Lethal arrhythmias in Tbx3 -deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis

Abstract

TBX3 is critical for human development: mutations in TBX3 cause congenital anomalies in patients with ulnar-mammary syndrome. Data from mice and humans suggest multiple roles for Tbx3 in development and function of the cardiac conduction system. The mechanisms underlying the functional development, maturation, and maintenance of the conduction system are not well understood. We tested the requirements for Tbx3 in these processes. We generated a unique series of Tbx3 hypomorphic and conditional mouse mutants with varying levels and locations of Tbx3 activity within the heart, and developed techniques for evaluating in vivo embryonic conduction system function. Disruption of Tbx3 function in different regions of the developing heart causes discrete phenotypes and lethal arrhythmias: sinus pauses and bradycardia indicate sinoatrial node dysfunction, whereas preexcitation and atrioventricular block reveal abnormalities in the atrioventricular junction. Surviving Tbx3 mutants are at increased risk for sudden death. Arrhythmias induced by knockdown of Tbx3 in adults reveal its requirement for conduction system homeostasis. Arrhythmias in Tbx3-deficient embryos are accompanied by disrupted expression of multiple ion channels despite preserved expression of previously described conduction system markers. These findings indicate that Tbx3 is required for the conduction system to establish and maintain its correct molecular identity and functional properties. In conclusion, Tbx3 is required for the functional development, maturation, and homeostasis of the conduction system in a highly dosage-sensitive manner. TBX3 and its regulatory targets merit investigation as candidates for human arrhythmias.heart rhythm | heart development | embryonic electrocardiogram | tissue regeneration

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

“…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 .…”

The T-box gene family: emerging roles in development, stem cells and cancer

“…Both genes are involved in establishing the identity and function of the CCS and in inducing atrioventricular cushion development through Bmp2. Although mutations in each gene produce a distinct cardiac phenotype, indicating unique functions, they also have redundant roles in the AVC (Frank et al, 2012;Greulich et al, 2011;Singh et al, 2012). Similarly, during the development of the arterial pole of the heart, Tbx2 and Tbx3 play roles in SHF deployment and OFT alignment.…”

A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

“…the transcription of Nkx2-5 target genes). Although Tbx3 blocks Cx40 activation in the SAN, Tbx3 is not required for Hcn4 expression (Frank et al, 2012;Wiese et al, 2009), implicating the involvement of other regulatory factors that are yet to be identified.…”