Journal articles: 'Tbx16'

1

Lardelli, Michael. "The evolutionary relationships of zebrafish genes tbx6 , tbx16 / spadetail and mga." Development Genes and Evolution 213, no. 10 (October 1, 2003): 519–22. http://dx.doi.org/10.1007/s00427-003-0348-2.

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Wells, Simon, Svanhild Nornes, and Michael Lardelli. "Transgenic Zebrafish Recapitulating tbx16 Gene Early Developmental Expression." PLoS ONE 6, no. 6 (June 24, 2011): e21559. http://dx.doi.org/10.1371/journal.pone.0021559.

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Payumo, Alexander Y., Lindsey E. McQuade, Whitney J. Walker, Sayumi Yamazoe, and James K. Chen. "Tbx16 regulates hox gene activation in mesodermal progenitor cells." Nature Chemical Biology 12, no. 9 (July 4, 2016): 694–701. http://dx.doi.org/10.1038/nchembio.2124.

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Muyskens, Jonathan B., and Charles B. Kimmel. "Tbx16 cooperates with Wnt11 in assembling the zebrafish organizer." Mechanisms of Development 124, no. 1 (January 2007): 35–42. http://dx.doi.org/10.1016/j.mod.2006.09.003.

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Warga, Rachel M., Rachel L. Mueller, Robert K. Ho, and Donald A. Kane. "Zebrafish Tbx16 regulates intermediate mesoderm cell fate by attenuating Fgf activity." Developmental Biology 383, no. 1 (November 2013): 75–89. http://dx.doi.org/10.1016/j.ydbio.2013.08.018.

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Nagel, Stefan, and Corinna Meyer. "Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma." PLOS ONE 16, no. 11 (November 22, 2021): e0259674. http://dx.doi.org/10.1371/journal.pone.0259674.

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T-box genes encode transcription factors which control basic processes in development of several tissues including cell differentiation in the hematopoietic system. Here, we analyzed the physiological activities of all 17 human T-box genes in early hematopoiesis and in lymphopoiesis including developing and mature B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells. The resultant expression pattern comprised six genes, namely EOMES, MGA, TBX1, TBX10, TBX19 and TBX21. We termed this gene signature TBX-code which enables discrimination of normal and aberrant activities of T-box genes in lymphoid malignancies. Accordingly, expression analysis of T-box genes in Hodgkin lymphoma (HL) patients using a public profiling dataset revealed overexpression of EOMES, TBX1, TBX2, TBX3, TBX10, TBX19, TBX21 and TBXT while MGA showed aberrant downregulation. Analysis of T-cell acute lymphoid leukemia patients indicated aberrant overexpression of six T-box genes while no deregulated T-box genes were detected in anaplastic large cell lymphoma patients. As a paradigm we focused on TBX3 which was ectopically activated in about 6% of HL patients analyzed. Normally, TBX3 is expressed in tissues like lung, adrenal gland and retina but not in hematopoiesis. HL cell line KM-H2 expressed enhanced TBX3 levels and was used as an in vitro model to identify upstream regulators and downstream targets in this malignancy. Genomic studies of this cell line showed focal amplification of the TBX3 locus at 12q24 which may underlie its aberrant expression. In addition, promoter analysis and comparative expression profiling of HL cell lines followed by knockdown experiments revealed overexpressed transcription factors E2F4 and FOXC1 and chromatin modulator KDM2B as functional activators. Furthermore, we identified repressed target genes of TBX3 in HL including CDKN2A, NFKBIB and CD19, indicating its respective oncogenic function in proliferation, NFkB-signaling and B-cell differentiation. Taken together, we have revealed a lymphoid TBX-code and used it to identify an aberrant network around deregulated T-box gene TBX3 in HL which promotes hallmark aberrations of this disease. These findings provide a framework for future studies to evaluate deregulated T-box genes in lymphoid malignancies.

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Ehrlich, Kenneth C., Michelle Lacey, Carl Baribault, Sagnik Sen, Pierre Olivier Esteve, Sriharsa Pradhan, and Melanie Ehrlich. "Promoter-Adjacent DNA Hypermethylation Can Downmodulate Gene Expression: TBX15 in the Muscle Lineage." Epigenomes 6, no. 4 (December 9, 2022): 43. http://dx.doi.org/10.3390/epigenomes6040043.

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TBX15, which encodes a differentiation-related transcription factor, displays promoter-adjacent DNA hypermethylation in myoblasts and skeletal muscle (psoas) that is absent from non-expressing cells in other lineages. By whole-genome bisulfite sequencing (WGBS) and enzymatic methyl-seq (EM-seq), these hypermethylated regions were found to border both sides of a constitutively unmethylated promoter. To understand the functionality of this DNA hypermethylation, we cloned the differentially methylated sequences (DMRs) in CpG-free reporter vectors and tested them for promoter or enhancer activity upon transient transfection. These cloned regions exhibited strong promoter activity and, when placed upstream of a weak promoter, strong enhancer activity specifically in myoblast host cells. In vitro CpG methylation targeted to the DMR sequences in the plasmids resulted in 86–100% loss of promoter or enhancer activity, depending on the insert sequence. These results as well as chromatin epigenetic and transcription profiles for this gene in various cell types support the hypothesis that DNA hypermethylation immediately upstream and downstream of the unmethylated promoter region suppresses enhancer/extended promoter activity, thereby downmodulating, but not silencing, expression in myoblasts and certain kinds of skeletal muscle. This promoter-border hypermethylation was not found in cell types with a silent TBX15 gene, and these cells, instead, exhibit repressive chromatin in and around the promoter. TBX18, TBX2, TBX3 and TBX1 display TBX15-like hypermethylated DMRs at their promoter borders and preferential expression in myoblasts. Therefore, promoter-adjacent DNA hypermethylation for downmodulating transcription to prevent overexpression may be used more frequently for transcription regulation than currently appreciated.

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Jahangiri, Leila, and Fiona Wardle. "Co-regulation of mutual target genes by Ntla and Tbx16 in zebrafish mesoderm development." Developmental Biology 356, no. 1 (August 2011): 261. http://dx.doi.org/10.1016/j.ydbio.2011.05.502.

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9

Manning, Alyssa J., and David Kimelman. "Tbx16 and Msgn1 are required to establish directional cell migration of zebrafish mesodermal progenitors." Developmental Biology 406, no. 2 (October 2015): 172–85. http://dx.doi.org/10.1016/j.ydbio.2015.09.001.

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10

Bouldin, C. M., A. J. Manning, Y. H. Peng, G. H. Farr, K. L. Hung, A. Dong, and D. Kimelman. "Wnt signaling and tbx16 form a bistable switch to commit bipotential progenitors to mesoderm." Development 142, no. 14 (June 10, 2015): 2499–507. http://dx.doi.org/10.1242/dev.124024.

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11

Morrow, Zachary T., Adrienne M. Maxwell, Kazuyuki Hoshijima, Jared C. Talbot, David J. Grunwald, and Sharon L. Amacher. "tbx6l and tbx16 are redundantly required for posterior paraxial mesoderm formation during zebrafish embryogenesis." Developmental Dynamics 246, no. 10 (August 30, 2017): 759–69. http://dx.doi.org/10.1002/dvdy.24547.

