Donovan Jena, Kordylewska Anna, Jan Yuh Nung, Utset Manuel F
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
Curr Biol. 2002 Sep 17;12(18):1605-10. doi: 10.1016/s0960-9822(02)01149-1.
Congenital malformations of the heart and circulatory system are the most common type of human birth defect. Recent studies have implicated the Notch signaling pathway in human cardiac development by demonstrating abnormalities of the JAG1 gene as the basis for Alagille syndrome and some cases of isolated tetralogy of Fallot or pulmonic stenosis. How the Notch pathway acts in cardiac development remains unknown, but the Hey family of basic helix-loop-helix (bHLH) transcription factors are candidates for mediating Notch signaling in the developing cardiovascular system. Here, we use gene targeting to determine the developmental functions of mouse Hey2, a Hey family member that is expressed during the embryonic development of the heart, arteries, and other organs. Homozygotes for the Hey2 mutant allele display a spectrum of cardiac malformations including ventricular septal defects, tetralogy of Fallot, and tricuspid atresia, defects that resemble those associated with mutations of human JAG1. These results establish Hey2 as an important regulator of cardiac morphogenesis and suggest a role for Hey2 in mediating or modulating Notch signaling in the developing heart.
心脏和循环系统的先天性畸形是人类出生缺陷中最常见的类型。最近的研究表明，Notch信号通路参与人类心脏发育，研究显示JAG1基因异常是阿拉吉耶综合征以及部分孤立性法洛四联症或肺动脉狭窄病例的病因。Notch通路如何在心脏发育过程中发挥作用尚不清楚，但碱性螺旋-环-螺旋（bHLH）转录因子Hey家族是发育中的心血管系统中介导Notch信号的候选因子。在此，我们利用基因靶向技术来确定小鼠Hey2的发育功能，Hey2是Hey家族的一个成员，在心脏、动脉和其他器官的胚胎发育过程中表达。Hey2突变等位基因的纯合子表现出一系列心脏畸形，包括室间隔缺损、法洛四联症和三尖瓣闭锁，这些缺陷与人类JAG1突变相关的缺陷相似。这些结果确立了Hey2作为心脏形态发生的重要调节因子，并表明Hey2在发育中的心脏中介导或调节Notch信号中发挥作用。
