1 act cooperatively in a gene regulatory network to establish the hindlimb bud; Tbx4 mutant mice show failure in early differentiation of chondroprogenitors into chondrocytes (shown by live imaging of micromass culture), explaining proximally biased limb defects in Tbx4 mutants. Genetic epistasis (triple mutant analysis), live image analysis of chondrogenesis in micromass culture, conditional KO Development High 34423345
2022 TBX4 directly regulates transcriptional activity of FGF10; TBX4 variant proteins with disrupted nuclear localization signal or poor DNA-binding affinity fail to activate the FGF10 gene as shown by luciferase assay and ChIP. Ex vivo inhibition of Tbx4 downregulates Tie2 and KLF4 in lung. Luciferase reporter assay, immunocytochemistry, ChIP, ex vivo lung explant inhibition Journal of molecular and cellular cardiology High 35914404
2022 Functional assessment using a luciferase reporter with T-BOX binding motifs revealed that TBX4 missense variants can cause either loss-of-function or gain-of-function effects; gain-of-function mutations are associated with older age at lung disease diagnosis compared to loss-of-function. Variants in the T-BOX and nuclear localization domains correlate with earlier and more severe disease. Luciferase reporter assay with T-BOX binding motifs for 42 missense variants, genotype-phenotype correlation in multicenter cohort American journal of respiratory and critical care medicine Medium 35852389
2022 TBX4 mutants with reduced binding efficiency to the FGF10 promoter show decreased FGF10 expression and reduced differentiation of mesenchymal stem cells; ChIP confirmed that TBX4 mutants still bind the FGF10 promoter but with reduced efficiency, and dual luciferase assays confirmed reduced transactivation. Stable overexpression in MSCs, immunofluorescence, ChIP, dual luciferase reporter assay International journal of molecular sciences Medium 35216193
2025 Loss of Tbx4 in lung mesenchyme-specific conditional KO mice causes postnatal alveolar simplification, decreased vessel density, increased vessel wall thickness, and pulmonary hypertension (elevated RVSP and Fulton index); RNA-seq revealed enrichment of pathways relevant to alveologenesis, angiogenesis, and PH. Conditional KO (Cre-lox, mesenchyme-specific), histomorphometry, right ventricular pressure measurement, bulk RNA-seq American journal of respiratory cell and molecular biology High 40106779
2025 TBX4 knockdown in lung fibroblasts and pericytes (combined RNA-seq and ChIP-seq) identified 555 direct TBX4 target genes involved in extracellular matrix, actin organization, migration guidance, serine/threonine kinase signaling, and GTPase signaling; functional migration and proliferation defects confirmed by TBX4 knockdown. RNA-seq (TBX4 KD in fibroblasts and pericytes) combined with ChIP-seq, migration and proliferation functional assays Pulmonary circulation Medium 39980707
2025 Lung mesenchyme-specific Tbx4 loss of function causes excessive postnatal smooth muscle differentiation across multiple pulmonary compartments including medial thickening, distal muscularization, and prominent subpleural smooth muscle bands, identifying TBX4 as a critical suppressor of smooth muscle differentiation. Additional heterozygous Tbx5 loss exacerbates vascular phenotypes. Conditional KO in mouse (lung mesenchyme-specific), echocardiography, 3D whole-mount analysis, high-resolution spatial quantitation, genetic interaction with Tbx5 bioRxivpreprint Medium
2019 TTTY15 lncRNA promotes TBX4 expression by interacting with DNMT3A; TTTY15 knockdown increased binding of DNMT3A to the TBX4 promoter, suppressing TBX4 expression in non-small cell lung cancer cells. RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), TTTY15 knockdown with TBX4 expression measurement International journal of molecular sciences Low 31311130

Source papers

Stage 0 corpus · 76 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature 234 10235264
1999 Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity. Science (New York, N.Y.) 232 10073939
2003 Loss of Tbx4 blocks hindlimb development and affects vascularization and fusion of the allantois. Development (Cambridge, England) 207 12736212
1999 Tbx5 and Tbx4 genes determine the wing/leg identity of limb buds. Nature 205 10235263
2012 Multiple roles and interactions of Tbx4 and Tbx5 in development of the respiratory system. PLoS genetics 156 22876201
2013 TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension. Journal of medical genetics 154 23592887
2004 Mutations in the human TBX4 gene cause small patella syndrome. American journal of human genetics 137 15106123
2005 Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth. Developmental cell 119 15621531
2003 Tbx4-Fgf10 system controls lung bud formation during chicken embryonic development. Development (Cambridge, England) 111 12588840
2016 Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis. The Journal of clinical investigation 100 27400124
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