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12

Ruvinsky, Ilya, Lee M. Silver, and R. K. Ho. "Characterization of the zebrafish tbx16 gene and evolution of the vertebrate T-box family." Development Genes and Evolution 208, no. 2 (May 5, 1998): 94–99. http://dx.doi.org/10.1007/s004270050158.

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13

Arrington, Cammon B., Annita G. Peterson, and H. Joseph Yost. "Sdc2 and Tbx16 regulate Fgf2-dependent epithelial cell morphogenesis in the ciliated organ of asymmetry." Development 140, no. 19 (September 17, 2013): 4102–9. http://dx.doi.org/10.1242/dev.096933.

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14

Wehn, Amy K., and Deborah L. Chapman. "Tbx18 and Tbx15 null-like phenotypes in mouse embryos expressing Tbx6 in somitic and lateral plate mesoderm." Developmental Biology 347, no. 2 (November 2010): 404–13. http://dx.doi.org/10.1016/j.ydbio.2010.09.001.

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15

Mueller, Rachel LOCKRIDGE, Cheng Huang, and Robert K. Ho. "Spatio-temporal regulation of Wnt and retinoic acid signaling by tbx16/spadetail during zebrafish mesoderm differentiation." BMC Genomics 11, no. 1 (2010): 492. http://dx.doi.org/10.1186/1471-2164-11-492.

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16

Weber, Gerhard J., Sung E. Choe, Kimberly A. Dooley, Noëlle N. Paffett-Lugassy, Yi Zhou, and Leonard I. Zon. "Mutant-specific gene programs in the zebrafish." Blood 106, no. 2 (July 15, 2005): 521–30. http://dx.doi.org/10.1182/blood-2004-11-4541.

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Abstract Hematopoiesis involves the production of stem cells, followed by the orchestrated differentiation of the blood lineages. Genetic screens in zebrafish have identified mutants with defects that disrupt specific stages of hematopoiesis and vasculogenesis, including the cloche, spadetail (tbx16), moonshine (tif1g), bloodless, and vlad tepes (gata1) mutants. To better characterize the blood program, gene expression profiling was carried out in these mutants and in scl-morphants (sclmo). Distinct gene clusters were demarcated by stage-specific and mutant-specific gene regulation. These were found to correlate with the transcriptional program of hematopoietic progenitor cells, as well as of the erythroid, myeloid, and vascular lineages. Among these, several novel hematopoietic and vascular genes were detected, for instance, the erythroid transcription factors znfl2 and ncoa4. A specific regulation was found for myeloid genes, as they were more strongly expressed in vlt mutants compared with other erythroid mutants. A unique gene expression pattern of up-regulated isoprenoid synthesis genes was found in cloche and sclmo, possibly in migrating cells. In conjunction with the high conservation of vertebrate hematopoiesis, the comparison of transcriptional profiles in zebrafish blood mutants represents a versatile and powerful tool to elucidate the genetic regulation of blood and blood vessel development.

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17

Burns, Caroline E., Jenna L. Galloway, Alexandra C. H. Smith, Matthew D. Keefe, Timothy J. Cashman, Elizabeth J. Paik, Elizabeth A. Mayhall, Adam H. Amsterdam, and Leonard I. Zon. "A genetic screen in zebrafish defines a hierarchical network of pathways required for hematopoietic stem cell emergence." Blood 113, no. 23 (June 4, 2009): 5776–82. http://dx.doi.org/10.1182/blood-2008-12-193607.

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Abstract Defining the genetic pathways essential for hematopoietic stem cell (HSC) development remains a fundamental goal impacting stem cell biology and regenerative medicine. To genetically dissect HSC emergence in the aorta-gonad-mesonephros (AGM) region, we screened a collection of insertional zebrafish mutant lines for expression of the HSC marker, c-myb. Nine essential genes were identified, which were subsequently binned into categories representing their proximity to HSC induction. Using overexpression and loss-of-function studies in zebrafish, we ordered these signaling pathways with respect to each other and to the Vegf, Notch, and Runx programs. Overexpression of vegf and notch is sufficient to induce HSCs in the tbx16 mutant, despite a lack of axial vascular organization. Although embryos deficient for artery specification, such as the phospholipase C gamma-1 (plcγ1) mutant, fail to specify HSCs, overexpression of notch or runx1 can rescue their hematopoietic defect. The most proximal HSC mutants, such as hdac1, were found to have no defect in vessel or artery formation. Further analysis demonstrated that hdac1 acts downstream of Notch signaling but upstream or in parallel to runx1 to promote AGM hematopoiesis. Together, our results establish a hierarchy of signaling programs required and sufficient for HSC emergence in the AGM.

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18

Jahangiri, Leila, Andrew C. Nelson, and Fiona C. Wardle. "A cis-regulatory module upstream of deltaC regulated by Ntla and Tbx16 drives expression in the tailbud, presomitic mesoderm and somites." Developmental Biology 371, no. 1 (November 2012): 110–20. http://dx.doi.org/10.1016/j.ydbio.2012.07.002.

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19

Farin, Henner F., Markus Bussen, Martina K. Schmidt, Manvendra K. Singh, Karin Schuster-Gossler, and Andreas Kispert. "Transcriptional Repression by the T-box Proteins Tbx18 and Tbx15 Depends on Groucho Corepressors." Journal of Biological Chemistry 282, no. 35 (June 21, 2007): 25748–59. http://dx.doi.org/10.1074/jbc.m703724200.

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20

Begemann, Gerrit, Yann Gibert, Axel Meyer, and Phillip W. Ingham. "Cloning of zebrafish T-box genes tbx15 and tbx18 and their expression during embryonic development." Mechanisms of Development 114, no. 1-2 (June 2002): 137–41. http://dx.doi.org/10.1016/s0925-4773(02)00040-0.

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21

Tazumi, Shunsuke, Shigeharu Yabe, and Hideho Uchiyama. "Paraxial T-box genes, Tbx6 and Tbx1, are required for cranial chondrogenesis and myogenesis." Developmental Biology 346, no. 2 (October 2010): 170–80. http://dx.doi.org/10.1016/j.ydbio.2010.07.028.

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22

Tazumi, S., S. Yabe, and H. Uchiyama. "P99. Paraxial T-box genes, Tbx6 and Tbx1, are required for cranial chondrogenesis and myogenesis." Differentiation 80 (November 2010): S50. http://dx.doi.org/10.1016/j.diff.2010.09.105.

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23

Lüdtke, Timo H. W., Marc-Jens Kleppa, Reginaldo Rivera-Reyes, Fairouz Qasrawi, Dervla M. Connaughton, Shirlee Shril, Friedhelm Hildebrandt, and Andreas Kispert. "Proteomic analysis identifies ZMYM2 as endogenous binding partner of TBX18 protein in 293 and A549 cells." Biochemical Journal 479, no. 1 (January 14, 2022): 91–109. http://dx.doi.org/10.1042/bcj20210642.

