Chamber-Specific Cardiac Expression of Tbx5 and Heart Defects in Holt–Oram Syndrome

Abstract

To further define the role of a T-box transcription factor, Tbx5, in cardiac development, we have examined its expression in the developing mouse and chick heart and correlated this pattern with cardiac defects caused by human TBX5 mutations in Holt-Oram syndrome. Early in the developing heart, Tbx5 is uniformly expressed throughout the entire cardiac crescent. Upon formation of the linear heart tube, Tbx5 is expressed in a graded fashion, stronger near the posterior end and weaker at the anterior end. As the heart tube loops, asymmetric Tbx5 expression continues; Tbx5 is expressed in the presumptive left ventricle, but not the right ventricle or outflow tract. This pattern of expression is maintained in more mature hearts. Expression in the ventricular septum is restricted to the left side and is contiguous with left ventricular free wall expression. Trabeculae, vena cavae (inferior and superior), and the atrial aspect of the atrioventricular valves also express high levels of Tbx5. These patterns of Tbx5 expression provide an embryologic basis for the prevalence of atrial septal defects (ostium primum and secundum), ventricular muscular septal defects, and left-sided malformations (endocardial cushion defects, hypoplastic left heart, and aberrant trabeculation) observed in patients with Holt-Oram syndrome.

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

“…These results are in line with the spatial expression of Tbx5 as it is highly expressed in the posterior part of the linear heart tube (later atria) and builds a gradient toward the anterior part of the heart tube (later ventricles; Bruneau et al, 1999). With the overexpression, we provide a high level of Tbx5, so that an atrial fate develops preferentially, while ventricular fates require lower doses of Tbx5.…”

“…The cardiac specific expression of Tbx5 in mice can first be detected at embryonic day (E) 7.5 in the cardiac crescent, the FHF (Bruneau et al, 1999;Liberatore et al, 2000). Later in development, Tbx5 is found in the posterior heart tube, in the forming left ventricle and in both atria (Chapman et al, 1996;Bruneau et al, 1999) and thus labels cells of the FHF lineage. As in mouse development, Tbx5 expression is designated to the FHF lineage in Xenopus laevis (Gessert and Kü hl, 2009).…”

Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis

“…Tbx5, which is normally expressed at highest levels in the atria and left ventricle 32 , was expressed at comparable levels in the Bop -/-and wildtype heart (Fig. 5o,p), consistent with the conclusion that the single ventricle in the absence of Bop is, on a molecular basis, primarily a left ventricle.…”

Podoplanin deficient mice show a rhoa‐related hypoplasia of the sinus venosus myocardium including the sinoatrial node

“…Lineage tracing experiments studying Isl1 (Cai et al, 2003), Fgf 10 (Kelly, 2005), and Tbx5 (Bruneau et al, 1999;Liberatore et al, 2000), 18 (Christoffels et al, 2006), and Shox2 (Blaschke et al, 2007) have demonstrated the contribution of the second heart field to the formation of the atrial myocardium which has a distinct molecular composition compared with the heart tube derived from the primary heart field (Cai et al, 2003;Kelly, 2005;Anderson et al, 2006).…”