Délot Emmanuèle C
Department of Pediatrics, Geffen School of Medicine at UCLA, Pediatric Cardiology, MRL 3-762, 675 Charles E Young Drive South, Los Angeles, CA 90095, USA.
Mol Genet Metab. 2003 Sep-Oct;80(1-2):27-35. doi: 10.1016/j.ymgme.2003.07.004.
Congenital heart defects, the leading cause of deaths from birth defects, are estimated to occur in close to 1% of live newborns. Among these, abnormal septation of the heart and valve anomalies are the most frequent forms. Despite progress defining several genes involved in normal heart development, we still have a limited understanding of the signaling pathways involved in morphogenesis of the outflow tract (OFT) and, to date, very few genes have been identified that are responsible for defects in humans. Bone Morphogenetic Protein (BMP) signaling pathways are emerging as vital regulators of multiple aspects of cardiogenesis, including the septation of the OFT and valve maturation. Genetic and other in vivo evidence is now supporting the role for BMPs as inducers of endocardial cushion epithelial-to-mesenchymal transformation that was suggested by in vitro explant studies as well as by their patterns of expression in the developing heart. Here, we review briefly the in vitro data, and detail the novel mouse models where perturbed BMP signaling pathways result in impaired OFT septation and semilunar valvulogenesis. We propose that growth of the OFT valve cushions is regulated by the level of BMP signaling, under the control of other signaling pathways.
先天性心脏缺陷是出生缺陷致死的主要原因，据估计在近1%的活产新生儿中出现。其中，心脏的异常分隔和瓣膜异常是最常见的形式。尽管在确定参与正常心脏发育的几个基因方面取得了进展，但我们对流出道（OFT）形态发生所涉及的信号通路仍了解有限，而且迄今为止，已确定的导致人类缺陷的基因非常少。骨形态发生蛋白（BMP）信号通路正逐渐成为心脏发生多个方面的重要调节因子，包括OFT的分隔和瓣膜成熟。遗传及其他体内证据现在支持了BMP作为心内膜垫上皮-间充质转化诱导剂的作用，这一作用是由体外外植体研究及其在发育中心脏的表达模式所提示的。在这里，我们简要回顾体外数据，并详细介绍新的小鼠模型，其中BMP信号通路受到干扰会导致OFT分隔和半月瓣发生受损。我们提出，在其他信号通路的控制下，OFT瓣膜垫的生长受BMP信号水平的调节。