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The TBX18 transcription factor regulates patterning and differentiation programs in the primordia of many organs yet the molecular complexes in which TBX18 resides to exert its crucial transcriptional function in these embryonic contexts have remained elusive. Here, we used 293 and A549 cells as an accessible cell source to search for endogenous protein interaction partners of TBX18 by an unbiased proteomic approach. We tagged endogenous TBX18 by CRISPR/Cas9 targeted genome editing with a triple FLAG peptide, and identified by anti-FLAG affinity purification and subsequent LC–MS analysis the ZMYM2 protein to be statistically enriched together with TBX18 in both 293 and A549 nuclear extracts. Using a variety of assays, we confirmed the binding of TBX18 to ZMYM2, a component of the CoREST transcriptional corepressor complex. Tbx18 is coexpressed with Zmym2 in the mesenchymal compartment of the developing ureter of the mouse, and mutations in TBX18 and in ZMYM2 were recently linked to congenital anomalies in the kidney and urinary tract (CAKUT) in line with a possible in vivo relevance of TBX18–ZMYM2 protein interaction in ureter development.

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Yano, Ayaka, Barbara Nicol, Adele Guerin, and Yann Guiguen. "The duplicated rainbow trout (Oncorhynchus mykiss ) T-box transcription factors 1, tbx1a and tbx1b , are up-regulated during testicular development." Molecular Reproduction and Development 78, no. 3 (February 9, 2011): 172–80. http://dx.doi.org/10.1002/mrd.21279.

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25

Gu, Jin-mo, Sandra I. Grijalva, Natasha Fernandez, Elizabeth Kim, D. Brian Foster, and Hee Cheol Cho. "Induced cardiac pacemaker cells survive metabolic stress owing to their low metabolic demand." Experimental & Molecular Medicine 51, no. 9 (September 2019): 1–12. http://dx.doi.org/10.1038/s12276-019-0303-6.

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Abstract Cardiac pacemaker cells of the sinoatrial node initiate each and every heartbeat. Compared with our understanding of the constituents of their electrical excitation, little is known about the metabolic underpinnings that drive the automaticity of pacemaker myocytes. This lack is largely owing to the scarcity of native cardiac pacemaker myocytes. Here, we take advantage of induced pacemaker myocytes generated by TBX18-mediated reprogramming (TBX18-iPMs) to investigate comparative differences in the metabolic program between pacemaker myocytes and working cardiomyocytes. TBX18-iPMs were more resistant to metabolic stresses, exhibiting higher cell viability upon oxidative stress. TBX18-induced pacemaker myocytes (iPMs) expensed a lower degree of oxidative phosphorylation and displayed a smaller capacity for glycolysis compared with control ventricular myocytes. Furthermore, the mitochondria were smaller in TBX18-iPMs than in the control. We reasoned that a shift in the balance between mitochondrial fusion and fission was responsible for the smaller mitochondria observed in TBX18-iPMs. We identified a mitochondrial inner membrane fusion protein, Opa1, as one of the key mediators of this process and demonstrated that the suppression of Opa1 expression increases the rate of synchronous automaticity in TBX18-iPMs. Taken together, our data demonstrate that TBX18-iPMs exhibit a low metabolic demand that matches their mitochondrial morphology and ability to withstand metabolic insult.

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26

Yi, Cheong-Ho, Jonathan A. Terrett, Quan-Yi Li, Kathryn Ellington, Elizabeth A. Packham, Lindsay Armstrong-Buisseret, Patrick McClure, Tim Slingsby, and J. David Brook. "Identification, Mapping, and Phylogenomic Analysis of Four New Human Members of the T-box Gene Family:EOMES, TBX6, TBX18,andTBX19." Genomics 55, no. 1 (January 1999): 10–20. http://dx.doi.org/10.1006/geno.1998.5632.

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27

Hu, Yannan, Ning Li, Liang Liu, Hao Zhang, Xiang Xue, Xin Shao, Yu Zhang, and Xilong Lang. "Genetically Modified Porcine Mesenchymal Stem Cells by Lentiviral Tbx18 Create a Biological Pacemaker." Stem Cells International 2019 (November 7, 2019): 1–9. http://dx.doi.org/10.1155/2019/3621314.

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Background. Tbx18 is a vital transcription factor involved in embryonic sinoatrial node (SAN) formation process but is gradually vanished after birth. Myocardial injection of lentiviral Tbx18 converts cardiomyocytes into pacemaker-like cells morphologically and functionally. In this in vitro and in vivo study, genetical modification of porcine bone mesenchymal stem cells (BMSCs) by recapturing the Tbx18 expression creates a biological pacemaker which was examined. Methods. The isolated porcine BMSCs were transfected with lentiviral Tbx18, and the induced pacemaker-like cells were analyzed using real-time polymerase chain reaction and western blotting to investigate the efficiency of transformation. Then, the induced pacemaker-like cells were implanted into the right ventricle of the SAN dysfunction porcine model after the differentiation process. Biological pacemaker activity and ectopic pacing region were tested by an electrocardiograph (ECG) monitor. Results. The isolated porcine BMSCs expressed specific surface markers of stem cells; meanwhile, the expression of myocardial markers was upregulated significantly after lentiviral Tbx18 transfection. The porcine SAN dysfunction model was constructed by electrocoagulation using a surgical electrotome. The results showed that the mean heart beat (HR) of BMSCs-Tbx18 was significantly higher than that of BMSCs-GFP. An ectopic pacing region was affirmed into the right ventricle by ECG after implantation of BMSCs-Tbx18. Conclusion. It was verified that Lenti-Tbx18 is capable of transducing porcine BMSCs into pacemaker-like cells. Genetically modified porcine BMSCs by lentiviral Tbx18 could create a biological pacemaker. However, further researches in large-scale animals are required to rule out unexpected complications prior to application in clinical practice.

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Gburcik, Valentina, William P. Cawthorn, Jan Nedergaard, James A. Timmons, and Barbara Cannon. "An essential role for Tbx15 in the differentiation of brown and “brite” but not white adipocytes." American Journal of Physiology-Endocrinology and Metabolism 303, no. 8 (October 15, 2012): E1053—E1060. http://dx.doi.org/10.1152/ajpendo.00104.2012.

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The transcription factor Tbx15 is expressed predominantly in brown adipose tissue and in those white adipose depots that are capable of giving rise to brown-in-white (“brite”/“beige”) adipocytes. Therefore, we have investigated a possible role here of Tbx15 in brown and brite adipocyte differentiation in vitro. Adipocyte precursors were isolated from interscapular and axilliary brown adipose tissues, inguinal white (“brite”) adipose tissue, and epididymal white adipose tissue in 129/Sv mouse pups and differentiated in culture. Differentiation was enhanced by chronic treatment with the PPARγ agonist rosiglitazone plus the sympathetic neurotransmitter norepinephrine. Using short interfering RNAs (siRNA) directed toward Tbx15 in these primary adipocyte cultures, we decreased Tbx15 expression >90%. This resulted in reduced expression levels of adipogenesis markers (PPARγ, aP2). Importantly, Tbx15 knockdown reduced the expression of brown phenotypic marker genes (PRDM16, PGC-1α, Cox8b/Cox4, UCP1) in brown adipocytes and even more markedly in inguinal white adipocytes. In contrast, Tbx15 knockdown had no effect on white adipocytes originating from a depot that is not brite competent in vivo (epididymal). Therefore, Tbx15 may be essential for the development of the adipogenic and thermogenic programs in adipocytes/adipomyocytes capable of developing brown adipocyte features.

