Wt1 and retinoic acid signaling in the subcoelomic mesenchyme control the development of the pleuropericardial membranes and the sinus horns.
Wt1 and retinoic acid signaling in the subcoelomic mesenchyme control the development of the pleuropericardial membranes and the sinus horns.
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DOI：
10.1161/circresaha.110.217455
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发表时间：
2010-04-16
影响因子：
20.1
通讯作者：
Kispert A
中科院分区：
文献类型：
--
作者：
Norden J;Grieskamp T;Lausch E;van Wijk B;van den Hoff MJ;Englert C;Petry M;Mommersteeg MT;Christoffels VM;Niederreither K;Kispert A
心脏静脉极是先天性畸形和房性心律失常的常见病灶，但对其发育调控的细胞和分子机制知之甚少。体静脉回流心肌（窦房结和窦角）仅在心脏发生的后期由心包间充质前体细胞形成。目的：探讨胎儿窦角形成的细胞和分子机制。我们分析了肾母细胞瘤1基因（Wt 1）缺陷的胚胎，并观察到未能形成心肌化窦角。相反，主静脉成为嵌入横向的胸膜心包膜（PPM），保持栓系到侧体壁的持续亚体腔间充质，这一发现与该地区的细胞凋亡减少。我们通过表达分析和谱系追踪研究表明，Wt 1在主静脉周围的亚体腔间充质中表达，但这种Wt 1阳性间充质不为窦角心肌细胞做出贡献。乙醛脱氢酶家族1，亚家族A2基因（Raldh 2）的表达在Wt 1 −/−胚胎的间充质中丢失。通过维甲酸（RA）食物供应从早期心脏缺陷中拯救出来的Raldh 2突变小鼠的表型分析显示，静脉极和心包的缺陷与Wt 1 −/−小鼠高度相似。窦角和前房角的形成是相互关联的，并依赖于PPM从底层体腔下间质的扩张和正确的暂时释放。Wt 1和下游Raldh 2/RA信号是这一过程的关键调节因子。因此，我们的研究结果提供了新的见解的遗传和细胞途径调节后延伸的哺乳动物心脏和体腔衬里的形成。
The cardiac venous pole is a common focus of congenital malformations and atrial arrhythmias, yet little is known about the cellular and molecular mechanisms that regulate its development. The systemic venous return myocardium (sinus node and sinus horns) forms only late in cardiogenesis from a pool of pericardial mesenchymal precursor cells. To analyze the cellular and molecular mechanisms directing the formation of the fetal sinus horns. We analyzed embryos deficient for the Wilms tumor 1 gene (Wt1) and observed a failure to form myocardialized sinus horns. Instead, the cardinal veins become embedded laterally in the pleuropericardial membranes (PPMs) that remain tethered to the lateral body wall by the persisting subcoelomic mesenchyme, a finding that correlates with decreased apoptosis in this region. We show by expression analysis and lineage tracing studies that Wt1 is expressed in the subcoelomic mesenchyme surrounding the cardinal veins, but that this Wt1-positive mesenchyme does not contribute cells to the sinus horn myocardium. Expression of the aldehyde dehydrogenase family 1, subfamily A2 gene (Raldh2) was lost from this mesenchyme in Wt1−/− embryos. Phenotypic analysis of Raldh2-mutant mice rescued from early cardiac defects by retinoic acid (RA) food supply revealed defects of the venous pole and pericardium highly similar to those of Wt1−/− mice. Pericardium and sinus horn formation are coupled and depend on the expansion and correct temporal release of PPMs from the underlying subcoelomic mesenchyme. Wt1 and downstream Raldh2/RA-signaling are crucial regulators of this process. Thus, our results provide novel insight into the genetic and cellular pathways regulating the posterior extension of the mammalian heart and the formation of its coelomic lining.