<i>Tbx20</i>is essential for cardiac chamber differentiation and repression of<i>Tbx2</i>

Singh, Manvendra K.; Christoffels, Vincent M.; Dias, José Maria Moreira; Trowe, Mark-Oliver; Petry, Marianne; Schuster-Gossler, Karin; Bürger, Antje; Ericson, Johan; Kispert, Andreas

doi:10.1242/dev.01854

Cited by 195 publications

(165 citation statements)

References 65 publications

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“…For example, deletion of Tbx20 leads to severe defects in cardiac chamber morphogenesis. Failure to form a multichambered heart was reported to be due to defective linear heart tube elongation, inappropriate gene expression, and reduced cell proliferation (Singh et al, 2005;Stennard et al, 2005). Whether the defects in heart tube elongation and/or gene expression are due to reduced cell proliferation (or vice versa) is unclear from the reported analyses.…”

Section: Advances In Phenotypic Analysismentioning

confidence: 99%

Novel tool to suppress cell proliferation in vivo demonstrates that myocardial and coronary vascular growth represent distinct developmental programs

Lavine

Schmid

Smith

et al. 2008

Developmental Dynamics

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Cell proliferation, differentiation, and vascular growth are coordinated processes that are essential for embryonic development, tissue repair, and disease pathogenesis. Of interest, whether these critical processes are dependent upon each other has not been thoroughly explored. We have generated mice that conditionally express the cell cycle inhibitor p27 Kip1 , following Cre-mediated recombination, as a tool to separate tissue proliferation from other cellular processes. Using the embryonic heart as a model, we show that myocardial proliferation and coronary development are genetically separable processes. Forced expression of p27, in both a wild-type and in a genetically sensitized background, resulted in ventricular hypoplasia without having any substantial effects on coronary development. We further demonstrate that Hedgehog signaling, which is essential for coronary vascular growth, does not control myocardial proliferation. Together, these studies strongly suggest that myocardial cell proliferation and coronary development are genetically separable programs exemplifying one of the many potential uses of this genetic tool. Developmental Dynamics 237:713-724, 2008.

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Section: Advances In Phenotypic Analysismentioning

confidence: 99%

Novel tool to suppress cell proliferation in vivo demonstrates that myocardial and coronary vascular growth represent distinct developmental programs

Lavine

Schmid

Smith

et al. 2008

Developmental Dynamics

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“…In this regard, the function of Tbx20, which is expressed throughout the entire heart, should be considered. Recently, Tbx20 was reported to be essential for chamber differentiation, as the loss of this gene results in the downregulation of chamber-specific markers, including Hesr1 and Hesr2, whereas the expression of the AV canal marker Tbx2 was found to be expanded (Cai et al, 2005;Singh et al, 2005;Stennard et al, 2005). Hence, Tbx20 is one of the positive upstream regulators of Hesr1 and Hesr2, although it is not known how Hesr1 and Hesr2 are restricted in the atrium or ventricle.…”

Section: Research Articlementioning

confidence: 99%

Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2

et al. 2007

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The establishment of chamber specificity is an essential requirement for cardiac morphogenesis and function. Hesr1 (Hey1) and Hesr2 (Hey2) are specifically expressed in the atrium and ventricle, respectively, implicating these genes in chamber specification. In our current study, we show that the forced expression of Hesr1 or Hesr2 in the entire cardiac lineage of the mouse results in the reduction or loss of the atrioventricular (AV) canal. In the Hesr1-misexpressing heart, the boundaries of the AV canal are poorly defined, and the expression levels of specific markers of the AV myocardium, Bmp2 and Tbx2, are either very weak or undetectable. More potent effects were observed in Hesr2-misexpressing embryos, in which the AV canal appears to be absent entirely. These data suggest that Hesr1 and Hesr2 may prevent cells from expressing the AV canal-specific genes that lead to the precise formation of the AV boundary. Our findings suggest that Tbx2 expression might be directly suppressed by Hesr1 and Hesr2. Furthermore, we find that the expression of Hesr1 and Hesr2 is independent of Notch2 signaling. Taken together, our data demonstrate that Hesr1 and Hesr2 play crucial roles in AV boundary formation through the suppression of Tbx2.

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“…Tbx20 is an ancient T-box family member whose expression in the heart is highly conserved across species (Griffin et al, 2000;Iio et al, 2001;Kraus et al, 2001;Meins et al, 2000). Previous studies showed that Tbx20 null (Tbx20 −/− ) mice die at E9.5-10.5 with severely hypoplastic myocardial tubes (Cai et al, 2005;Singh et al, 2005;Stennard et al, 2005). By contrast, Tbx20 knockdown mice exhibit failed OFT septation and hypoplastic right ventricle (Takeuchi et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Cai

Zhang

et al. 2013

Development

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SUMMARYCardiac valves are essential to direct forward blood flow through the cardiac chambers efficiently. Congenital valvular defects are prevalent among newborns and can cause an immediate threat to survival as well as long-term morbidity. Valve leaflet formation is a rigorously programmed process consisting of endocardial epithelial-mesenchymal transformation (EMT), mesenchymal cell proliferation, valve elongation and remodeling. Currently, little is known about the coordination of the diverse signals that regulate endocardial cushion development and valve elongation. Here, we report that the T-box transcription factor Tbx20 is expressed in the developing endocardial cushions and valves throughout heart development. Ablation of Tbx20 in endocardial cells causes severe valve elongation defects and impaired cardiac function in mice. Our study reveals that endocardial Tbx20 is crucial for valve endocardial cell proliferation and extracellular matrix development, but is not required for initiation of EMT. Elimination of Tbx20 also causes aberrant Wnt/β-catenin signaling in the endocardial cushions. In addition, Tbx20 regulates Lef1, a key transcriptional mediator for Wnt/β-catenin signaling, in this developmental process. Our study suggests a model in which Tbx20 regulates the Wnt pathway to direct endocardial cushion maturation and valve elongation, and provides new insights into the etiology of valve defects in humans.

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Tbx20is essential for cardiac chamber differentiation and repression ofTbx2

Cited by 195 publications

References 65 publications

Novel tool to suppress cell proliferation in vivo demonstrates that myocardial and coronary vascular growth represent distinct developmental programs

Novel tool to suppress cell proliferation in vivo demonstrates that myocardial and coronary vascular growth represent distinct developmental programs

Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

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