REGULATION OF FGF-4 GENE EXPRESSION IN DEVELOPMENT

胚胎发育需要一系列复杂的事件， 以精确有序的方式执行。 大部分的协调工作 这些事件是通过细胞外的指令来实现的， 用于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 或目标细胞的身份。 因为这些信号分子 对细胞生长和分化的深远影响， 这些分子的表达必须严格而特异地 监管. 因此，阐明管理的调节机制 这些信号分子的差异表达是 对发展过程的理解。 这个目标 研究项目是阐明机制，决定 极端离散的时空表达模式， FGF-4基因在胚胎发育中的作用。 FGF-4，FGF成员 是一种重要的信号分子， 已经证明对胚胎发生的至少两个阶段是必需的， 植入后小鼠的发育和生长以及 四肢 FGF-4基因表达特异性的一个方面是 由细胞特异性增强子决定，其可以促进转录 仅在未分化胚胎癌（EC）和胚胎干细胞中 (ES)细胞 该元件与两个特定的转录因子相互作用， 在EC和ES细胞中共表达的调节因子Sox 2和Oct-3， 在囊胚的内细胞团（ICM）中， FGF-4在发育过程中的表达 我们计划1）确定 这两种转录调节因子Oct-3和Sox 2， 协同激活FGF-4基因的表达。 2)识别和 表征控制FGF-4表达的新的独特调控元件 在胚胎发育的后期， 影响他们的活动。 3)FGF-4无效胚胎不发育 因此，排除了对其在以后的 发展 我们将利用从研究中获得的知识 鉴定驱动表达的特定调控DNA元件 FGF-4基因绕过FGF-4无效胚胎的早期致死性 并进一步研究FGF-4在胚胎发育中的作用， 尤其是肌节和肢芽。

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.