DORSOVENTRAL PATTERNING THROUGH TRANSCRIPTIONAL CONTROL

简介(改编自研究人员摘要)：建议的研究包括 旨在了解单一形态素如何启动复杂的层次结构 在动物发育过程中导致轴规范的事件。这个 研究中的形态原，DRADAL，是一种转录因子，它是 分布在背侧/腹侧核的浓度梯度中 果蝇胚层胚胎。这一因素既有激活剂的作用，又有 转录抑制因子建立基因活性的多个结构域 胚胎的背轴/腹轴。背部运动功能的变化 不同的方式取决于 背部Rel同源结构域(RHD)和大量相互作用蛋白。一 在调节背侧/腹侧的过程中起关键作用的Dorsal相互作用蛋白 模式的形成是核心抑制因子Groucho。这一因素的作用是 同源四聚体，可能介导背部和组蛋白脱乙酰酶之间的相互作用 Rpd3.具体目的是：1)识别RHD中干扰的突变 具有特定的背部活动，并利用这些突变直接 背部生化功能与发育功能的联系；2) 确定格劳乔的结构基础和发展作用 通过体外诱变、生物物理相结合的四聚 分析和反向遗传分析；3)确定Rpd3在 通过对新的rpd3等位基因的表型分析， 并通过对RPD3的结构/功能分析来表征其 GrouchoInteraction结构域；4)新的背部和GrouchoInteraction结构域特征 蛋白质，并通过遗传分析确定编码基因是否 在由背部或GRO控制的发育过程中起重要作用。这个 调节果蝇背侧/腹侧模式的通路与 脊椎动物免疫反应的调控途径与脊椎动物模式 队形。因此，这些研究可能会导致对人类更好的理解 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.