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Murakami et al. (2005) found that TAZ (WWTR1; 300394) was a potent TBX5 transactivator. TAZ associated with TBX5 and stimulated TBX5-dependent promoters by interacting with the histone acetyltransferases p300 (EP300; 602700) and PCAF (602303). YAP (606608), a TAZ-related protein, also stimulated TBX5-dependent transcription. TBX5 with HOS-associated truncation mutations could not be stimulated by TAZ, but TBX5 with HOS-associated point mutations was unimpaired in its ability to respond to TAZ.
In 3 members of a family with ulnar-mammary syndrome, Meneghini et al. (2006) identified a single-basepair insertion ( 601621.0007) in exon 6 of the TBX3 gene, resulting in a frameshift and premature stop codon. This mutation was downstream of the T-box DNA-binding domain and thus did not disrupt or alter the T-domain. The authors reviewed the data on previously reported variants and hypothesized a genotype-phenotype correlation, with mutations that disrupt the T-box DNA-binding domain associated with a more severe phenotype. Basson et al. (1999) showed that TBX5 mutations predicted to create null alleles caused substantial abnormalities in both limb and heart. In contrast, missense mutations of the TBX5 gene produced distinct phenotypes: gly80 to arg ( 601620.0004) caused significant cardiac malformations but only minor skeletal abnormalities, whereas 2 mutations of codon 237, arg237 to gln ( 601620.0003) and arg237 to trp ( 601620.0005), caused extensive upper limb malformations but less significant cardiac abnormalities. They noted that residue 80 is highly conserved within T-box sequences that interact with the major groove of target DNA, whereas residue 237 is located in the T-box domain that selectively binds to the minor groove of DNA. Niwa et al. (2009) showed that 2 LIF ( 159540) signaling pathways are each connected to the core circuitry required to maintain pluripotency via different transcription factors. In mouse embryonic stem cells, Klf4 ( 602253) is mainly activated by the Jak-Stat3 pathway and preferentially activates Sox2 ( 184429), whereas Tbx3 is preferentially regulated by the phosphatidylinositol-3-OH kinase-Akt and mitogen-activated protein kinase pathways and predominantly stimulates Nanog ( 607937). In the absence of Lif, artificial expression of Klf4 or Tbx3 was sufficient to maintain pluripotency while maintaining the expression of Oct3/4 ( 164177). Notably, overexpression of Nanog supported Lif-independent self-renewal of mouse embryonic stem cells in the absence of Klf4 and Tbx3 activity. Therefore, Niwa et al. (2009) concluded that KLF4 and TBX3 are involved in mediating LIF signaling to the core circuitry but are not directly associated with the maintenance of pluripotency, because embryonic stem cells keep pluripotency without their expression in the particular context.
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Human mutations in TBX5, a gene encoding a T-box transcription factor, and SALL4 (607343), a gene encoding a zinc finger transcription factor, cause similar upper limb and heart defects. Mutations in SALL4 are responsible for the Duane-radial ray syndrome (607323); mutations in TBX5 are responsible for the Holt-Oram syndrome (142900). Koshiba-Takeuchi et al. (2006) showed that Tbx5 regulates Sall4 expression in the developing mouse forelimb and heart; mice heterozygous for a gene trap allele of Sall4 showed limb and heart defects that modeled human disease. Tbx5 and Sall4 interacted both positively and negatively to finely regulate patterning and morphogenesis of the anterior forelimb and heart. Thus, a positive and negative feed-forward circuit between Tbx5 and Sall4 ensures precise patterning of embryonic limb and heart and provides a unifying mechanism for heart/hand syndromes. Conception and design: ZY, XW, and QZ. Administrative support: XW, HL, and QZ. Experiment operation: HL, ZY, LS, YK, RL, XZ, YG, and CL. Data analysis and interpretation: HL, QZ, ZY, and LS. Manuscript writing: all authors. Final approval of manuscript: all authors. All authors contributed to the article and approved the submitted version. Funding Liquid Chromatography Coupled to Mass Spectrometry (LC-MS) Detection and Principal Component Analysis (PCA) They receive free parking between the hours of 7.30pm and 8.00am while visiting the child. This would apply to a maximum of 2 vehicles.
