REGULATION OF FGF-4 GENE EXPRESSION IN DEVELOPMENT

胚胎发育需要一个复杂的事件计划，必须 以精确有序的方式执行。的很大一部分协调 这些事件是通过细胞外指令实现的 用来激活或抑制转录的信号分子 特定的基因亚群并最终影响增殖状态 或目标小区的身份。因为这些信号分子有 对细胞生长和分化的深刻影响，它势在必行 这些分子的表达是严格和特定的 受监管的。因此，阐明监管机制 这些信号分子的差异表达是 对发展过程的理解。这样做的目的是 研究项目的目的是阐明决定这些因素的机制 极端离散的时间和空间模式的表达 胚胎发育过程中的成纤维细胞生长因子-4基因。成纤维细胞生长因子-4，成纤维细胞生长因子成员 生长因子家族是一种重要的信号分子，具有 已被证明对胚胎发育的至少两个阶段是必不可少的， 小鼠植入后的发育、生长和纹饰 四肢。成纤维细胞生长因子-4基因表达的特异性的一个方面是 由细胞特异性增强子决定，它可以促进转录 仅限于未分化胚胎癌(EC)和胚胎干细胞 (ES)细胞。该元件与两个特定的转录因子相互作用 在EC和ES细胞中共表达的调控因子Sox2和Oct-3， 在胚泡的内细胞团(ICM)中，第一个部位 成纤维细胞生长因子-4在发育过程中的表达。我们计划1)确定 这两种转录调控因子Oct-3和Sox2， 协同作用激活成纤维细胞生长因子-4基因的表达。2)识别和 表征调控成纤维细胞生长因子-4表达的新的不同调控元件 在胚胎发育的后期，信号和因素 影响他们的活动。3)成纤维细胞生长因子-4缺失胚胎不发育 超越植入，从而排除了对其在以后的作用的评估 发展。我们将利用从研究中获得的知识 确定驱动表达的特定调控DNA元件 利用成纤维细胞生长因子-4基因绕过成纤维细胞生长因子4缺失胚胎的早期致死 并进一步研究成纤维细胞生长因子-4在胚胎发育中的作用， 尤其是肌肉瘤和肢芽。

Embryonic development entails a complex program of events that must be executed in a precise and ordered fashion. Much of the coordination of these events is achieved by the directive instructions of extracellular signaling molecules that serve to activate or repress transcription of specific gene subsets and ultimately influence the proliferative state or identity of the target cell. Because these signaling molecules have a profound effect on cell growth and differentiation, it is imperative that the expression of these molecules be rigorously and specifically regulated. Thus, elucidation of the regulatory mechanisms that govern differential expression of these signaling molecules is fundamental to an understanding of the process of development. The goal of this research project is to elucidate the mechanisms which determine the extremely discrete temporal and spatial pattern of expression of the FGF-4 gene during embryonic development. FGF-4, a member of the FGF family of growth factors, is an important signaling molecule which has been shown to be essential for at least two stages of embryogenesis, post-implantation mouse development and growth and patterning of the limb. One aspect of the specificity of FGF-4 gene expression is determined by a cell-specific enhancer, which can promote transcription only in undifferentiated embryonal carcinoma (EC) and embryonal stem (ES) cells. This element interacts with two specific transcriptional regulators, Sox2 and Oct-3, which are coexpressed in EC and ES cells, and in the inner cells mass (ICM) of the blastocyst, the first site of FGF-4 expression during development. We plan 1) to determine the mechanism by which these two transcriptional regulators, Oct-3 and Sox2, synergize to activate expression of the FGF-4 gene. 2) To identify and characterize new distinct regulatory elements governing FGF-4 expression during later stages of embryonic development and the signal and factors influencing their activity. 3) FGF-4 null embryos do not develop beyond implantation, thus precluding the assessment of its role in later development. We will utilize the knowledge obtained from the studies identifying the specific regulatory DNA elements driving the expression of the FGF-4 gene to bypass the early lethality of FGF-4 null embryos and further investigate the role of FGF-4 in embryonic development, particularly the myotomes and the limb bud.