THE NOTCH SIGNALING PATHWAY: STRUCTURE AND MECHANISM

描述（由申请人提供）：该项目的长期目标是详细了解动物发育过程中细胞间信号如何控制细胞命运。在后生动物包括神经发生在内的多种发育过程中，通过Notch (N)受体的细胞信号传导是分配细胞命运的主要机制。尽管N信号通路已被广泛研究，但其结构和运作的许多基本要素仍然是神秘的或知之甚少。我们在果蝇身上发现了一组新的基因，我们将其称为“胡须家族”，以其创始成员的名字命名。这些基因编码的小蛋白质都具有强烈的基本两亲性和螺旋结构域。Brd家族基因是完整的，是果蝇N通路的核心成员。它们在两个胚胎的多个N信号位点特异性表达；和胚胎后发育，并直接受到n激活转录因子抑制因子的调控。当过表达时，它们是N信号活性的有效调节剂。最初的功能缺失遗传研究表明，Brd家族蛋白在神经系统和肌肉发育中都是N信号的效应器。显然，对节肢动物N通路功能的机制理解将需要阐明Brd蛋白家族的发育作用和生化作用模式。本申请中描述的研究计划旨在实现这一目标，并有3个具体目标：(1)Brd家族基因和蛋白质功能的遗传分析。(2) Brd家族蛋白表达和定位的Ceil生物学和分子分析。(3) Brd家族蛋白伴侣及其相互作用的鉴定与分析。我们期望我们的研究将大大扩大我们对古老的细胞-细胞细胞信号通路如何决定细胞命运的认识，并可能为N通路疾病综合征（如Alagille和CADASIL）的发病机制提供见解。

DESCRIPTION (provided by applicant): The long-term goal of this project is a detailed understanding of how intercellular signals control cell fate during animal development. Cell-cell signaling via the Notch (N) receptor is a principal mechanism for assigning cell fates in a broad variety of developmental processes in metazoans, including neurogenesis. Though the N signaling pathway has been studied extensively, many essential elements of its structure and operation remain mysterious or poorly understood. We have identified a novel group of genes in Drosophila that we refer to as the Bearded (Brd) family, after the founding member. These genes all encode small proteins with a strongly basic amphipathic a helical domain. Brd family genes are integral, core members of the N pathway in Drosophila. They are expressed specifically at multiple sites of N signaling in both embryonic; and post-embryonic development, and are directly regulated by the N-activated transcription factor Suppressor of Hairless. When overexpressed, they are potent modulators of N signaling activity. Initial loss-of-function genetic studies indicate that Brd family proteins act as effectors of N signaling in both nervous system and muscle development. Clearly, a mechanistic understanding of N pathway function in arthropods will require elucidating the developmental role and biochemical mode of action of the Brd protein family. The research program described in this application is designed to achieve this goal, and has 3 specific aims: (1) Genetic analysis of Brd family gene and protein function. (2) Ceil biological and molecular analysis of Brd family protein expression and localization. (3) Identification and analysis of Brd family protein partners and interactions. We expect that our investigation will greatly enlarge our knowledge of how an ancient cell-ceil signaling pathway specifies cell fate, and may offer insight into the pathogenesis of N pathway disease syndromes such as Alagille and CADASIL.