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Vitelli, Francesca, Ilaria Taddei, Masae Morishima, Erik N. Meyers, Elizabeth A. Lindsay, and Antonio Baldini. "A genetic link between Tbx1 and fibroblast growth factor signaling." Development 129, no. 19 (October 1, 2002): 4605–11. http://dx.doi.org/10.1242/dev.129.19.4605.

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Tbx1 haploinsufficiency causes aortic arch abnormalities in mice because of early growth and remodeling defects of the fourth pharyngeal arch arteries. The function of Tbx1 in the development of these arteries is probably cell non-autonomous, as the gene is not expressed in structural components of the artery but in the surrounding pharyngeal endoderm. We hypothesized that Tbx1 may trigger signals from the pharyngeal endoderm directed to the underlying mesenchyme. We show that the expression patterns of Fgf8 and Fgf10, which partially overlap with Tbx1 expression pattern, are altered in Tbx1–/– mutants. In particular, Fgf8 expression is abolished in the pharyngeal endoderm. To understand the significance of this finding for the pathogenesis of the mutant Tbx1 phenotype, we crossed Tbx1 and Fgf8 mutants. Double heterozygous Tbx1+/–;Fgf8+/– mutants present with a significantly higher penetrance of aortic arch artery defects than do Tbx1+/–;Fgf8+/+ mutants, while Tbx1+/+;Fgf8+/– animals are normal. We found that Fgf8 mutation increases the severity of the primary defect caused by Tbx1 haploinsufficiency, i.e. early hypoplasia of the fourth pharyngeal arch arteries, consistent with the time and location of the shared expression domain of the two genes. Hence, Tbx1 and Fgf8 interact genetically in the development of the aortic arch. Our data provide the first evidence of a genetic link between Tbx1 and FGF signaling, and the first example of a modifier of the Tbx1 haploinsufficiency phenotype. We speculate that the FGF8 locus might affect the penetrance of cardiovascular defects in individuals with chromosome 22q11 deletions involving TBX1.

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Wehn, Amy K., Deborah R. Farkas, Carly E. Sedlock, Dibya Subedi, and Deborah L. Chapman. "Functionally distinct roles for T and Tbx6 during mouse development." Biology Open 9, no. 8 (August 15, 2020): bio054692. http://dx.doi.org/10.1242/bio.054692.

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ABSTRACTThe mouse T-box transcription factors T and Tbx6 are co-expressed in the primitive streak and have unique domains of expression; T is expressed in the notochord, while Tbx6 is expressed in the presomitic mesoderm. T-box factors are related through a shared DNA binding domain, the T-domain, and can therefore bind to similar DNA sequences at least in vitro. We investigated the functional similarities and differences of T and Tbx6 DNA binding and transcriptional activity in vitro and their interaction genetically in vivo. We show that at one target, Dll1, the T-domains of T and Tbx6 have different affinities for the binding sites present in the mesoderm enhancer. We further show using in vitro assays that T and Tbx6 differentially affect transcription with Tbx6 activating expression tenfold higher than T, that T and Tbx6 can compete at target gene enhancers, and that this competition requires a functional DNA binding domain. Next, we addressed whether T and Tbx6 can compete in vivo. First, we generated embryos that express Tbx6 at greater than wild-type levels embryos and show that these embryos have short tails, resembling the T heterozygous phenotype. Next, using the dominant-negative TWis allele, we show that Tbx6+/− TWis/+ embryos share similarities with embryos homozygous for the Tbx6 hypomorphic allele rib-vertebrae, specifically fusions of several ribs and malformation of some vertebrae. Finally, we tested whether Tbx6 can functionally replace T using a knockin approach, which resulted in severe T null-like phenotypes in chimeric embryos generated with ES cells heterozygous for a Tbx6 knockin at the T locus. Altogether, our results of differences in affinity for DNA binding sites and transcriptional activity for T and Tbx6 provide a potential mechanism for the failure of Tbx6 to functionally replace T and possible competition phenotypes in vivo.

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Fang, Pan-Feng, Rui-Ying Hu, Xing-Yue He, and Xiao-Yan Ding. "Multiple Signaling Pathways Control Tbx6 Expression during Xenopus Myogenesis." Acta Biochimica et Biophysica Sinica 36, no. 6 (June 1, 2004): 390–96. http://dx.doi.org/10.1093/abbs/36.6.390.

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Abstract Tbx6 is critical for somite specification and myogenesis initiation. It has been shown that Activin/Nodal, VegT/Nodal, FGF, and BMP signaling pathways are involved early in specifying mesoderm or later in patterning mesoderm, and Xnot plays roles in setting up the boundary between notochord and paraxial mesoderm. In this study, we introduce the dominant negative form of above genes into embryos to evaluate if they are responsible for regulating Tbx6 expression. The results show that: (1) Activin/Nodal and VegT/Nodal signals are necessary for both initiation and maintenance of Tbx6 expression, and Nodal is sufficient to induce ectopic Tbx6 expression; (2) FGF signal is necessary for the initiation and maintenance of Tbx6, but it is not sufficient to induce Tbx6 expression; (3) BMP is also necessary for the expression of Tbx6, and the induction of Tbx6 expression by BMP is dose dependent; (4) Xnot has no effect on the expression of Tbx6. Our results suggest that several signaling pathways are involved in regulating Tbx6 expression, and pave the route to reveal the molecular mechanism of initiating myogenesis.

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Morine, Yuji, Tohru Utsunomiya, Satoru Imura, Tetsuya Ikemoto, Shuichi Iwahashi, Yu Saito, and Mitsuo Shimada. "Reduction of T-Box 15 gene expression in tumor tissue as a prognostic biomarker for patients with hepatocellular carcinoma." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 341. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.341.

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341 Background: Genome-wide analysis is widely applied to detect molecular alterations in tumor and non-tumor tissue during oncogenesis and tumor progression. We analyzed DNA methylation profiles of hepatocellular carcinoma (HCC), which was is the third-highest cause of cancer-related deaths worldwide, and investigated the clinical role of most heyper-methylated gene, encodes T-box 15 (TBX15), which was originally involved in mesodermal differentiation. Methods: We used an Illumina Infinium HumanMethylation450 BeadChip Kit to conduct a genome-wide analysis of DNA methylation of tumor and non-tumor tissue of 15 patients with HCC. Methylation scores for CpG sites were assigned a Beta-value. Another validation set, which comprised 58 patients with HCC who underwent radical resection, was analyzed to investigate the relationships between tumor phenotype, prognosis, and TBX15 mRNA expression. Results: TBX15 was the most hyper-methylated gene (Beta-value in tumor tissue = 0.52 compared with non-tumor tissue), and TBX15 mRNA levels in tumor tissues were significantly lower compared with those of non-tumor tissues (p < 0.0001). When we assigned a cutoff value = 0.5-fold to define differential expression of TBX15 mRNA, low TBX15 expression significantly correlated with higher serum DCP levels, and the overall survival 5-year survival rates of the low-expression group (n = 17) were significantly shorter compared with those of the high-expression group (n = 41) (43.3% vs. 86.2%, p = 0.001). Multivariate analysis identified low TBX15 expression as an independent prognostic factor for overall and disease-free survival. Conclusions: Genome-wide DNA methylation profiling indicates that hypermethylation and reduced expression of TBX15 in tumor tissue represents a potential biomarker for predicting tumor progression and poor survival of patients with HCC.

