Genetic Regulation of Cardiac Septation

描述（由申请人提供）：先天性心脏病（CHD）是最常见的出生缺陷类型，发生在近1%的活产儿中。心脏间隔缺损占CHD的近50%。大多数CHD具有多因素起源，但越来越多的证据表明遗传因素起着重要作用。罕见的家族性CHD病例的鉴定有助于揭示遗传病因。我们研究的长期目标是了解人类CHD遗传病因的分子途径。利用全基因组连锁分析，我们发现了GATA 4的点突变，GATA 4编码一种对正常心脏发育至关重要的锌指转录因子，与心脏间隔缺损和其他心脏畸形相关。一个CHD大家系中的GATA 4 G296 S突变揭示了GATA 4和TBX 5之间的一种新的功能性相互作用，TBX 5是以CHD为特征的Holt-Oram综合征的遗传原因。与这一体外发现一致，Gata 4和Tbx 5表现出遗传相互作用，因为Gata 4和Tbx 5杂合的小鼠具有独特的心脏表型，这是由有缺陷的内膜垫发育引起的。这些发现使我们能够切入点，剖析导致CHD的分子通路被破坏。虽然Gata 4和Tbx 5以及其他转录因子在心脏发育和CHD中发挥着重要作用，但在了解介导这些发育调节因子作用的靶基因方面存在重大空白。这是该提案的重要目标之一。总的假设是，GATA 4和TBX 5调节心脏分隔和其他心脏形态发生过程的关键共同途径。本提案的目标是：具体目标1。确定Gata 4-Tbx 5相互作用是导致Gata 4 Tbx 5胚胎中观察到的心脏缺陷所必需的发育过程和细胞谱系。具体目标2。了解Hedgehog信号通路在Gata 4 Tbx 5胚胎心脏表型中的作用。具体目标3。确定Gata 4 G296 S突变蛋白在胚胎发生中的作用。将产生在Gata 4中携带G296 S突变的小鼠，并用于定义该点突变的分子和功能体内缺陷。

DESCRIPTION (provided by applicant): Congenital heart disease (CHD) is the most common type of birth defect occurring in nearly 1% of live births. Cardiac septation defects account for nearly 50% of CHD. The majority of CHD has a multifactorial origin but increasing evidence suggests that genetic factors play a significant role. The identification of rare cases of familial CHD has been instrumental in uncovering genetic etiologies. The long-term goal of our research is to understand the molecular pathways that underlie the genetic etiologies of human CHD. Utilizing genome-wide linkage analysis, we discovered point mutations in GATA4, which encodes a zinc finger transcription factor critical for normal cardiac development, that were associated with cardiac septal defects and other cardiac malformations. A GATA4 G296S mutation in a large pedigree with CHD revealed a novel functional interaction between GATA4 and TBX5, the genetic cause of Holt-Oram syndrome that is characterized by CHD. Consistent with this in vitro finding, Gata4 and Tbx5 displayed a genetic interaction as mice heterozygous for Gata4 and Tbx5 have a unique cardiac phenotype that results from defective endocardial cushion development. These findings allowed us an entry point to dissect the molecular pathways that are disrupted leading to CHD. While it is clear that Gata4 and Tbx5, as well as other transcription factors, play central roles in cardiac development and CHD, there is a major void in the understanding of the target genes that mediate the actions of these developmental regulators. This is one of the important goals of this proposal. The overall hypothesis is that GATA4 and TBX5 regulate common pathways critical for cardiac septation and other cardiac morphogenetic processes. The aims of this proposal are: Specific Aim 1. To determine the developmental processes and cell lineage(s) in which Gata4-Tbx5 interaction is necessary to result in cardiac defects seen in Gata4 Tbx5 embryos. Specific Aim 2. To understand the role of the Hedgehog signaling pathway in the cardiac phenotype of the Gata4 Tbx5 embryos. Specific Aim 3. To determine the role of the Gata4 G296S mutant protein during embryogenesis. Mice that harbor the G296S mutation in Gata4 will be generated and used to define the molecular and functional in vivo deficits of this point mutation.