Transcriptional Regulators of Cardiac Gene Expression

描述(申请人提供)：先天性心脏畸形， 最常见的是每1000名活产儿中就有8名 在儿童身上观察到的先天缺陷。这类畸形的频率在 流产和死产可能会增加10倍之多。一个 对这些异常的遗传基础的理解需要详细的 控制心脏形态发生和基因表达的因素的信息。 心脏调节网络的几个关键成员被保存下来 在果蝇和包括人类在内的高等真核生物之间。关于 转录调节因子，苍蝇遗传学的利用允许一种 Tinman、Pannier、U型、D-MEF2的快速功能分析七和七 UP蛋白，阐明它们在心脏形成和心脏形成中的独特作用 心肌细胞特化。这份提案将进一步分析以下方面 这些基本调节因子的调节、相互作用和功能 各种因素。虽然Tinman是已知的Pannier转录激活因子，但 十足瘫痪信号可能共同诱导GATA基因的表达 事件仍有待调查。这两种基因输入很可能在 Tinman和Pannier在心脏形成区的重叠表达，以及 这两种因子功能相互作用的分子基础 D-MEF2基因转录的调控将被确定。此外，心脏 诱导试验可以用来表征保守的心源性结构域 Pannier和小鼠GATA-4。U型对心脏的形成有负面作用 以及它能够将Pannier从转录的 必须阐明激活剂对抑制物的作用。最后，对 Seven Up的无翼基因及其分泌型生长因子在植物生长中的作用 将确定心肌细胞的功能多样化。总体而言， 进一步阐述这些普遍性的功能和相互作用 心源性因子及其控制的细胞过程应该提供 对控制心脏发育的基本机制的有意义的见解 以及基因表达，在这种模式生物和更高级的物种中也是如此。

DESCRIPTION (provided by applicant): Congenital malformations of the heart, which occur with a frequency of 8 per 1000 live births, are the most common birth defects observed in children. The frequency of such malformations in miscarriages and stillbirths may be as much as 10-fold greater. An understanding of the genetic bases of these anomalies will require detailed information on the factors controlling heart morphogenesis and gene expression. Several key members of the cardiac regulatory network have been conserved between Drosophila and higher eukaryotes including humans. Concerning transcriptional regulators, the utilization of fly genetics has allowed for a rapid functional analysis of the Tinman, Pannier, U-shaped, D-MEF2. and Seven Up proteins, illuminating their distinct roles in heart formation and myocardial cell specialization. This proposal will further analyze aspects of the regulation, interaction, and function of these essential regulatory factors. While Tinman is a known transcriptional activator of pannier, the probable co-induction of this GATA gene by Decapentaplegic-mediated signaling events remains to be investigated. Both genetic inputs likely culminate in the overlapping expression of Tinman and Pannier in the heart-forming region, and the molecular bases of the functional interaction of these two factors in the regulation of D-mef2 gene transcription will be determined. Additionally, heart induction assays can be used to characterize the conserved cardiogenic domains of Pannier and mouse GATA-4. U-shaped plays a negative role in heart formation and the mechanism of its ability to change Pannier from a transcriptional activator to a repressor must be elucidated. Finally, the regulation of the wingless gene by Seven Up and the role of this secreted growth factor in the functional diversification of cardial cells will be ascertained. Overall, the further elaboration of the functions and interactions of these universal cardiogenic factors, and the cellular processes they control, should provide meaningful insights into fundamental mechanisms controlling heart development and gene expression, in this model organism and more advanced species as well.