Transcriptional Regulators of Cardiac Gene Expression

描述（由申请人提供）：先天性心脏畸形， 发生率为每1000例活产8例， 在儿童中观察到的出生缺陷。这种畸形的频率在 流产和死产的几率可能高达10倍。一个 了解这些异常的遗传基础将需要详细的 关于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 果蝇和包括人类在内的高等真核生物之间的差异。关于 转录调节因子，苍蝇遗传学的利用允许 Tinman、Pannier、U形、D-MEF 2的快速功能分析。和七 蛋白质，阐明它们在心脏形成中的独特作用， 心肌细胞特化该提案将进一步分析以下方面： 这些重要调节因子的调节、相互作用和功能 因素虽然Tinman是一种已知的pannier转录激活因子， 通过十肢麻痹介导的信号传导可能共诱导该加塔基因 事件仍有待调查。这两种基因输入可能最终导致 Tinman和Pannier在心脏形成区的重叠表达，以及 这两种因子在细胞中功能相互作用的分子基础 将确定D-mef 2基因转录的调节。此外，心脏 诱导测定可用于表征保守的心源性结构域 Pannier和小鼠加塔-4的。U形在心脏形成中起负面作用 以及其将Pannier从转录水平改变为转录水平的能力的机制 必须阐明激活剂对抑制剂的作用。最后，监管 无翅基因的研究，以及这种分泌的生长因子在 将确定可再生能源电池的功能多样化。总体看 进一步阐述这些普遍性的职能和相互作用， 心源性因子及其控制的细胞过程， 对控制心脏发育的基本机制的有意义的见解 以及基因表达的影响。

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.