Molecular mechanisms in development

发展中的分子机制

• 批准号: 10406603
• 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/10406603
• 关键词: Animals; Axon; Calcium; Calcium Channel; Caliber; Cell Adhesion Molecules; Cells; Chemical Synapse; Chemicals; Development; Disease; Drosophila genus; EGF gene; Elements; Erinaceidae; Fibroblast Growth Factor; Filopodia; Fingers; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Grant; Imaging Device; 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; base; fascinate; intercellular communication; neuroglian; notch protein; novel; paracrine; 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 该程序的目的是了解如何在 开发过程中的空间和时间。我们在果蝇中研究了这一过程，研究了脱皮术， 刺猬，FGF，EGF，WG和Notch-Delta信号系统。移动这些蛋白质的机制 从它们的来源并将其分配到目标，涉及蜂窝机和细胞器 精确控制他们的运动，我们的工作已经确定了我们命名为“细胞质”的新颖结构 调解它们的分散。该建议描述了我们将采取的进一步表征的方法 细胞质以及使它们起作用的机器和细胞器。 细胞质是专门的丝状疾病，在产生信号蛋白及其其信号蛋白的细胞之间延伸 信号目标。我们的工作现在已经确定了细胞质是旁分泌细胞细胞的关键要素 信号传导及其特性使我们提出信号蛋白在A中的非神经元细胞之间移动 与神经元与突触后靶细胞交换信号的方式相似 - 通过交换 连接电池扩展的突触接触处的信息，例如横跨距离的轴突 信号传导和靶细胞。当前赠款期间提出的结果表明，构成和 细胞体的活性与轴突和化学突触非常相似。构成细胞 在神经元突触中已显示出功能和需要的蛋白质，例如细胞 粘附蛋白具有反复无常和神经元的蛋白质，并且依赖性钙，令人兴奋和谷氨酸能。他们 需要谷氨酸受体，谷氨酸转运蛋白，电压门控钙通道，Synaptobrevin和 Synaptotagmin。我们还了解到，细胞质具有类似薄直径的替代区域 要“在弦上进行珠子”，然后深入靶向目标细胞的内陷。这些意外的特性具有 对探路和信号转导机制的迷人含义，我们提出的工作 开发新的工具来成像细胞质，并基于我们以前的发现，以确定角色， 这些非凡的细胞器的组成和功能以及这种基于接触信号的机制。