To understand better the role of TBX5 in forelimb and heart development, Basson et al. (1999) studied the clinical features of Holt-Oram syndrome caused by 10 different TBX5 mutations. Defects predicted to create null alleles caused substantial abnormalities in both limb and heart. In contrast, missense mutations produced distinct phenotypes: gly80-to-arg (601620.0004) caused significant cardiac malformations but only minor skeletal abnormalities, whereas arg237-to-gln (601620.0003) and arg237-to-trp (601620.0005) caused extensive upper limb malformations but less significant cardiac abnormalities. Amino acids altered by missense mutations were located on the 3-dimensional structure of a related T-box transcription factor, Xbra (of X. laevis), bound to DNA. Residue 80 is highly conserved within T-box sequences that interact with the major groove of target DNA; residue 237 is located in the T-box domain that selectively binds to the minor groove of DNA. These structural data, taken together with the predominant cardiac or skeletal phenotype produced by each missense mutation, suggested that organ-specific gene activation by TBX5 is predicated on biophysical interactions with different target DNA sequences. Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q.
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Wiese, C., Grieskamp, T., Airik, R., Mommersteeg, M. T. M., Gardiwal, A., de Gier-de Vries, C., Schuster-Gossler, K., Moorman, A. F. M., Kispert, A., Christoffels, V. M.
In the mouse, 4 of the T-box genes, i.e., the T locus (601397), Tbx1 (602054), Tbx6 (602427), and Tbr1, are dispersed throughout the genome. Li et al. (1997) noted that the other family members, Tbx2 (600747) to Tbx5, exist as 2 clusters, having evolved from a common ancestor by 2 duplication events. Tbx2 and Tbx4 (601719) map together on mouse chromosome 11 (TBX2 is on 17q in the human), and Tbx3 and Tbx5 map on mouse chromosome 5 and human chromosome 12, respectively. However, it is Tbx2 and Tbx3 that form a cognate pair, likewise Tbx4 and Tbx5, with each pair showing related limb-associated expression. Sowden et al. (2001) examined the role of Drosophila 'optomotor blind' (omb)-related T-box genes in the development of human and mouse retina. Murine Tbx2 ( 600747), Tbx3, and Tbx5 and human TBX2 cDNAs were isolated from retina cDNA libraries by hybridization to the Drosophila omb gene. Human and mouse TBX2, TBX3, and TBX5 were expressed asymmetrically across the embryonic neural retina, with highest levels of mRNA within dorsal and peripheral retina. The dorsoventral gradient of TBX2 expression disappeared before the ganglion cell layer (GCL) formed. Its expression became restricted to the inner neuroblastic retina and later to the GCL and inner nuclear layer (INL). The dorsal expression domains of TBX5 and TBX3 were maintained during formation of the GCL. As the retina matured, TBX3 expression was restricted to the INL, and TBX5 was expressed within the GCL. The authors concluded that the expression patterns of TBX2, TBX3, and TBX5 within the developing retina support the idea that the encoded transcription factors play a role in providing positional information important for topographic mapping in differentiation of distinct cell types across the laminar axis of the retina. After WI-38 cells were irradiated by carbon ion 2 Gy, the culture medium was collected at 24h, and the differential factors in the culture medium were detected by LC-MS.LC-TOFMS (Agilent,1290 Infinity LC, 6530 UHD, and Accurate-Mass Q-TOF/MS) was used for the metabonomic profiling of all samples in the study. The profiling procedure (sample preparation, metabolite separation and detection, metabonomic data preprocessing, metabolite annotation, and statistical analysis for biomarker identification) was performed following our previously published protocols with minor modifications. The separation column was a C18 column (Agilent, 100mm × 2.1mm, 1.8 μm). The chromatographic separation conditions are as follows: column temperature 40 °C, flow rate 0.4 ml/min; mobile phase A: water + 0.1% formic acid, B: acetonitrile + 0.1% formic acid; according to a certain gradient elution procedure. The injection volume is 4ul and the temperature of the automatic injector is 4°C. Data Analysis and Statistics Basson et al. (1999) identified heterozygous mutations in the TBX5 gene in affected members of several families segregating HOS (see, e.g., 601620.0002- 601620.0005).