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Calmont, Amélie, Naomi Anderson, Jenifer Suntharalingham, Richard Ang, Andrew Tinker, and Peter Scambler. "Defective Vagal Innervation in Murine Tbx1 Mutant Hearts." Journal of Cardiovascular Development and Disease 5, no. 4 (September 23, 2018): 49. http://dx.doi.org/10.3390/jcdd5040049.

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Haploinsufficiency of the T-box transcription factor TBX1 is responsible for many features of 22q11.2 deletion syndrome. Tbx1 is expressed dynamically in the pharyngeal apparatus during mouse development and Tbx1 homozygous mutants display numerous severe defects including abnormal cranial ganglion formation and neural crest cell defects. These abnormalities prompted us to investigate whether parasympathetic (vagal) innervation of the heart was affected in Tbx1 mutant embryos. In this report, we used an allelic series of Tbx1 mouse mutants, embryo tissue explants and cardiac electrophysiology to characterise, in detail, the function of Tbx1 in vagal innervation of the heart. We found that total nerve branch length was significantly reduced in Tbx1+/− and Tbx1neo2/− mutant hearts expressing 50% and 15% levels of Tbx1. We also found that neural crest cells migrated normally to the heart of Tbx1+/−, but not in Tbx1neo2 mutant embryos. In addition, we showed that cranial ganglia IXth and Xth were fused in Tbx1neo2/− but neuronal differentiation appeared intact. Finally, we used telemetry to monitor heart response to carbachol, a cholinergic receptor agonist, and found that heart rate recovered more quickly in Tbx1+/− animals versus controls. We speculate that this condition of decreased parasympathetic drive could result in a pro-arrhythmic substrate in some 22q11.2DS patients.

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Agulnik, Sergei I., Nancy Garvey, Sarah Hancock, Ilya Ruvinsky, Deborah L. Chapman, Irina Agulnik, Roni Bollag, Virginia Papaioannou, and Lee M. Silver. "Evolution of Mouse T-box Genes by Tandem Duplication and Cluster Dispersion." Genetics 144, no. 1 (September 1, 1996): 249–54. http://dx.doi.org/10.1093/genetics/144.1.249.

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Abstract The T-box genes comprise an ancient family of putative transcription factors conserved across species as divergent as Mus musculus and Caenorhabditis elegans. All T-box gene products are characterized by a novel 174-186amino acid DNA binding domain called the T-box that was first discovered in the polypeptide products of the mouse T locus and the Drosophila melanogaster optomotor-blind gene. Earlier studies allowed the identification of five mouse T-box genes, T, Tbx1-3, and Tbr1, that all map to different chromosomal locations and are expressed in unique temporal and spatial patterns during embryogenesis. Here, we report the discovery of three new members of the mouse T-box gene family, named Tbx4, Tbx5, and Tbx6. Two of these newly discovered genes, Tbx4 and Tbx5, were found to be tightly linked to previously identified T-box genes. Combined results from phylogenetic, linkage, and physical mapping studies provide a picture for the evolution of a T-box subfamily by unequal crossing over to form a two-gene cluster that was duplicated and dispersed to two chromosomal locations. This analysis suggests that Tbx4 and Tbx5 are cognate genes that diverged apart from a common ancestral gene during early vertebrate evolution.

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Cao, Mei-Ling, Bin-Lu Zhu, Yuan-Yuan Sun, Guang-Rong Qiu, Wei-Neng Fu, and Hong-Kun Jiang. "MicroRNA-144 Regulates Cardiomyocyte Proliferation and Apoptosis by Targeting TBX1 through the JAK2/STAT1 Pathway." Cytogenetic and Genome Research 159, no. 4 (2019): 190–200. http://dx.doi.org/10.1159/000505143.

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It is currently believed that the TBX1 gene is one of the core genes of congenital heart disease (CHD). However, there are few studies on the abnormal regulation of TBX1 gene expression. The purpose of this work was to investigate the role of miR-144 and TBX1 in cardiac development by studying the regulatory relationship and mechanism of miR-144 on TBX1/JAK2/STAT1 in cardiomyocytes. Cell proliferation was detected by MTT and clone formation assay and cell cycle and apoptosis by flow cytometry. The levels of miR-144 and TBX1 in H9c2 cells were assessed by qRT-PCR. Dual luciferase reporter assay was used to validate the direct targeting of TBX1 with miR-144. The protein expression levels of TBX1 and its downstream proteins were measured by Western blot analysis. miR-144 inhibited H9c2 cell proliferation by arresting cells in G1 phase. Furthermore, miR-144 induced H9c2 cell apoptosis and activated the JAK2/STAT1 signaling pathway. Bioinformatic predictions and luciferase reporter assay showed that miR-144 directly targets TBX1. Co-overexpression of miR-144 and TBX1 upregulated cell proliferation by accelerating G1 to S phase transition and downregulated cell apoptosis through inhibiting the JAK2/STAT1 signaling pathway. miR-144 acts as a proliferation inhibitor in cardiomyocytes via the TBX1/JAK2/STAT1 axis and is therefore a potential novel therapeutic target for CHD treatment.

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Alfano, Daniela, Alessandra Altomonte, Claudio Cortes, Marchesa Bilio, Robert G. Kelly, and Antonio Baldini. "Tbx1 regulates extracellular matrix-cell interactions in the second heart field." Human Molecular Genetics 28, no. 14 (April 1, 2019): 2295–308. http://dx.doi.org/10.1093/hmg/ddz058.

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Abstract Tbx1, the major candidate gene for DiGeorge or 22q11.2 deletion syndrome, is required for efficient incorporation of cardiac progenitors of the second heart field (SHF) into the heart. However, the mechanisms by which TBX1 regulates this process are still unclear. Here, we have used two independent models, mouse embryos and cultured cells, to define the role of TBX1 in establishing morphological and dynamic characteristics of SHF in the mouse. We found that loss of TBX1 impairs extracellular matrix (ECM)-integrin-focal adhesion (FA) signaling in both models. Mosaic analysis in embryos suggested that this function is non-cell autonomous, and, in cultured cells, loss of TBX1 impairs cell migration and FAs. Additionally, we found that ECM-mediated integrin signaling is disrupted upon loss of TBX1. Finally, we show that interfering with the ECM-integrin-FA axis between E8.5 and E9.5 in mouse embryos, corresponding to the time window within which TBX1 is required in the SHF, causes outflow tract dysmorphogenesis. Our results demonstrate that TBX1 is required to maintain the integrity of ECM-cell interactions in the SHF and that this interaction is critical for cardiac outflow tract development. More broadly, our data identifies a novel TBX1 downstream pathway as an important player in SHF tissue architecture and cardiac morphogenesis.

