Molecular mechanisms in development

发展中的分子机制

• 批准号: 10621277
• 负责人: THOMAS B. KORNBERG
• 金额: $ 96.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621277
• 关键词: Animals; Axon; Calcium; Calcium Channel; Cell Adhesion Molecules; Cells; Chemical Synapse; Chemicals; Development; Diameter; Disease; Drosophila genus; EGF gene; Elements; Erinaceidae; Fibroblast Growth Factor; Filopodia; Fingers; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Grant; Imaging Device; Learning; Mediating; Molecular; Movement; Names; Neuroglia; Neurons; Organ; Organelles; Pattern; Play; Process; Property; Proteins; Research; Role; Signal Transduction; Signaling Protein; Source; Structure; Synapses; System; Thinness; Time; Tissues; Viral Cancer; Virus Diseases; Work; fascinate; intercellular communication; neuroglian; notch protein; novel; paracrine; postsynaptic; programs; response; synaptotagmin; vesicle-associated membrane protein; voltage

Project Summary/Abstract The goal of this program is to understand how informational signaling proteins that pattern tissues distribute in space and time during development. We study this process in Drosophila, investigating the Decapentaplegic, Hedgehog, FGF, EGF, Wg, and Notch-Delta signaling systems. The mechanisms that move these proteins from their sources and distribute them to their targets involve cellular machines and organelles whose actions precisely control their movement, and our work has identified novel structures we named “cytonemes” that mediate their dispersion. This proposal describes the approaches we will take to further characterize cytonemes and the machines and organelles that make them work. Cytonemes are specialized filopodia that extend between cells that produce signaling proteins and their signaling targets. Our work has now established that cytonemes are key elements of paracrine cell-cell signaling, and their properties led us to propose that signaling proteins move between non-neuronal cells in a manner similar to the way neurons exchange signals with post-synaptic target cells – by exchanging information at synaptic contacts that connect cell extensions such as axons that span the distance between signaling and target cells. Findings made during the current grant period show that both the composition and activities of cytonemes are remarkably similar to axons and chemical synapses. Cytonemes are constituted with proteins that have been shown to function and to be required at neuronal synapses, such as the cell adhesion proteins Capricious and Neuroglian, and are calcium dependent, excitable, and glutamatergic. They require the glutamate receptor, glutamate transporter, voltage-gated calcium channel, synaptobrevin, and synaptotagmin. We have also learned that cytonemes have alternating regions of thin and wide diameter akin to “beads on a string”, and borrow deep into invaginations of target cells. These unexpected properties have fascinating implications for mechanisms of pathfinding and signal transduction, and the work we propose both develops new tools for imaging cytonemes and builds upon our previous findings to determine the roles, composition and functions of these remarkable organelles and this mechanism of contact-based signaling.

项目摘要/摘要 这个项目的目标是了解形成组织模式的信息信号蛋白是如何分布在 发展中的空间和时间。我们在果蝇身上研究了这一过程，调查了十足瘫痪， Hedgehog、Fgf、EGF、Wg和Notch-Delta信号系统。移动这些蛋白质的机制 从它们的来源并分发到它们的目标涉及细胞机器和细胞器，它们的活动 精确地控制它们的运动，我们的工作发现了被我们命名为“细胞素”的新结构 调停他们的散布。这份提案描述了我们将采取的方法，以进一步确定 细胞素以及使它们工作的机器和细胞器。 细胞素是在产生信号蛋白的细胞和细胞之间延伸的特殊丝状基团。 发信号给目标。我们的工作现已证实，细胞素是旁分泌细胞的关键成分 信号，以及它们的性质导致我们提出，信号蛋白在非神经细胞之间移动 类似于神经元与突触后靶细胞交换信号的方式-通过交换 连接细胞延伸的突触接触处的信息，例如跨越 信令和目标细胞。目前赠款期间的调查结果表明，组成和 细胞线的活动与轴突和化学突触非常相似。细胞素是由 与已被证明具有功能并在神经元突触上所需的蛋白质，如细胞 黏附蛋白，反复无常和神经胶质细胞，是钙依赖的，可兴奋的，谷氨酸能的。他们 需要谷氨酸受体、谷氨酸转运体、电压门控钙通道、突触素和 突触集合素。我们还了解到，细胞素有细长和粗细交替的区域，类似于 “串珠子”，借入目标细胞凹陷的深处。这些意外的属性具有 对寻路和信号转导机制的有趣暗示，以及我们提出的这两方面的工作 开发新的细胞素成像工具，并在我们先前发现的基础上确定其作用， 这些显着细胞器的组成和功能，以及这种基于接触的信号机制。