Tbx5specifies the left/right ventricles and ventricular septum position during cardiogenesis

Abstract

Extensive misexpression studies were carried out to explore the roles played by Tbx5, the expression of which is excluded from the right ventricle (RV) during cardiogenesis. When Tbx5 was misexpressed ubiquitously,ventricular septum was not formed, resulting in a single ventricle. In such heart, left ventricle (LV)-specific ANF gene was induced. In search of the putative RV factor(s), we have found that chick Tbx20 is expressed in the RV, showing a complementary fashion to Tbx5. In the Tbx5-misexpressed heart, this gene was repressed. When misexpression was spatially partial, leaving small Tbx5-negative area in the right ventricle,ventricular septum was shifted rightwards, resulting in a small RV with an enlarged LV. Focal expression induced an ectopic boundary of Tbx5-positive and-negative regions in the right ventricle, at which an additional septum was formed. Similar results were obtained from the transient transgenic mice. In such hearts, expression patterns of dHAND and eHAND were changed with definitive cardiac abnormalities. Furthermore, we report that human ANF promoter is synergistically activated by Tbx5, Nkx2.5 and GATA4. This activation was abrogated by Tbx20, implicating the pivotal roles of interactions among these heart-specific factors. Taken together, our data indicate that Tbx5 specifies the identity of LV through tight interactions among several heart-specific factors, and highlight the essential roles of Tbx5 in cardiac development.

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

“…The atrial and ventricular septal defects associated with HOS and the phenotype of tbx5 heterozygous mutant mice are consistent with a critical role for Tbx5 in cardiac septation (Bruneau et al, 1999). The restricted expression of tbx5 in the left but not right ventricles is hypothesized to control the position of the ventricular septum (Takeuchi et al, 2003). Although it has been demonstrated that Tbx5 is required for normal septation, the downstream targets regulated by Tbx5 during septation are not fully characterized.…”

“…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).…”

Association analysis identifies new risk loci for congenital heart disease in Chinese populations

“…Another nearby gene, TBX5, plays important roles in chamber formation, septation and cardiomyocyte differentiation 25 . Both gain-and loss-of-function experiments on Tbx5 have resulted in abnormal heart phenotypes in animal models, such as looping defects, loss of the ventricular septum and arrested development of the AV cushions, hypoplastic sinoatrial region and left ventricle 26,27 . The polymorphisms in the upstream region potentially influence the transcriptional activity, and the haplo-insufficiency of TBX3 and TBX5 has also been proven to be associated with CHD 28,29 .…”

Essential roles of the bHLH transcription factor Hrt2 in repression of atrial gene expression and maintenance of postnatal cardiac function

“…Atrialization of gene expression in the ventricle may also play a role in the distended RV phenotype observed in the hearts of Hrt2 CKO mice. It is interesting to note that retrovirus-mediated misexpression of Tbx5 in the presumptive RV results in a shift of the interventricular septum to the right and a distended and hypoplastic RV (33). The abnormal RV phenotype accompanying the ectopic expression of atrial-enriched genes, especially Tbx5 in the LV of Hrt2 CKO mice, may suggest a role for Hrt2 in the specification or maturation of the RV and LV.…”