Transcriptional control of cardiac development

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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.