GENE THAT CONTROLS LATERALITY IN EARLY CARDIOGENESIS

我们将讨论双边对称性在正常和 通过解剖学、生物化学和遗传学研究发现的异常心脏发生 常染色体隐性遗传IV/IV小鼠突变体。 iv/iv小鼠是一种 公认的人内脏逆位和多脾-无脾综合征模型， 显示心脏和其他内脏的随机偏侧，以及 高频率的心脏畸形，如完全AV管， 大动脉转位和右心室双出口 我们 还将利用实验性的鸟类模型。 这些模型将允许我们 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 右心室出口 人类先天性心脏病的外推 将利用人类常染色体隐性突变的可用性， 表型与小鼠突变体相似。 这项工作将有四个主要 推力： 1.目的探讨先天性内脏逆位和内脏异位的遗传特点， 选择的近交系对于iv纯合。 将特别注意 支付给SWV-iv，其中该基因偶尔显示显性效应。 2.为了鉴定在测定过程中独特合成的多肽， 胚胎的偏侧性，并利用它们来克隆基因。 我们将 确定IV基因是否与任何同源盒簇连锁。 我们将 从8天小鼠胚胎构建基因（cDNA）文库，并尝试 从该文库中分离IV基因。 3.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旋转的细胞分化（遗传和实验） 心脏，看看是否肌球蛋白表达的遗传程序是逆转在l 循环. 由于这些小鼠具有高的CAVC（一种内皮细胞癌）发病率， 垫缺陷），该基因表达的形态学后果 将在形态学和 实验性的 4.为了测试心脏循环模型，利用遗传缺陷和 实验鸟类系统

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.