DORSOVENTRAL PATTERNING THROUGH TRANSCRIPTIONAL CONTROL

描述（改编自研究者摘要）：拟定的研究是 旨在了解单个形态发生原如何启动复杂的等级结构 动物开发期间导致轴规范的事件。的 正在研究的形态发生蛋白Dorsal是一种转录因子， 分布在背/腹核浓度梯度在 果蝇胚盘胚胎。这个因素既起着激活剂的作用， 转录阻遏物，以建立多个基因活性域，沿着 胚胎的背腹轴。Dorsal的功能， 不同的方式取决于直接和间接的相互作用， 背相关同源结构域（RHD）和大量相互作用的蛋白质。一 在调节背/腹神经元功能中起关键作用的背相互作用蛋白 模式形成是Groucho的辅阻遏物。这个因素，作为一个 同源四聚体，可能介导Dorsal和组蛋白脱乙酰酶之间的相互作用 Rpd3。具体的目的是：1）识别干扰RHD的突变 具有特定的背侧活动，并利用这些突变来直接 Dorsal的生物化学和发育功能之间的联系; 2） 确定格劳乔的结构基础和发展作用 通过体外诱变、生物物理 分析和反向遗传测定; 3）确定Rpd 3在 通过新rpd 3等位基因的表型分析， 并通过Rpd 3的结构/功能分析，旨在表征其 群相互作用域; 4）刻画新的Dorsal和群相互作用域 蛋白质，并确定，通过遗传分析，如果编码基因有 在由Dorsal或Gro控制的发育过程中发挥重要作用。的 调节果蝇背腹图案形成的途径与 调节脊椎动物免疫应答和脊椎动物模式的途径 阵因此，这些研究可能会导致更好地了解人类 免疫和发育障碍。

DESCRIPTION (adapted from investigator's abstract): The proposed studies are aimed at understanding how a single morphogen initiates the complex hierarchy of events leading to axis specification during animal development. The morphogen under investigation, Dorsal, is a transcription factor that is distributed in a dorsal/ventral nuclear concentration gradient in the Drosophila blastoderm embryo. This factor functions as both an activator and a repressor of transcription to establish multiple domains of gene activity along the dorsal/ventral axis of the embryo. The ability of Dorsal to function in diverse ways is dependent upon direct and indirect interactions between the Dorsal rel homology domain (RHD) and a large array of interacting proteins. One Dorsalinteracting protein that plays a key role in regulating dorsal/ventral pattern formation is the corepressor Groucho. This factor, which functions as a homotetramer, may mediate an interaction between Dorsal and histone deacetylase Rpd3. The specific aims are to: 1) Identify mutations in the RHD that interfere with specific Dorsal activities and utilize these mutations to make direct links between the biochemical and developmental functions of Dorsal; 2) Determine the structural basis and developmental role of Groucho tetramerization through a combination of in vitro mutagenesis, biophysical analysis, and reverse genetic assays; 3) Determine the role of Rpd3 in Grouchomediated repression through the phenotypic analysis of new rpd3 alleles, and through a structure/function analysis of Rpd3 aimed at characterizing its Grouchointeraction domain; 4) Characterize new Dorsal and Grouchointeracting proteins and determine, via genetic analysis, if the encoding genes have important roles in the developmental processes governed by Dorsal or Gro. The pathway regulating dorsal/ventral patterning in Drosophila is homologous to pathways regulating the vertebrate immune response and vertebrate pattern formation. Thus, these studies may lead to a better understanding of human immunological and developmental disorders.