Molecular Mechanisms in Development

发育中的分子机制

• 批准号: 9276924
• 负责人: THOMAS B. KORNBERG
• 金额: $ 24.74万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276924
• 关键词: Animals; Blastoderm; Cells; Chemicals; Cytokinesis; Development; Drosophila genus; EGF gene; Embryo; Embryonic Development; Erinaceidae; Fibroblast Growth Factor; Filopodia; Fingers; Gene Expression; Genes; Genetic; Genome; Goals; Imaging Device; Investigation; Mediating; Molecular; Movement; Neuroglia; Neurons; Neurotransmitters; Nuclear; Oocytes; Organ; Organelles; Paracrine Communication; Pattern; Play; Process; Property; Proteins; Research; Role; Signal Transduction; Signaling Protein; Site; Source; Structure; Synapses; Thinness; Time; Tissues; Vertebrates; Wing; Work; base; blastocyst; cohort; fascinate; gastrulation; imaginal disc; intercellular communication; morphogens; notch protein; novel; nuclear division; programs; response

Project Summary/Abstract The goal of this program is to understand how informational molecules that pattern tissues and embryos distribute in space and time during development. We study signaling in Drosophila, investigating the Decapentaplegic, Hedgehog, FGF, EGF, Wg, Notch-Delta and Bicoid morphogen signaling proteins. Our thesis is that the mechanisms that move these proteins from their sources and distribute them to their targets involve cellular machines and organelles whose actions precisely regulate protein movement. Our work has identified novel processes that mediate movement of morphogen signaling proteins in tissues and embryos, and this proposal describes the approaches we will take to further characterize these processes and the machines and organelles that drive them. This work has its origins in two separate investigations. The first began with an analysis of the roles and functions of the engrailed (en) segmentation gene. Like most vertebrates, the Drosophila embryo undergoes a mid-blastula transition (MBT) prior to gastrulation, but the early stages of Drosophila development have unusual features - 13 synchronous, rapid nuclear divisions without cytokinesis. Although the dogma has been that the zygotic genome does not contribute to pre-MBT development, we discovered that zygotic gene expression in nuclear cycle 2 embryos is essential for normal development. We discovered functionally important zygotic en expression in nuclear cycle 2 embryos and identified a small cohort of genes expressed by the pre-blastoderm embryo. We also discovered that the Bicoid concentration gradient that organizes the embryo A/P axis forms from protein that is made in stage 14 oocytes and functions prior to nuclear cycle 7. These findings are the basis for the proposed program that investigates patterning in the early embryo and that already reveals that our understanding of this early, critical stage of development must change radically. The second began with our discovery of cytonemes, specialized filopodia that are involved in cell-cell signaling. This discovery led us to propose that signaling proteins move between cells in a manner similar to the way neurotransmitters exchange between pre- and post-synaptic cells – by transferring between signaling cells at synapses. Our work has established that synapses are present in the Drosophila wing imaginal disc at sites of cytoneme contact, that they involve proteins that have previously been shown to function and to be required at neuronal synapses, and that they are essential for paracrine signaling between non-neuronal cells. We have also obtained strong experimental evidence that cytonemes ferry signaling proteins between producing and receiving cells and we have identified several unexpected properties of cytonemes that have significant implications for mechanisms of pathfinding and signal transduction. The work we pursue 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 fascinating mechanism of contact-based signaling.

项目摘要/摘要 该程序的目的是了解该组织和胚胎的信息分子如何 开发过程中的时空分布。我们研究果蝇中的信号，研究了 dec骨，刺猬，FGF，EGF，WG，Notch-delta和Bicoid形态学信号传导蛋白。我们的 论文是将这些蛋白质从其来源移动并分配到目标的机制 涉及细胞机和细胞器，其作用准确地调节了蛋白质的运动。我们的工作有 确定了介导组织和胚胎中形态学信号蛋白运动的新过程， 该建议描述了我们将采取的方法，以进一步表征这些过程和 驱动它们的机器和细胞器。 这项工作起源于两项单独的调查。第一个开始，分析角色和 插入的（EN）分割基因的功能。像大多数脊椎动物一样，果蝇胚胎也经历 过度之前，中期过渡（MBT），但果蝇发育的早期阶段已经 异常特征 - 13个同步的，快速的核分裂，没有细胞因子。虽然教条一直在 合子基因组对MBT前发育没有贡献，我们发现合子基因组 核周期2胚胎中的表达对于正常发育至关重要。我们在功能上发现 核周期2胚胎中重要的合子EN表达，并鉴定出一小部分表达的基因 由芽前胚胎胚胎。我们还发现，组织的双子体浓度梯度 胚胎A/P轴由蛋白质形成，在核周期7之前在第14阶段的卵母细胞和功能中形成。 这些发现是拟议程序的基础，该计划调查了早期胚胎的图案，并且 已经揭示了我们对这一早期，关键发展阶段的理解必须根本变化。 第二个开始，我们发现细胞 - 细胞信号传导涉及的细胞体，专门的丝状虫。 这一发现使我们提出信号蛋白在细胞之间以类似方式移动 神经递质在突触前和突触后细胞之间交换 - 通过在信号细胞之间转移 突触。我们的工作已经确定突触在果蝇翼的想象盘中呈现 细胞接触，它们涉及以前已显示起作用的蛋白质，在 神经元突触，它们对于非神经元细胞之间的旁分泌信号至关重要。我们有 还获得了有力的实验证据，表明生产和生产之间的渡轮信号传导蛋白 接收细胞，我们已经确定了具有显着性的细胞体的几种意外特性 对探路和信号翻译机制的影响。我们从事的工作开发了新工具 用于成像细胞组并建立在我们以前的发现上以确定角色，组成和功能 这些显着的细胞器和这种令人着迷的基于接触信号的机制。