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The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Author Contributions Hiroi et al. (2001) found that TBX5 associates with NKX2-5 (600584) and synergistically promotes cardiomyocyte differentiation. Both directly bind to the promoter of the gene encoding cardiac-specific natriuretic peptide precursor type A (NPPA; 108780) in tandem, and the 2 transcription factors show synergistic activation. P19CL6 cells efficiently differentiate into beating cardiomyocytes expressing cardiac-specific genes after treatment with 1% dimethyl sulfoxide (DMSO). Hiroi et al. (2001) found that P19CL6 cell lines overexpressing wildtype Tbx5 started to beat earlier and expressed cardiac-specific genes more abundantly than did parental P19CL6 cells, whereas cell lines expressing the G80R mutation (601620.0004), which causes substantial cardiac defects with minor skeletal abnormalities in HOS, did not differentiate into beating cardiomyocytes. Contrariwise, the R237Q mutation (601620.0003), which causes upper limb malformations without cardiac abnormalities, activated the Nppa promoter to an extent similar to that of wildtype TBX5. Newbury-Ecob et al. (1996) reported a detailed study of a large cohort of patients that included 44 familial and 11 sporadic cases. Association of cardiac and radial abnormalities was a criterion for inclusion of familial cases. Limb defects were found in all affected persons. The thumb was the most commonly affected structure, although in 7 of 44 cases, the thumbs were normal. In most cases, the thumb defects (absence in 19/44, hypoplasia in 17/44, triphalangeal thumbs in 8/44) were associated with hypoplastic thenar or limited supination of the forearm. Radial hypoplasia (18/44) was more frequent than absence of radius (10/44). Ulnar hypoplasia occurred only in patients with radial defects. Most patients had narrow, sloping shoulders. Limb defects were always bilateral and often asymmetrical, the left side being more severely affected. Cardiac involvement was found in 95% of familial cases; secundum atrial septal defect (15) and ventricular septal defect (11) were the most common defects. In 17 of the familial cases, only ECG abnormalities were found. Both cardiac and limb abnormalities were more severe in the sporadic group. Newbury-Ecob et al. (1996) found a significant positive correlation (r = 0.49) between severity of the limb and cardiac defects. The patients with atrial septal defects had more severe limb abnormalities. Correlation between sibs was greater than that between parent and offspring.
Koshiba-Takeuchi, K., Takeuchi, J. K., Matsumoto, K., Momose, T., Uno, K., Hoepker, V., Ogura, K., Takahashi, N., Nakamura, H., Yasuda, K., Ogura, T.In affected members of a large 3-generation Turkish family segregating autosomal dominant ulnar-mammary syndrome, Wollnik et al. (2002) identified heterozygosity for a frameshift mutation in TBX3 ( 601621.0004). Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3. By microdissection of the mouse ventricular conduction system, followed by serial analysis of gene expression (SAGE) of the left bundle branch, Moskowitz et al. (2007) identified Id2 (600386) as a conduction system-specific transcript. Analysis of the Id2 promoter showed that conduction system-specific expression of Id2 was dependent on Nkx2.5 and Tbx5. Moskowitz et al. (2007) concluded that a molecular pathway including Id2, Nkx2.5, and Tbx5 coordinates specification of ventricular myocytes into the ventricular conduction system lineage. The article were supported by the Lanzhou Innovation and Entrepreneurship Talent Project (award number: 2017-RC-23/2020-RC-113) and the Science and Technology Plan Project of Chengguan District, Lanzhou (award number: no. 2020-2-2-5). Conflict of Interest
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