A Murine Model of Holt-Oram Syndrome Defines Roles of the T-Box Transcription Factor Tbx5 in Cardiogenesis and Disease

Bruneau, Benoit G.; Nemer, Georges; Schmitt, Joachim P.; Charron, Frédéric; Robitaille, Lucie; Caron, Sophie; Conner, David A.; Gessler, Manfred; Nemer, Mona; Seidman, Christine E.

doi:10.1016/s0092-8674(01)00493-7

Cited by 972 publications

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References 44 publications

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“…Experiments eliminating or ectopically expressing tbx5 at these stages suggest a role for Tbx5 in cardiac chamber specification and morphogenesis (Liberatore et al, 2000;Bruneau et al, 2001). Investigation of Tbx5 function by genetic manipulation in mice has demonstrated a requirement for Tbx5 in atrial and ventricular septation, a process that is also disrupted in HOS (Bruneau et al, 2001;Takeuchi et al, 2003). Mice heterozygous null for tbx5 display atrioventricular block, a disruption in conduction system function that resembles what is observed in HOS (Bruneau et al, 2001;Moskowitz et al, 2004).…”

Section: Introductionmentioning

confidence: 98%

“…Tbx5 belongs to the T-box family of transcription factors and is required for the embryonic development of the heart and forelimbs (Koshiba-Takeuchi et al, 2000;Bruneau et al, 2001). Mutations in TBX5 are associated with Holt-Oram syndrome (HOS), a congenital disorder characterized by limb malformations, cardiac septal defects, and conduction system anomalies (Basson et al, 1997;Li et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Subsequent to the formation of the heart tube, tbx5 expression becomes restricted to the posterior regions that are fated to form the atria and left ventricle (Bruneau et al, 1999;Liberatore et al, 2000). Experiments eliminating or ectopically expressing tbx5 at these stages suggest a role for Tbx5 in cardiac chamber specification and morphogenesis (Liberatore et al, 2000;Bruneau et al, 2001). Investigation of Tbx5 function by genetic manipulation in mice has demonstrated a requirement for Tbx5 in atrial and ventricular septation, a process that is also disrupted in HOS (Bruneau et al, 2001;Takeuchi et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Microarray analysis of Tbx5‐induced genes expressed in the developing heart

Plageman

Yutzey

2006

Developmental Dynamics

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Tbx5 is a member of the T-box family of transcription factors and is associated with Holt-Oram syndrome (HOS), a congenital disorder characterized by heart and limb defects. Although implicated in several processes during development, only a few genes regulated by Tbx5 have been reported. To identify candidate genes regulated by Tbx5 during heart development, a microarray approach was used. A cardiacderived mouse cell line (1H) was infected with adenoviruses expressing Tbx5 or ␤-galactosidase and RNA was isolated for analysis using an Affymetrix gene chip representing over 39,000 transcripts. Real-time reverse transcriptase-polymerase chain reaction confirmed Tbx5 induction of a subset of the genes, including nppa, photoreceptor cadherin, brain creatine kinase, hairy/enhancer-of-split related 2, and gelsolin. In situ hybridization analysis indicated overlapping expression of these genes with tbx5 in the embryonic mouse heart. In addition, the effect of HOS-associated mutations on the ability of Tbx5 to induce target gene expression was evaluated. Together, these data identify several genes induced by Tbx5 that are potentially important during cardiac development. These genes represent new candidate gene targets of Tbx5 that may be related to congenital heart malformations associated with HOS. Developmental Dynamics 235:2868 -2880, 2006.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Microarray analysis of Tbx5‐induced genes expressed in the developing heart

Plageman

Yutzey

2006

Developmental Dynamics

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“…In mice and humans with Holt-Oram syndrome, caused by mutations in the Tbx5 gene, severe cardiac malformations are observed (Basson et al, 1997;Bruneau et al, 2001). In Xenopus laevis, heart formation is severely impaired when a repressing form of Tbx5 is overexpressed shortly before endogenous Tbx5 expression starts.…”

Section: Introductionmentioning

confidence: 99%

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Herrmann

Bundschu

Kühl

et al. 2011

Developmental Dynamics

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The T-box transcription factor Tbx5 is involved in several developmental processes including cardiogenesis. Early steps of cardiac development are characterised by the formation of two cardiogenic lineages, the first (FHF) and the second heart field (SHF) lineage, which arise from a common cardiac progenitor cell population. To further investigate the function of Tbx5 during cardiogenesis, we generated a murine embryonic stem cell line constitutively overexpressing Tbx5. Differentiation of these cells is characterised by an earlier and increased appearance of contracting cardiomyocytes that beat with a higher frequency than control cells. In semi-quantitative and quantitative RT-PCR analyses, we observed an up-regulation of cardiac marker genes such as Troponin T, endogenous Tbx5, and Nkx2.5 and a down-regulation of others like BMP4 and Hand2. Similar data were gained in Xenopus laevis arguing for a conserved function of Tbx5. Furthermore, markers of the conduction system and atrial cardiomyocytes were increased.

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“…More recently application of magnetic resonance imaging (MRI) has enabled detailed assessment of heart structure and even congenital malformations (e.g. atrial and ventricular septal defects) in mice [71]. Murine models of human cardiac disease therefore appear to be valuable reagents for delineating the mechanisms of disease, analyses of complex events such as sudden death and important tools for evaluating pharmacologic therapies and devices.…”

Section: Animal Modelsmentioning

confidence: 99%

Hypertrophic cardiomyopathy: from gene defect to clinical disease

2003

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Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in which a genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiac disorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes. At least ten genes have now been identified, defects in which cause HCM. All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere. While much is now known about which genes cause disease and the various clinical presentations, very little is known about how these gene defects cause disease, and what factors modify the expression of the mutant genes. Studies in both cell culture and animal models of HCM are now beginning to shed light on the signalling pathways involved in HCM, and the role of both environmental and genetic modifying factors. Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function, and will therefore provide new avenues for treating cardiovascular disease in man.

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A Murine Model of Holt-Oram Syndrome Defines Roles of the T-Box Transcription Factor Tbx5 in Cardiogenesis and Disease

Cited by 972 publications

References 44 publications

Microarray analysis of Tbx5‐induced genes expressed in the developing heart

Microarray analysis of Tbx5‐induced genes expressed in the developing heart

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Hypertrophic cardiomyopathy: from gene defect to clinical disease

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