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Zhong, Yu, Yunqiu Li, and Hua Zhang. "Silencing TBX1 Exerts Suppressive Effects on Epithelial–Mesenchymal Transition and Inflammation of Chronic Rhinosinusitis Through Inhibition of the TGFβ-Smad2/3 Signaling Pathway in Mice." American Journal of Rhinology & Allergy 34, no. 1 (August 18, 2019): 16–25. http://dx.doi.org/10.1177/1945892419866543.

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Background Chronic rhinosinusitis (CRS) is a multifactorial inflammatory disease characterized by high prevalence and morbidity, and little is known about the mechanisms that underlie its pathogenesis. Objective This study focuses on the effect of T-box 1 (TBX1) on the epithelial–mesenchymal transition (EMT) and inflammation of CRS via the transforming growth factor (TGF)β-Smad2/3 signaling pathway. Methods CRS mice models were established by Merocel nasal packing material, followed by the streptococcus pneumoniae cultivation. The expression levels of TBX1 in the sinus mucosa tissues of mice were measured accordingly. The successfully modeled mice were subsequently injected with TBX1 mimic or TBX1 inhibitor and the TGFβ-Smad2/3 signaling pathway inhibitor (SB-431542) to elucidate the influence of TBX1 on EMT and inflammation in CRS, with the expression of the EMT-related factors (E-cadherin, Vimentin, alpha-smooth muscle actin [α-SMA]), Th1 cytokines (interleukin [IL]-2, interferon-γ), and Th2 cytokines (IL-4, IL-8, total immunoglobulin E) assayed. Results TBX1 expression exhibited upregulated levels in the sinus mucosa tissues of the mice. In addition, TBX1 downregulation was found to inhibit the expression of TGFβ as well as the extent of Smad2 and Smad3 phosphorylation. Silencing TBX1 was shown to elevate the expression of Th1 cytokines and E-cadherin, while diminishing expression of Th2 cytokines, Vimentin and α-SMA. Conclusions Taken together, the key findings of our study highlight the inhibitory role of TBX1 in the process of EMT and inflammation in CRS mice via the inhibition of the TGFβ-Smad2/3 signaling pathway, underlining the promise of TBX1 as a potential target for CRS therapy.

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Rahayuningsih, Sri Endah. "Transposisi Arteri Besar dan mutasi gen TBX1." Sari Pediatri 11, no. 1 (November 29, 2016): 21. http://dx.doi.org/10.14238/sp11.1.2009.21-5.

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Latar belakang. Transposisi arteri besar (TAB) adalah suatu penyakit jantung bawaan (PJB) yang termasuk dalam malformasi konotrunkal. Kelainan terasebut ditemukan sekitar 5% dari seluruh PJB. Seperti pada PJB yang lain penyebab TAB multifaktor yaitu faktor genetik, nongenetik, dan interaksi antara genetik dan nongenetik. Gen TBX1 adalah suatu gen yang termasuk gen faktor transkripsi dan berperan pada pembentukan konotrunkal saat embriogensis jantung. Mutasi pada gen TBX1 akan menyebabkan malformasi konotrunkal.Tujuan. Mengetahui peran mutasi gen TBX1 pada PJB dengan malformasi konotrunkal.Metode. Subjek penelitian adalah 42 anak PJB dengan malformasi konotrunkal dan 42 anak tanpa PJB sebagai kontrol, yang memenuhi kriteria inklusi. Deteksi mutasi gen TBX1 dilakukan dengan pemeriksaan sekuensing terhadap isolasi DNA.Hasil. Ditemukan satu anak dengan mutasi TBX1, mutasi yang terjadi adalah missense mutations dan tempat mutasi terletak pada. Ekson 04 c.614 A>T (p.Gln205Leu). Mutasi ini tidak ditemukan pada kontrol.Kesimpulan. Ditemukan missense mutation pada TAB, mutasi tidak ditemukan pada kontrol, sehingga TAB pada pasien tersebut diduga akibat mutasi gen TBX1, karena seperti pada PJB yang lain penyebab dari TAB adalah multifaktor. Dengan ditemukannya mutasi gen TBX1 pada TAB, maka hal ini dapat digunakan sebagai bahan konseling genetika.

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Chen, Li, Annalisa Mupo, Tuong Huynh, Sara Cioffi, Matthew Woods, Chengliu Jin, Wallace McKeehan, LuAnn Thompson-Snipes, Antonio Baldini, and Elizabeth Illingworth. "Tbx1 regulates Vegfr3 and is required for lymphatic vessel development." Journal of Cell Biology 189, no. 3 (May 3, 2010): 417–24. http://dx.doi.org/10.1083/jcb.200912037.

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Lymphatic dysfunction causes several human diseases, and tumor lymphangiogenesis is implicated in cancer spreading. TBX1 is the major gene for DiGeorge syndrome, which is associated with multiple congenital anomalies. Mutation of Tbx1 in mice recapitulates the human disease phenotype. In this study, we use molecular, cellular, and genetic approaches to show, unexpectedly, that Tbx1 plays a critical role in lymphatic vessel development and regulates the expression of Vegfr3, a gene that is essential for lymphangiogenesis. Tbx1 activates Vegfr3 transcription in endothelial cells (ECs) by binding to an enhancer element in the Vegfr3 gene. Conditional deletion of Tbx1 in ECs causes widespread lymphangiogenesis defects in mouse embryos and perinatal death. Using the mesentery as a model tissue, we show that Tbx1 is not required for lymphatic EC differentiation; rather, it is required for the growth and maintenance of lymphatic vessels. Our findings reveal a novel pathway for the development of the lymphatic vessel network.

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Huang, Shuya, Xiang Shu, Jie Ping, Jie Wu, Jifeng Wang, Chris Shidal, Xingyi Guo, et al. "TBX1 functions as a putative oncogene of breast cancer through promoting cell cycle progression." Carcinogenesis 43, no. 1 (December 17, 2021): 12–20. http://dx.doi.org/10.1093/carcin/bgab111.

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Abstract We have previously identified a genetic variant, rs34331122 in the 22q11.21 locus, as being associated with breast cancer risk in a genome-wide association study. This novel variant is located in the intronic region of the T-box transcription factor 1 (TBX1) gene. Cis-expression quantitative trait loci analysis showed that expression of TBX1 was regulated by the rs34331122 variant. In the current study, we investigated biological functions and potential molecular mechanisms of TBX1 in breast cancer. We found that TBX1 expression was significantly higher in breast cancer tumor tissues than adjacent normal breast tissues and increased with tumor stage (P < 0.05). We further knocked-down TBX1 gene expression in three breast cancer cell lines, MDA-MB-231, MCF-7 and T47D, using small interfering RNAs and examined consequential changes on cell oncogenicity and gene expression. TBX1 knock-down significantly inhibited breast cancer cell proliferation, colony formation, migration and invasion. RNA sequencing and flow cytometry analysis revealed that TBX1 knock-down in breast cancer cells induced cell cycle arrest in the G1 phase through disrupting expression of genes involved in the cell cycle pathway. Furthermore, survival analysis using the online Kaplan–Meier Plotter suggested that higher TBX1 expression was associated with worse outcomes in breast cancer patients, especially for estrogen receptor-positive breast cancer, with HRs (95% CIs) for overall survival (OS) and distant metastasis free survival (DMFS) of 1.5 (1.05–2.15) and 1.55 (1.10–2.18), respectively. In conclusion, our results suggest that the TBX1 gene may act as a putative oncogene of breast cancer through regulating expressions of cell cycle-related genes.

