REGULATION OF CARDIAC MYOGENESIS

了解心肌细胞发育的分子调控是了解胚胎发育过程中心脏缺陷发生的重要前提。尽管近年来关于心脏基因表达的转录调控已经有了很多的研究，但对调控心肌细胞规范、增殖和分化途径的信号相互作用知之甚少。我们已经在鸟类中开发了检测方法，以研究与心肌细胞发育有关的最早的信号相互作用。利用这些分析，信号相互作用和信号分子已被确定为调节心肌细胞发育的重要步骤。从这些研究中，我们提出，分化的心肌细胞的出现需要来自下胚层和前外侧内胚层的信号。信号分子也已被确定是由低母细胞启动上胚层中的心肌细胞发育而产生的。该项目的目标是更清楚地定义组织相互作用和调控鸟类心肌细胞发育的信号分子，并利用这些信息开始研究小鼠心肌发生的早期阶段。研究将使用显微外科、解释和重组技术来研究调节前原肠胚和原肠胚期小鼠胚胎中胚层发育的信号相互作用。实验将验证这一假设，即来自内脏内胚层和前外侧内胚层的信号是小鼠心肌发生所必需的。实验还将研究几种类型的信号分子在哺乳动物心肌发生中的作用，包括成纤维细胞生长因子、激活素、转化生长因子β和表皮生长因子相关分子Cripto-1。最后，实验将研究Hex基因在前外侧内胚层中的表达如何调节心肌形成的后期阶段。这些信息将增加我们对正常和异常心脏发育的理解，并可能提出改变心脏发育或心肌细胞复制的方法。

An understanding of the molecular regulation of heart muscle cell development is an important prerequisite to understanding how heart defects arise during embryonic development. Although much has been learned in recent years concerning the transcriptional regulation of cardiac gene expression, less is known about signaling interactions that regulate steps along the pathway of heart muscle cell specification, proliferation and differentiation. We have developed assays in avians to investigate the earliest signaling interactions involved in development of cardiac myocyte development. Using these assays, signaling interactions and signaling molecules have been identified that regulate important steps in heart muscle cell development. From these studies we have proposed that signals from both the hypoblast and anterior lateral endoderm are required for the appearance of differentiated heart muscle cells. Signaling molecules have also been identified that are produced by the hypoblast initiate heart muscle cell development in the epiblast. The goals of this project are to more clearly define tissue interactions and signaling molecules regulating cardiac myocyte development in avians, and to use that information to begin investigating the earliest stages of cardiac myogenesis in mouse. Studies will investigate signaling interactions regulating mesoderm development in pregastrula and gastrula stage mouse embryos using microsurgical, explanation and recombination techniques. Experiments will test the hypothesis that signals from both visceral endoderm and anterior lateral endoderm are required for cardiac myogenesis in mouse. Experiments will also investigate the role of several types of signaling molecules in mammalian cardiac myogenesis, including fibroblast growth factors, activin, transforming growth factor beta, and the epidermal growth factor related molecule cripto-1. Finally experiments will investigate how expression of the homeobox gene Hex in anterior lateral endoderm regulates later stages of cardiac myogenesis. This information will increase our understanding of both normal and abnormal heart development and may suggest ways to alter heart development or replication of cardiac myocytes.