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.

项目概要/摘要 该计划的目标是了解组织模式中的信息信号蛋白如何分布 我们研究果蝇发育过程中的空间和时间，研究十肢瘫痪， Hedgehog、FGF、EGF、Wg 和 Notch-Delta 信号系统移动这些蛋白质的机制。 从它们的来源并将它们分发到目标涉及细胞机器和细胞器，其行为 精确控制它们的运动，我们的工作已经确定了我们称之为“细胞因子”的新结构 该提案描述了我们将采取的进一步表征的方法。 细胞因子以及使它们发挥作用的机器和细胞器。 细胞质是一种特殊的丝状伪足，在产生信号蛋白的细胞和它们的细胞之间延伸。 我们的工作现已确定细胞因子是旁分泌细胞间的关键要素。 信号传导及其特性使我们提出，信号传导蛋白在非神经元细胞之间移动 方式类似于神经元与突触后目标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，例如跨越细胞间距离的轴突 在当前资助期间所做的研究结果表明，组成和靶细胞。 细胞因子的活动与轴突和化学突触的构成非常相似。 含有已被证明具有功能并且是神经元突触所需的蛋白质，例如细胞 粘附蛋白 Capricious 和 Neuroglian 是钙依赖性的、可兴奋的和谷氨酸能的。 需要谷氨酸受体、谷氨酸转运蛋白、电压门控钙通道、突触短蛋白和 我们还了解到，细胞线具有类似的细直径和宽直径的交替区域。 到“串珠”，并深入到目标细胞的内陷中，这些意想不到的特性。 对寻路和信号转导机制的有趣影响，以及我们提出的工作 开发用于成像细胞因子的新工具，并根据我们之前的发现来确定其作用， 这些非凡细胞器的组成和功能以及基于接触的信号传导机制。