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Otomo, Nao, Kazuki Takeda, Shunsuke Kawai, Ikuyo Kou, Long Guo, Mitsujiro Osawa, Cantas Alev, et al. "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 56, no. 9 (April 22, 2019): 622–28. http://dx.doi.org/10.1136/jmedgenet-2018-105920.

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BackgroundCongenital scoliosis (CS) is a common vertebral malformation. Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia characterised by multiple vertebral malformations and rib anomalies. In a previous study, a compound heterozygosity for a null mutation and a risk haplotype composed by three single-nucleotide polymorphisms in TBX6 have been reported as a disease-causing model of CS. Another study identified bi-allelic missense variants in a SCD patient. The purpose of our study is to identify TBX6 variants in CS and SCD and examine their pathogenicity.MethodsWe recruited 200 patients with CS or SCD and investigated TBX6 variants. We evaluated the pathogenicity of the variants by in silico prediction and in vitro experiments.ResultsWe identified five 16p11.2 deletions, one splice-site variant and five missense variants in 10 patients. In vitro functional assays for missense variants identified in the previous and present studies demonstrated that most of the variants caused abnormal localisation of TBX6 proteins. We confirmed mislocalisation of TBX6 proteins in presomitic mesoderm cells induced from SCD patient-derived iPS cells. In induced cells, we found decreased mRNA expressions of TBX6 and its downstream genes were involved in somite formation. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype.ConclusionsOur study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.

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Yu, Deli, Yuri Iwamura, Yutaka Satou, and Izumi Oda-Ishii. "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 483 (March 2022): 1–12. http://dx.doi.org/10.1016/j.ydbio.2021.12.012.

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Law, David J., Nancy Garvey, Sergei I. Agulnik, Victor Perlroth, Olwen M. Hahn, Rita E. Rhinehart, Thomas C. Gebuhr, and Lee M. Silver. "TBX10, a member of the Tbx1-subfamily of conserved developmental genes, is located at human Chromosome 11q13 and proximal mouse Chromosome 19." Mammalian Genome 9, no. 5 (May 1998): 397–99. http://dx.doi.org/10.1007/s003359900780.

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Cioffi, Sara, Gemma Flore, Stefania Martucciello, Marchesa Bilio, Maria Giuseppina Turturo, and Elizabeth Illingworth. "VEGFR3 modulates brain microvessel branching in a mouse model of 22q11.2 deletion syndrome." Life Science Alliance 5, no. 12 (October 10, 2022): e202101308. http://dx.doi.org/10.26508/lsa.202101308.

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The loss of a single copy of TBX1 accounts for most of the clinical signs and symptoms of 22q11.2 deletion syndrome, a common genetic disorder that is characterized by multiple congenital anomalies and brain-related clinical problems, some of which likely have vascular origins. Tbx1 mutant mice have brain vascular anomalies, thus making them a useful model to gain insights into the human disease. Here, we found that the main morphogenetic function of TBX1 in the mouse brain is to suppress vessel branching morphogenesis through regulation of Vegfr3. We demonstrate that inactivating Vegfr3 in the Tbx1 expression domain on a Tbx1 mutant background enhances brain vessel branching and filopodia formation, whereas increasing Vegfr3 expression in this domain fully rescued these phenotypes. Similar results were obtained using an in vitro model of endothelial tubulogenesis. Overall, the results of this study provide genetic evidence that VEGFR3 is a regulator of early vessel branching and filopodia formation in the mouse brain and is a likely mediator of the brain vascular phenotype caused by Tbx1 loss of function.

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Funato, N., D. Srivastava, S. Shibata, and H. Yanagisawa. "TBX1 Regulates Chondrocyte Maturation in the Spheno-occipital Synchondrosis." Journal of Dental Research 99, no. 10 (May 22, 2020): 1182–91. http://dx.doi.org/10.1177/0022034520925080.

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The synchondrosis in the cranial base is an important growth center for the craniofacial region. Abnormalities in the synchondroses affect the development of adjacent regions, including the craniofacial skeleton. Here, we report that the transcription factor TBX1, the candidate gene for DiGeorge syndrome, is expressed in mesoderm-derived chondrocytes and plays an essential and specific role in spheno-occipital synchondrosis development by inhibiting the expression of genes involved in chondrocyte hypertrophy and osteogenesis. In Tbx1-deficient mice, the spheno-occipital synchondrosis was completely mineralized at birth. TBX1 interacts with RUNX2, a master molecule of osteoblastogenesis and a regulator of chondrocyte maturation, and suppresses its transcriptional activity. Indeed, deleting Tbx1 triggers accelerated mineralization due to accelerated chondrocyte differentiation, which is associated with ectopic expression of downstream targets of RUNX2 in the spheno-occipital synchondrosis. These findings reveal that TBX1 acts as a regulator of chondrocyte maturation and osteogenesis during the spheno-occipital synchondrosis development. Thus, the tight regulation of endochondral ossification by TBX1 is crucial for the normal progression of chondrocyte differentiation in the spheno-occipital synchondrosis.

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Chen, Jiaofeng, Xue Zhang, Jie Li, Chenmeng Song, Yichang Jia, and Wei Xiong. "Identification of a Novel ENU-Induced Mutation in Mouse Tbx1 Linked to Human DiGeorge Syndrome." Neural Plasticity 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/5836143.

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The patients with DiGeorge syndrome (DGS), caused by deletion containing dozens of genes in chromosome 22, often carry cardiovascular problem and hearing loss associated with chronic otitis media. Inside the deletion region, a transcription factor TBX1 was highly suspected. Furthermore, similar DGS phenotypes were found in the Tbx1 heterozygous knockout mice. Using ENU-induced mutagenesis and G1 dominant screening strategy, here we identified a nonsynonymous mutation p.W118R in T-box of TBX1, the DNA binding domain for transcription activity. The mutant mice showed deficiency of inner ear functions, including head tossing and circling, plus increased hearing threshold determined by audiometry. Therefore, our result further confirms the pathogenic basis of Tbx1 in DGS, points out the crucial role of DNA binding activity of TBX1 for the ear function, and provides additional animal model for studying the DGS disease mechanisms.

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Reeh, Kaitlin, Virginia Bain, Julia Lorenz, Yan Bai, James Martin, Nancy Manley, and Ellen Richie. "MicroRNA-17-92 regulates Tbx1 expression in third pharyngeal pouch endoderm (HEM7P.232)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 188.12. http://dx.doi.org/10.4049/jimmunol.194.supp.188.12.

