Molecular mechanisms in development

项目概要/摘要 该计划的目标是了解组织模式的信息信号蛋白如何在组织中分布。 发展中的空间和时间。我们在果蝇中研究这个过程，研究十肢瘫痪者， 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，并将它们分配给它们的目标涉及细胞机器和细胞器， 精确地控制它们的运动，我们的工作已经确定了我们命名为“细胞素”的新结构， 调解他们的分散。该提案描述了我们将采取的进一步表征 细胞丝和使它们工作的机器和细胞器。 细胞丝是特化的丝状伪足，其在产生信号蛋白的细胞和它们的细胞之间延伸。 信号目标。我们的工作现在已经确定，细胞丝是旁分泌细胞-细胞的关键要素， 信号，以及它们的特性使我们提出信号蛋白在非神经元细胞之间移动， 类似于神经元与突触后靶细胞交换信号的方式-通过交换 信息在突触接触，连接细胞的延伸，如轴突，跨越之间的距离 信号传导和靶细胞。在本赠款期间进行的调查结果表明， 细胞丝的活动与轴突和化学突触非常相似。细胞丝由 这些蛋白质已经被证明在神经元突触中起作用，并且是神经元突触所需要的，例如细胞 粘附蛋白Capricious和神经胶质细胞，并且是钙依赖性的、可兴奋的和神经元能的。他们 需要谷氨酸受体、谷氨酸转运蛋白、电压门控钙通道、小突触泡蛋白， 突触结合蛋白我们还了解到，细胞丝具有细直径和宽直径的交替区域， 变成“串珠”，并深入到靶细胞的内陷中。这些意想不到的特性 对寻路和信号转导机制的迷人影响，以及我们提出的工作， 开发了新的工具，成像cytonemes和建立在我们以前的发现，以确定的作用， 这些非凡的细胞器的组成和功能以及这种基于接触的信号机制。

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.