Transcriptional control of cardiac development

描述（申请人提供）：心脏是脊椎动物胚胎发生过程中第一个形成并发挥作用的器官。尽管脊椎动物心脏的形成已被广泛地形态学描述，但在分子水平上，决定心肌形成谱系和控制心脏特异性基因表达的调控途径尚未明确定义。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体外和体内心脏发育。心肌素是血清反应因子（SRF）的一种新型转录辅助因子，在心肌和平滑肌中特异性表达。我们的假设是，心肌素是心脏和平滑肌决定和分化的关键调节因子，并且心肌素与其他转录因子在转录复合体中起作用，控制心脏和平滑肌特异性靶基因的表达。本提案的总体目标是利用心肌素作为分子工具探索哺乳动物心脏规范的分子机制。特别是，我们将研究心肌素如何特异性反激活心脏基因，以及心肌素在小鼠心脏发育过程中的体内功能。

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.