2019 Phenotype characterisation of TBX4 mutation and deletion carriers with neonatal and paediatric pulmonary hypertension. The European respiratory journal 86 31151956
2008 Dual hindlimb control elements in the Tbx4 gene and region-specific control of bone size in vertebrate limbs. Development (Cambridge, England) 78 18579682
2013 Spatial-temporal targeting of lung-specific mesenchyme by a Tbx4 enhancer. BMC biology 76 24225400
2007 Tbx4 is not required for hindlimb identity or post-bud hindlimb outgrowth. Development (Cambridge, England) 75 17164415
2004 Tbx5 and Tbx4 transcription factors interact with a new chicken PDZ-LIM protein in limb and heart development. Developmental biology 62 15302601
2016 Phenotypic expansion of TBX4 mutations to include acinar dysplasia of the lungs. American journal of medical genetics. Part A 56 27374786
2010 Familial isolated clubfoot is associated with recurrent chromosome 17q23.1q23.2 microduplications containing TBX4. American journal of human genetics 55 20598276
1999 Differential expression of Tbx4 and Tbx5 in Zebrafish fin buds. Mechanisms of development 55 10495283
2011 Microdeletion of 17q22q23.2 encompassing TBX2 and TBX4 in a patient with congenital microcephaly, thyroid duct cyst, sensorineural hearing loss, and pulmonary hypertension. American journal of medical genetics. Part A 54 21271665
2020 Phenotype and outcome of pulmonary arterial hypertension patients carrying a TBX4 mutation. The European respiratory journal 53 32079640
2011 Identity and fate of Tbx4-expressing cells reveal developmental cell fate decisions in the allantois, limb, and external genitalia. Developmental dynamics : an official publication of the American Association of Anatomists 50 21932311
2011 Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control. Development (Cambridge, England) 50 22071103
2009 Tbx4/5 gene duplication and the origin of vertebrate paired appendages. Proceedings of the National Academy of Sciences of the United States of America 47 19995988
2018 Neonatal Lung Disease Associated with TBX4 Mutations. The Journal of pediatrics 46 30413314
2017 TBX4 is involved in the super-enhancer-driven transcriptional programs underlying features specific to lung fibroblasts. American journal of physiology. Lung cellular and molecular physiology 43 28971975
2002 Different regulation of T-box genes Tbx4 and Tbx5 during limb development and limb regeneration. Developmental biology 41 12376111
2012 Studies of TBX4 and chromosome 17q23.1q23.2: an uncommon cause of nonsyndromic clubfoot. American journal of medical genetics. Part A 35 22678995
2019 Male-Specific Long Noncoding RNA TTTY15 Inhibits Non-Small Cell Lung Cancer Proliferation and Metastasis via TBX4. International journal of molecular sciences 32 31311130
2022 First Genotype-Phenotype Study in TBX4 Syndrome: Gain-of-Function Mutations Causative for Lung Disease. American journal of respiratory and critical care medicine 30 35852389
2016 Molecular Analysis of BMPR2, TBX4, and KCNK3 and Genotype-Phenotype Correlations in Spanish Patients and Families With Idiopathic and Hereditary Pulmonary Arterial Hypertension. Revista espanola de cardiologia (English ed.) 29 27453251
2023 Molecular Function and Contribution of TBX4 in Development and Disease. American journal of respiratory and critical care medicine 27 36367783
2014 Familial microduplication of 17q23.1–q23.2 involving TBX4 is associated with congenital clubfoot and reduced penetrance in females. American journal of medical genetics. Part A 25 24592505
2020 Clinical heterogeneity of Pulmonary Arterial Hypertension associated with variants in TBX4. PloS one 23 32348326
2019 Identification of a deletion containing TBX4 in a neonate with acinar dysplasia by rapid exome sequencing. American journal of medical genetics. Part A 22 30828993
2000 Virtual cloning and physical mapping of a human T-box gene, TBX4. Genomics 22 10945475
2020 TBX4 variants and pulmonary diseases: getting out of the 'Box'. Current opinion in pulmonary medicine 21 32195678
2021 Potential interactions between the TBX4-FGF10 and SHH-FOXF1 signaling during human lung development revealed using ChIP-seq. Respiratory research 17 33478486
2006 Level-specific role of paraxial mesoderm in regulation of Tbx5/Tbx4 expression and limb initiation. Developmental biology 16 16480709
2021 Tbx4 function during hindlimb development reveals a mechanism that explains the origins of proximal limb defects. Development (Cambridge, England) 15 34423345
2014 Tbx4 interacts with the short stature homeobox gene Shox2 in limb development. Developmental dynamics : an official publication of the American Association of Anatomists 15 24347445
2012 Candidate gene approach identifies multiple genes and signaling pathways downstream of Tbx4 in the developing allantois. PloS one 14 22952711
2006 Genitopatellar syndrome: expanding the phenotype and excluding mutations in LMX1B and TBX4. American journal of medical genetics. Part A 14 16761293
