REGULATION OF CARDIAC MYOGENESIS

了解心肌细胞发育的分子调控是了解胚胎发育期间心脏缺陷如何产生的重要前提。尽管近年来对心脏基因表达的转录调控有了很大的了解，但对心肌细胞特异性、增殖和分化途径中沿着调控步骤的信号相互作用却知之甚少。我们已经在鸟类中开发了检测方法来研究心肌细胞发育过程中最早的信号相互作用。使用这些测定，已经确定了调节心肌细胞发育重要步骤的信号相互作用和信号分子。从这些研究中，我们提出，信号从下胚层和前外侧内胚层分化的心肌细胞的外观所需的。也已经鉴定出由下胚层产生的信号分子启动上胚层中的心肌细胞发育。本项目的目标是更清楚地定义组织相互作用和调节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最早阶段。研究将调查信号的相互作用，调节中胚层发育的前原肠胚和原肠胚阶段的小鼠胚胎，使用显微外科，解释和重组技术。实验将检验来自内脏内胚层和前外侧内胚层的信号都是小鼠心肌发生所需的假设。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，实验将探讨同源异型盒基因Hex在前外侧内胚层的表达如何调节心肌发生的后期阶段。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.