GENE THAT CONTROLS LATERALITY IN EARLY CARDIOGENESIS

我们将讨论双边对称性在正常和非对称中的基础作用 解剖、生化和遗传学研究中的心脏发生异常 常染色体隐性遗传IV/IV小鼠突变体。IV/IV鼠标是一种 公认的人体内翻及多脾无脾综合征模型， 表现出心脏和其他脏器的随机侧向，以及 心脏畸形发生率高，如完全性房室管， 大动脉转位，右心室双出口。我们 还将利用一种实验鸟类模型。这些型号将允许我们 对正常发育进行基线研究，并开始辨别 可能导致人类畸形、动脉和双胎的机制 右心室出口。人类先天性心脏缺陷的外推 将利用人类常染色体隐性突变的可用性，其 表型与小鼠突变体相似。这项工作将主要有四个方面 推力： 1.确定倒位和异位的遗传方式 选择纯合子的自交系进行静脉注射。我们将特别注意 支付给SWV-IV，在那里基因偶尔表现出显性效应。 2.鉴定在测定过程中唯一合成的多肽 胚胎的偏侧性，并利用它们试图克隆基因。我们会 确定iv基因是否与任何同源盒簇相连。我们会 构建8天小鼠胚胎基因(CDNA)文库并尝试 从这个文库中分离出iv基因。 3.辨别基因作用与心血管疾病的关系 形态发生。我们将研究心肌的偏侧性。 D和L的细胞分化轮换(遗传和实验) 心脏，看看肌球蛋白表达的遗传程序是否在L身上逆转 循环播放。由于这些小鼠有很高的CAVC(一种心内膜血管)的发生率 垫状缺陷)，该基因表达的形态后果 将在垫子的形态和发育过程中进行研究 试验性的。 4.测试同时利用遗传缺陷和基因突变的心脏循环模型 实验禽类系统。

We will address the fundamental role of bilateral symmetry in normal and abnormal cardiogenesis by anatomic, biochemical and genetic investigations of the autosomal recessive iv/iv mouse mutant. The iv/iv mouse is a recognized model of human situs inversus and polysplenia-asplenia syndrome, demonstrating random sidedness of the heart and other viscera, as well as a high frequency of cardiac malformations such as complete AV canal, transposition of the great arteries, and double outlet right ventricle. We will also utilize an experimental avian model. These models will permit us to make baseline studies of normal development as well as begin to discern the mechanisms that can cause human malformations, arteries, and double outlet right ventricle. Extrapolation to human congenital heart defects will utilize the availability of human autosomal recessive mutations whose phenotype parallels the mouse mutant. This work will have four main thrusts: 1. To determine paterns of inheritance of situs inversus and heterotaxia in selected inbred strains homozygous for iv. Particular attention will be paid to SWV-iv where the gene occasionally shows a dominant effect. 2. To identify polypeptides uniquely synthesized during determination of embryonic laterality and use them in an attempt to clone the gene. We will determine if the iv gene is linked to any homeo box cluster. We will construct a genic (cDNA) library from 8 day mouse embryos and attempt to isolate the iv gene from this library. 3. To discern the relation between gene action and cardiovascular morphogenesis. We will study the laterality of myocardial cytodifferentiation in d and l rotated (both genetic and experimental) hearts to see if the genetic program for myosin expression is reversed in l loop. Since these mice have a high incidence of CAVC (an endocardial cushion defect), the morphological consequences of expression of this gene will be examined in cushion development both morphologically and experimentally. 4. To test models of heart looping utilizing both the genetic defect and an experimental avian system.