2022 Genetic and functional analyses of TBX4 reveal novel mechanisms underlying pulmonary arterial hypertension. Journal of molecular and cellular cardiology 12 35914404
2020 A newly recognized multiple malformation syndrome with caudal regression associated with a biallelic c.402G>A variant in TBX4. European journal of human genetics : EJHG 11 31965066
2022 Persistence of persistent pulmonary hypertension of the newborn: A case of de novo TBX4 variant. Pulmonary circulation 9 35874850
2019 Genome Sequencing of the Japanese Eel (Anguilla japonica) for Comparative Genomic Studies on tbx4 and a tbx4 Gene Cluster in Teleost Fishes. Marine drugs 9 31330852
2022 Divergence of Tbx4 hindlimb enhancer HLEA underlies the hindlimb loss during cetacean evolution. Genomics 7 35134498
2024 Neonatal persistent pulmonary hypertension related to a novel TBX4 mutation: case report and review of the literature. Italian journal of pediatrics 6 38443964
2023 Diminished TMEM100 Expression in a Newborn With Acinar Dysplasia and a Novel TBX4 Variant: A Case Report. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 6 38044468
2013 Investigating the role of tbx4 in the female germline in mice. Biology of reproduction 6 24089201
2024 Computed tomographic findings in TBX4 mutation: a common cause of severe pulmonary artery hypertension in children. Pediatric radiology 5 38191808
2023 An intronic variant in TBX4 in a single family with variable and severe pulmonary manifestations. NPJ genomic medicine 5 36878902
2010 Mesenchymal expression of Tbx4 gene is not altered in Adriamycin mouse model. Pediatric surgery international 5 20182749
2025 Loss of Tbx4 Affects Postnatal Lung Development and Predisposes to Pulmonary Hypertension. American journal of respiratory cell and molecular biology 4 40106779
2023 COL1A1 regulates the apoptosis of embryonic stem cells by mediating the PITX1/TBX4 signaling. Birth defects research 4 38158794
2022 Identification and Functional Evaluation of a Novel TBX4 Mutation Underlies Small Patella Syndrome. International journal of molecular sciences 4 35216193
2022 Screening and identification of miRNAs regulating Tbx4/5 genes of Pampus argenteus. PeerJ 4 36312751
2021 Rare TBX4 Variant Causing Pulmonary Arterial Hypertension With Small Patella Syndrome in an Adult Man. JACC. Case reports 4 34557690
2007 Sequence variation in the Tbx4 gene in marine mammals. Zoological science 4 17867844
2024 Loss of Tbx4 Affects Postnatal Lung Development and Predisposes to Pulmonary Hypertension. bioRxiv : the preprint server for biology 3 39345561
2023 A novel non-recurrent CNV deletion involving TBX4 and leaving TBX2 intact causes congenital alveolar dysplasia. Clinical genetics 3 37821225
2019 Abnormal expression of TBX4 during anorectal development in rat embryos with ethylenethiourea-induced anorectal malformations. Biological research 3 31054579
2024 Novel function of Hox13 in regulating outgrowth of the newt hindlimb bud through interaction with Fgf10 and Tbx4. Development, growth & differentiation 2 39725403
2024 The Glu86 Residue in TBX4 Proves Critical for Human Lung Development. American journal of medical genetics. Part A 1 39552269
2023 Long-Term Effect of TBX4 Germline Mutation on Pulmonary Clinico-Histopathologic Phenotype. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 1 37801629
2025 RNA-Seq and ChIP-Seq Identification of Unique and Overlapping Target Genes and Pathways Regulated by TBX4 in Human Pulmonary Fibroblasts and Pericytes. Pulmonary circulation 0 39980707
2025 Primary Pulmonary Hypoplasia With Congenital Alveolar Dysplasia Associated With TBX4 Gene Deletion: A Case With Autopsy and Molecular Findings. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 0 40008593
2025 Functional evidence supports the potential role of Tbx4-HLEA in the hindlimb degeneration of cetaceans. EvoDevo 0 40121501
2025 Decreased Level of TMEM100 in Neonates With Lethal Lung Developmental Disorders due to Abnormalities in SHH-FOXF1 and TBX4-FGF10 Signaling Pathways. American journal of medical genetics. Part A 0 40145339
2025 Implementing pulmonary arterial hypertension screening among TBX4 mutation carriers: a timely endeavour. ERJ open research 0 40166048
2025 Postnatally induced TBX4 insufficiency confers pulmonary hypertension and impairs lung development in infant mice. Pediatric research 0 40542095
2025 Highly Variable Expressivity of a CNV Deletion Involving TBX4 in Three Deceased Siblings With Lung Developmental Disorder and Their Mildly Affected Mother and Grandfather. Clinical genetics 0 40542660
2025 Pulmonary Arterial Hypertension Onset in an Adult Woman With a TBX4 Likely Pathogenic Variant Following Imatinib Administration: A Case Report. American journal of medical genetics. Part A 0 40613724
2025 Generation of 5 hiPSC lines from pediatric patients with Heritable pulmonary arterial hypertension (HPAH) caused by heterozygous mutations in the TBX4 gene. Stem cell research 0 41406515
2024 A novel frameshift TBX4 variant in a family with ischio-coxo-podo-patellar syndrome and variable severity. Genes & genomics 0 39467966