Transcriptional control of cardiac development

描述（由申请人提供）：心脏是脊椎动物胚胎发生过程中形成和发挥功能的第一个器官。虽然脊椎动物心脏的形成已在形态学上得到了广泛的描述，但决定心肌细胞谱系和控制心脏特异性基因表达的调控途径在分子水平上还没有很好的定义。我们研究的长期目标是了解控制早期心肌决定和分化的细胞和分子机制，特别是在转录水平上。我们正在应用各种分子，细胞和遗传方法来研究小鼠心脏发育的体外和体内。肌心素是一种新的血清反应因子（SRF）转录辅因子，特异性表达于心肌和平滑肌。我们的假设是，myocardin是一个关键的调节心脏和平滑肌的决定和分化，myocardin功能的转录复合物与其他转录因子，以控制心脏和平滑肌特异性靶基因的表达。本研究的总体目标是以心肌蛋白为分子工具，探索哺乳动物心脏特化的分子机制。特别是，我们将研究如何myocardin特异性反式激活心脏基因和myocardin在小鼠心脏发育过程中的体内功能。 具体目标是：目标1。明确心肌素介导心肌分化和心肌特异性基因激活的分子机制。目标2.为了表征小鼠，我们已经产生了在心肌蛋白基因座处的无效突变纯合的小鼠，并检查心肌蛋白在小鼠心脏发育期间的体内作用。目标3。鉴定和表征与心肌素相互作用的蛋白质，作为理解心肌素依赖性基因表达的转录机制的诱导方法。这些研究应该为我们理解控制哺乳动物心脏发育的转录网络提供重要的见解。这些研究揭示的分子策略可能适用于病理生理相关的心脏事件，如心力衰竭和肥大。

DESCRIPTION (provided by applicant): The heart is the first organ to be formed and function during vertebrate embryogenesis. Although the formation of vertebrate heart has been extensively described morphologically, the regulatory pathways that determine cardiomyogenic lineage and control cardiac-specific gene expression are not well-defined at the molecular level. The long-term goal of our study is to understand the cellular and molecular mechanisms that control the early cardiac muscle determination and differentiation, particularly at the transcriptional level. We are applying a variety of molecular, cellular, and genetic approaches to study mouse heart development both in vitro and in vivo. Myocardin is a novel transcriptional cofactor for serum response factor (SRF) and is specifically expressed in cardiac and smooth muscles. Our hypothesis is that myocardin is a key regulator of cardiac and smooth muscle determination and differentiation and that myocardin functions in a transcriptional complex with other transcription factors to control cardiac and smooth muscle specific target gene expression. The overall goal of this proposal is to explore the molecular mechanisms of mammalian cardiac specification using myocardin as a molecular tool. In particular, we will study how myocardin specifically transactivate cardiac genes and the in vivo function of myocardin during mouse heart development. The specific aims are: Aim 1. To define the molecular mechanisms of myocardin functions that mediate cardiac-muscle differentiation and cardiac-specific gene activation. Aim 2. To characterize mice we have generated that are homozygous for null mutation at the myocardin locus and examine the in vivo role of myocardin during mouse heart development. Aim 3. To identify and characterize proteins that interact with myocardin as an inductive approach to understand the transcriptional mechanisms of myocardin-dependent gene expression. These studies should provide an important insight into our understanding the transcriptional networks that control mammalian heart development. The molecular strategies revealed in these studies may apply to pathophysiologically related cardiac events such as cardiac failure and hypertrophy.