THE NOTCH SIGNALING PATHWAY: STRUCTURE AND MECHANISM

NOTCH 信号通路：结构和机制

• 批准号: 6956749
• 负责人: James W. POSAKONY
• 金额: $ 26.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6956749
• 关键词: Drosophilidae; arthropod genetics; biological signal transduction; cell cell interaction; cell differentiation; developmental genetics; gene expression; immunocytochemistry; invertebrate embryology; laboratory mouse; laboratory rabbit; molecular genetics; monoclonal antibody; myogenesis; neurogenesis; protein localization; protein protein interaction; protein structure function; yeast two hybrid system

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.

描述（由申请人提供）：该项目的长期目标是详细了解细胞间信号如何控制动物发育过程中的细胞命运。通过Notch（N）受体的细胞-细胞信号传导是在后生动物的多种发育过程（包括神经发生）中分配细胞命运的主要机制。虽然N信号通路已被广泛研究，但其结构和操作的许多基本要素仍然是神秘的或知之甚少。我们已经在果蝇中发现了一组新的基因，我们称之为Bearded（Brd）家族，以创始成员的名字命名。这些基因都编码具有强碱性两亲性α螺旋结构域的小蛋白。Brd家族基因是果蝇N通路的核心成员。它们在胚胎和胚胎后发育中的N信号传导的多个位点特异性表达，并直接受N激活转录因子Hairless抑制子的调节。当过表达时，它们是N信号传导活性的有效调节剂。最初的功能丧失遗传学研究表明，Brd家族蛋白在神经系统和肌肉发育中作为N信号传导的效应子。显然，在节肢动物中N途径功能的机械理解将需要阐明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，并且具有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细胞生物学和分子分析。(3)Brd家族蛋白伴侣和相互作用的鉴定和分析。我们希望我们的研究将大大扩大我们的知识如何一个古老的细胞-细胞信号通路指定细胞的命运，并可能提供深入了解N通路疾病综合征，如Alagille和CADASIL的发病机制。