Molecular pathway for the localized formation of the sinoatrial node
Molecular pathway for the localized formation of the sinoatrial node
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DOI：
10.1161/01.res.0000258019.74591.b3
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发表时间：
2007-02-16
影响因子：
20.1
通讯作者：
Christoffels, Vincent M.
中科院分区：
文献类型：
--
作者：
Mommersteeg, Mathilda T. M.;Hoogaars, Willem M. H.;Christoffels, Vincent M.
窦房结位于右心房和上腔静脉的交界处，包含启动心跳的特殊心肌细胞。尽管在心脏功能中发挥着重要作用，但窦房结的胚胎起源和局部形成机制尚未确定。在这里，我们表明，在 Nkx2-5 阳性心管形成后，心管流入道边缘的细胞产生窦房结和窦角的 Nkx2-5 阴性心肌细胞。使用遗传模型，我们表明，随着心管心肌的成熟，Nkx2-5 抑制起搏器通道基因 Hcn4 和 T-box 转录因子基因 Tbx3，从而将它们的表达逐渐限制在正在形成的 Nkx2-5 阴性窦房结和窦角。因此，Nkx2-5 对于建立心房和窦房结之间的基因表达边界至关重要。人们发现 Tbx3 可以抑制心室分化，从而提供了一种额外的机制，可以防止 Tbx3 阳性窦房结分化为心房心肌。 Pitx2c 缺陷的胎儿在左右窦房交界处形成窦房结，其分子特征无法区分，表明 Pitx2c 在左/右通路内发挥作用，抑制左侧窦房结形成的默认程序。我们的分子途径提供了一种机制，使起搏器活动逐渐降级到心脏静脉极最近添加的成分，并最终降级到右心房和上腔静脉的交界处。
The sinoatrial node, which resides at the junction of the right atrium and the superior caval vein, contains specialized myocardial cells that initiate the heart beat. Despite this fundamental role in heart function, the embryonic origin and mechanisms of localized formation of the sinoatrial node have not been defined. Here we show that subsequent to the formation of the Nkx2-5-positive heart tube, cells bordering the inflow tract of the heart tube give rise to the Nkx2-5-negative myocardial cells of the sinoatrial node and the sinus horns. Using genetic models, we show that as the myocardium of the heart tube matures, Nkx2-5-suppresses pacemaker channel gene Hcn4 and T-box transcription factor gene Tbx3, thereby enforcing a progressive confinement of their expression to the forming Nkx2-5-negative sinoatrial node and sinus horns. Thus, Nkx2-5 is essential for establishing a gene expression border between the atrium and sinoatrial node. Tbx3 was found to suppress chamber differentiation, providing an additional mechanism by which the Tbx3-positive sinoatrial node is shielded from differentiating into atrial myocardium. Pitx2c-deficient fetuses form sinoatrial nodes with indistinguishable molecular signatures at both the right and left sinuatrial junction, indicating that Pitx2c functions within the left/right pathway to suppress a default program for sinuatrial node formation on the left. Our molecular pathway provides a mechanism for how pacemaker activity becomes progressively relegated to the most recently added components of the venous pole of the heart and, ultimately, to the junction of the right atrium and superior caval vein.