Expression of the BMP Receptor Alk3 in the Second Heart Field Is Essential for Development of the Dorsal Mesenchymal Protrusion and Atrioventricular Septation
Expression of the BMP Receptor Alk3 in the Second Heart Field Is Essential for Development of the Dorsal Mesenchymal Protrusion and Atrioventricular Septation
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DOI：
10.1161/circresaha.112.300821
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发表时间：
2013-05-24
影响因子：
20.1
通讯作者：
Wessels, Andy
中科院分区：
文献类型：
--
作者：
Briggs, Laura E.;Phelps, Aimee L.;Wessels, Andy
基本原理：背侧间充质突起（dorsal mesenchymal protrusion，简称DEP）是发育中心脏静脉极第二心野（second heart field，简称SHF）的一个分支。最近的研究表明，其发展的干扰与房室间隔缺损的发病机制有关。虽然房室分隔的重要性已经确立，但其发展的分子和细胞机制还远未完全了解。先前的研究已经证明，骨形态发生蛋白（BMP）信号传导对于AV内膜垫和心脏流出道的正确形成是必不可少的。BMP信号的作用，在调节的tumor development仍然有待澄清。目的：要确定的作用，BMP信号在tumor development.Methods和结果：条件删除的BMP受体Alk 3从静脉极SHF细胞导致受损的形成的tumor和一个完全渗透表型的口primum缺陷，一个标志性特征的AV间隔缺损。突变体的分析表明，SHF细胞的增殖指数下降，因此，减少SHF细胞在心脏静脉极的数量。相反，与增殖和活性BMP/转化生长因子β信号相关的标记物的体积和表达没有显着改变在AV垫的SHF-Alk 3 mutants.Conclusions：BMP信号是必需的SHF衍生的血管生成祖细胞群体在心脏静脉极的扩张。来自SHF的Alk 3介导的BMP信号传导的扰动导致了骨缺损和原发口缺陷的受损发展。
Rationale: The dorsal mesenchymal protrusion (DMP) is a prong of mesenchyme derived from the second heart field (SHF) located at the venous pole of the developing heart. Recent studies have shown that perturbation of its development is associated with the pathogenesis of atrioventricular (AV) septal defect. Although the importance of the DMP to AV septation is now established, the molecular and cellular mechanisms underlying its development are far from fully understood. Prior studies have demonstrated that bone morphogenetic protein (BMP) signaling is essential for proper formation of the AV endocardial cushions and the cardiac outflow tract. A role for BMP signaling in regulation of DMP development remained to be elucidated.Objective: To determine the role of BMP signaling in DMP development.Methods and Results: Conditional deletion of the BMP receptor Alk3 from venous pole SHF cells leads to impaired formation of the DMP and a completely penetrant phenotype of ostium primum defect, a hallmark feature of AV septal defects. Analysis of mutants revealed decreased proliferative index of SHF cells and, consequently, reduced number of SHF cells at the cardiac venous pole. In contrast, volume and expression of markers associated with proliferation and active BMP/transforming growth factor beta signaling were not significantly altered in the AV cushions of SHF-Alk3 mutants.Conclusions: BMP signaling is required for expansion of the SHF-derived DMP progenitor population at the cardiac venous pole. Perturbation of Alk3-mediated BMP signaling from the SHF results in impaired development of the DMP and ostium primum defects.