BMP signaling is required for septation of the outflow tract of the mammalian heart
BMP signaling is required for septation of the outflow tract of the mammalian heart
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DOI：
10.1242/dev.00181
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发表时间：
2003-01-01
期刊：
影响因子：
4.6
通讯作者：
Lyons, KM
中科院分区：
文献类型：
--
作者：
Délot, EC;Bahamonde, ME;Lyons, KM
骨形态发生蛋白(BMPs)构成了一个类似于20种生长因子的家族，参与了多种胚胎诱导过程。BMP在原肠形成过程中对构图产生剂量依赖效应，BMP活性的梯度被认为是通过调节BMP受体、配体和拮抗剂的相对浓度而建立的。我们测试了后期发育事件是否也对BMP信号水平的降低敏感。我们设计了一种表达BMP II型受体的基因敲除小鼠，该受体缺乏一半的配体结合域。这种改变的受体的表达水平与野生型等位基因相当，但信号传递能力降低。与Bmpr2缺失的小鼠不同，这种亚型受体纯合子的小鼠具有正常的原肠形成，这为BMPs在哺乳动物发育过程中的剂量依赖效应提供了遗传证据。然而，突变的人会在怀孕中期死于心血管和骨骼缺陷，这表明这些组织的发育需要野生型水平的BMP信号。最显著的缺陷发生在心脏流出道，瓣膜水平以下的圆锥动脉干没有分隔，主动脉弓中断，这种表型在人类被称为永久性动脉干(A4型)。此外，半月瓣在突变体中不会形成，而房室瓣似乎没有受到影响。心脏间隔异常和瓣膜异常是人类先天性心脏缺陷最常见的形式；然而，大多数小鼠模型在整个心脏组织中都显示出广泛的缺陷。Bmpr2(DeltaE2)突变体中心脏异常的更有限的频谱使该菌株成为了解人类永久性动脉干胚胎缺陷和半月瓣形成受损的关键小鼠模型。
Bone morphogenetic proteins (BMPs) constitute a family of similar to20 growth factors involved in a tremendous variety of embryonic inductive processes. BMPs elicit dose-dependent effects on patterning during gastrulation and gradients of BMP activity are thought to be established through regulation of the relative concentrations of BMP receptors, ligands and antagonists. We tested whether later developmental events also are sensitive to reduced levels of BMP signaling. We engineered a knockout mouse that expresses a BMP type II receptor that lacks half of the ligand-binding domain. This altered receptor is expressed at levels comparable with the wild-type allele, but has reduced signaling capability. Unlike Bmpr2-null mice, mice homozygous for this hypomorphic receptor undergo normal gastrulation, providing genetic evidence of the dose-dependent effects of BMPs during mammalian development. Mutants, however, die at midgestation with cardiovascular and skeletal defects, demonstrating that the development of these tissues requires wild-type levels of BMP signaling. The most striking defects occur in the outflow tract of the heart, with absence of septation of the conotruncus below the valve level and interrupted aortic arch, a phenotype known in humans as persistent truncus arteriosus (type A4). In addition, semilunar valves do not form in mutants, while the atrioventricular valves appear unaffected. Abnormal septation of the heart and valve anomalies are the most frequent forms of congenital cardiac defects in humans; however, most mouse models display broad defects throughout cardiac tissues. The more restricted spectrum of cardiac anomalies in Bmpr2(DeltaE2) mutants makes this strain a key murine model to understand the embryonic defects of persistent truncus arteriosus and impaired semilunar valve formation in humans.