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Abstract The thymus and parathyroids originate from bilateral 3rd pharyngeal pouch (pp) endoderm. At E11.5, thymus- and parathyroid-fated domains express Foxn1 and Gcm2 respectively, transcription factors that regulate differentiation but do not specify organ fate. Tbx1, which encodes a T-box transcription factor required for segmentation of the pharyngeal endoderm is initially widely expressed in the 3rd pp, but by E10.5 is excluded from the ventral, thymus-fated domain. We recently reported that Tbx1 is a negative regulator of thymus development (Reeh et al. Development 141:2950, 2014). Ectopic expression of Tbx1 in the thymus-fated domain of the 3rd pp suppresses Foxn1 and inhibits thymic epithelial cell proliferation and differentiation. MicroRNAs (miRs) are important regulators of gene expression. We find that members of the miR-17-92 cluster are expressed in the ventral domain of the 3rd pp in wildtype embryos. Moreover, miR-17-92 downregulates Tbx1 in cardiac progenitor cells to promote their differentiation (Wang et al. Developmental Cell 19:903, 2010). Therefore, we proposed that miR-17-92 regulates Tbx1 expression in 3rd pp endoderm. In support of this hypothesis, we find that deletion of miR-17-92 enhances TBX1 and reduces FOXN1 in 3rd pp endoderm. The data support a model in which miR-17-92 plays an essential role in thymus development by regulating Tbx1 expression in the 3rd pp.

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Cardenas, Kim T., Zhijie Liu, Micheline Laurent, Carla Carter, Nancy Manley, and Ellen Richie. "Tbx1 antagonizes thymus organogenesis (86.4)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 86.4. http://dx.doi.org/10.4049/jimmunol.182.supp.86.4.

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Abstract The thymus and parathyroids originate from organ-specific domains in endoderm of the 3rd pharyngeal pouch (PP), identified by Foxn1 and Gcm2 expression respectively at embryonic day 11 (E11). The molecular mechanisms regulating fate determination in the 3rd PP are not clear. Our studies show that neural crest cells (NCCs) play a role in this process (Griffin et al, in press). We also showed that lack of Sonic hedgehog (Shh) results in absence of the parathyroid domain and expansion of the thymus domain (Moore-Scott et al, 2005). It has been proposed that the Tbx1 transcription factor is also required for thymus development and is regulated by Shh. However, Tbx1 is expressed in the Gcm2, but not the Foxn1 domain of 3rd PP at E10.5. We propose a model of thymus organogenesis in which 3rd PP endoderm assumes a thymus fate unless Shh plus NCC-derived signals specify a parathyroid fate. We further propose that Tbx1 is required to establish parathyroid fate and is non-permissive for thymus fate. To test the model, we generated knock-in mice containing a Cre-inducible allele that allows temporal and spatial control of Tbx1 expression. Ectopic Tbx1 expression using Foxn1Cre resulted in markedly hypoplastic thymi, supporting the notion that Tbx1 antagonizes thymus differentiation. Current studies focus on determining the molecular basis for this phenotype and testing the effects of activating Tbx1 expression at earlier stages. Supported by NIH HD056315 to ER and HD035920 to NM.

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Ren, Xiaojun, Nan Yang, Nan Wu, Ximing Xu, Weisheng Chen, Ling Zhang, Yingping Li, et al. "Increased TBX6 gene dosages induce congenital cervical vertebral malformations in humans and mice." Journal of Medical Genetics 57, no. 6 (December 30, 2019): 371–79. http://dx.doi.org/10.1136/jmedgenet-2019-106333.

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BackgroundCongenital vertebral malformations (CVMs) manifest with abnormal vertebral morphology. Genetic factors have been implicated in CVM pathogenesis, but the underlying pathogenic mechanisms remain unclear in most subjects. We previously reported that the human 16p11.2 BP4-BP5 deletion and its associated TBX6 dosage reduction caused CVMs. We aim to investigate the reciprocal 16p11.2 BP4-BP5 duplication and its potential genetic contributions to CVMs.Methods and resultsPatients who were found to carry the 16p11.2 BP4-BP5 duplication by chromosomal microarray analysis were retrospectively analysed for their vertebral phenotypes. The spinal assessments in seven duplication carriers showed that four (57%) presented characteristics of CVMs, supporting the contention that increased TBX6 dosage could induce CVMs. For further in vivo functional investigation in a model organism, we conducted genome editing of the upstream regulatory region of mouse Tbx6 using CRISPR-Cas9 and obtained three mouse mutant alleles (Tbx6up1 to Tbx6up3) with elevated expression levels of Tbx6. Luciferase reporter assays showed that the Tbx6up3 allele presented with the 160% expression level of that observed in the reference (+) allele. Therefore, the homozygous Tbx6up3/up3 mice could functionally mimic the TBX6 dosage of heterozygous carriers of 16p11.2 BP4-BP5 duplication (approximately 150%, ie, 3/2 gene dosage of the normal level). Remarkably, 60% of the Tbx6up3/up3 mice manifested with CVMs. Consistent with our observations in humans, the CVMs induced by increased Tbx6 dosage in mice mainly affected the cervical vertebrae.ConclusionOur findings in humans and mice consistently support that an increased TBX6 dosage contributes to the risk of developing cervical CVMs.

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Yuan, Xin, Jianlin Du, Qin Qin, Xiaoqun Li, Songbai Deng, Yunqing Chen, Ling Zhang, and Qiang She. "The impact of sperm-expressed transcription factors on fate-mapping models." REPRODUCTION 150, no. 4 (October 2015): 323–30. http://dx.doi.org/10.1530/rep-15-0014.

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Genetic lineage tracing has been used extensively in developmental biology. Many transcription factors expressed in sperm may induce Cre-mediated loxP recombination during early zygote development. In this study, we investigated the effect of sperm-expressed Cre on cell type-specific Cre-mediated loxP recombination in fate-mapping models of Tbx18+ progenitor cells. We found the recombination frequency in a reverse mating (RM) lineage was inconsistent with a normal Mendelian distribution. However, the recombination frequency in a positive mating (PM) lineage agreed with a Mendelian distribution. In the PM lineage, LacZ and EYFP were expressed in specific locations, such as the limb buds, heart, and hair follicles. Therefore, the reporter genes accurately and reliably traced cell differentiation in the PM lineage. In contrast, EYFP and LacZ were expressed throughout the embryo in the RM lineage. Thus, the reporter genes did not trace cell differentiation specifically in the RM lineage. Furthermore, Tbx18 mRNA and protein were expressed in the testicles of male mice, but almost no Tbx18 expression was detected in the ovaries of female mice. Similarly, reporter genes and Tbx18 were coexpressed in the seminiferous tubules and sperm cells of testicles. These results revealed that Cre-loxP-mediated pre-recombination in zygotes is due to Tbx18 expressed in testicle sperm cells when Cre is transmitted paternally. Our results indicate that Cre-mediated specific recombination in fate-mapping models of sperm-expressed genes may be influenced by the paternal origin of Cre. Therefore, a careful experimental design is critical when using the Cre-loxP system to trace spatial, temporal or tissue-specific fates.

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Journal articles on the topic 'Tbx16'

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