TRANSCRIPTIONAL REGULATORY MECHANISMS DURING DEVELOPMENT

描述（改编自申请人的摘要）：胚胎调节它们的发育。 生长和发育在许多方面，但控制基因转录 是引导细胞沿着不同方向 发展路径。 在果蝇中，一个级联的核调节 这些事件通过产生 复杂的基因表达模式 许多这些模式形成 基因编码DNA结合蛋白， 表达，并随后以某种方式指导基因组的其余部分， 适合于生物体中的每个位置。 最近的证据表明 这些调节蛋白中的许多在整个细胞中是保守的， 苍蝇和人类之间的进化距离， 一级结构，意味着机制相似，至少 在某种程度上，就其发展的“意义”而言，也就是说， 它们所嵌入的监管方案解决了常见的问题 多细胞有机体的发育过程 因此，详细的 了解一个系统中保守调节因子的相互作用 很可能对它们在其他物种中的同源物有重要的影响。 系统. 在胚胎发生的研究中似乎有一个关键点， 重要的是建立两类具体机制。 首先， 基因产物与哪些其他基因或基因产物直接相互作用; 第二，这些分子的具体结果是什么？ 交互. 这一建议将有助于理解这一点。 通过关注两种机制的相互作用和功能， 同源结构域（HD）含有转录调节因子，参与 果蝇的模式形成 一个是Engrailed（En），激活自己的 基因并抑制胚胎中的其他几个基因， 在培养的细胞中具有转录抑制活性。 的 另一个是Ftz，它激活了许多基因，包括它自己的基因（ftz），在一个 相互作用被认为是直接的，并具有很强的 在培养细胞中的转录激活功能。 的嵌合蛋白 其中En HD被Ftz HD替换，像En一样，表现为 阻遏物。 当这种蛋白质在胚胎中表达时， 它与ftz基因相互作用，抑制它。 两种特定相互作用的要求，由En自身激活 基因和ftz基因的嵌合蛋白的阻遏，这项研究 将解决的问题，如何含HD的靶基因， 调节因子在果蝇胚胎中被识别和控制， 从而阐明复合物中的转录调控机制， 发展环境。

DESCRIPTION (Adapted from Applicant's Abstract): Embryos regulate their growth and development in many ways, but control of gene transcription is one of the most important for directing cells along different developmental pathways. In Drosophila, a cascade of nuclear regulatory events establishes very early differences in cell fates by producing intricate patterns of gene expression. Many of these pattern forming genes encode DNA binding proteins which regulate each other's expression, and subsequently instruct the rest of the genome in a manner appropriate to each position in the organism. Recent evidence suggests that many of these regulatory proteins are conserved across the evolutionary distance separating flies and humans, both in terms of primary structure, implying similarity in mechanism, and, at least to some extent, in terms of their developmental "meaning", that is, how the regulatory scheme in which they are embedded solves the common problems of a developing multi-cellular organism. Therefore, a detailed understanding of the interactions of conserved regulators in one system is likely to have important implications for their homologs in other systems. There appears to be a juncture in the study of embryogenesis where it is important to establish specific mechanisms of two types. First, which gene products interact directly with which other genes or gene products; and second, what are the specific molecular consequences of those interactions. This proposal will contribute to the understanding of such mechanisms by focusing on the interactions and function of two homeodomain (HD) containing transcriptional regulators involved in pattern formation in Drosophila. One, Engrailed (En), activates its own gene and represses several other genes in embryos, and has been shown to possess a transcriptional repression activity in cultured cells. The other, Ftz, activates a number of genes, including its own (ftz), in an interaction that is thought to be direct, and possesses a strong transcription activation function in cultured cells. A chimeric protein in which the En HD is replaced by the Ftz HD, like En, behaves as a repressor in cultured cells. When this protein is expressed in embryos, it interacts with the ftz gene, repressing it. By dissecting the requirements for two specific interactions, activation by En of its own gene and repression of the ftz gene by the chimeric protein, this study will address the question of how the target genes of HD-containing regulators are recognized and controlled in Drosophila embryos and thereby elucidate mechanisms of transcriptional regulation in a complex developmental environment.