Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria
Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria
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DOI：
10.1101/gad.416007
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发表时间：
2007-05-01
影响因子：
10.5
通讯作者：
Christoffels, Vincent M.
中科院分区：
文献类型：
--
作者：
Hoogaars, Willem M. H.;Engel, Angela;Christoffels, Vincent M.
窦房结启动心跳并控制收缩的速率和节奏，从而充当心脏的起搏器。尽管窦房结在心脏功能中起着至关重要的作用，但其特化和形成的机制尚不清楚。Tbx3是脊椎动物发育所必需的转录抑制因子，在发育的传导系统中表达。在这里，我们表明，Tbx3的表达描绘了窦房结区域，它运行的基因表达程序，这是从接壤的心房细胞不同。我们发现Tbx3阴性心房和Tbx3阳性窦房结前体细胞的谱系分离，只要心脏细胞打开心房基因表达程序。Tbx3缺陷导致心房基因程序的表达扩展到窦房结域，并且部分丧失窦房结特异性基因表达。Tbx3在小鼠中的异位表达揭示了Tbx3抑制心房表型并将起搏器表型强加于心房。这些小鼠表现出心律失常，并产生了功能性异位起搏器。这些数据确定了Tbx3依赖性途径的规范和形成的窦房结，并表明，Tbx3调节起搏器基因的表达程序和表型。
The sinoatrial node initiates the heartbeat and controls the rate and rhythm of contraction, thus serving as the pacemaker of the heart. Despite the crucial role of the sinoatrial node in heart function, the mechanisms that underlie its specification and formation are not known. Tbx3, a transcriptional repressor required for development of vertebrates, is expressed in the developing conduction system. Here we show that Tbx3 expression delineates the sinoatrial node region, which runs a gene expression program that is distinct from that of the bordering atrial cells. We found lineage segregation of Tbx3-negative atrial and Tbx3-positive sinoatrial node precursor cells as soon as cardiac cells turn on the atrial gene expression program. Tbx3 deficiency resulted in expansion of expression of the atrial gene program into the sinoatrial node domain, and partial loss of sinoatrial node-specific gene expression. Ectopic expression of Tbx3 in mice revealed that Tbx3 represses the atrial phenotype and imposes the pacemaker phenotype on the atria. The mice displayed arrhythmias and developed functional ectopic pacemakers. These data identify a Tbx3-dependent pathway for the specification and formation of the sinoatrial node, and show that Tbx3 regulates the pacemaker gene expression program and phenotype.