Molecular Mechanisms in Development

发育中的分子机制

• 批准号: 9894651
• 负责人: THOMAS B. KORNBERG
• 金额: $ 91.99万
• 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/9894651
• 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.

项目概要/摘要 该项目的目标是了解信息分子如何塑造组织和胚胎 我们研究果蝇中的信号传导，研究其在发育过程中的空间和时间分布。 我们的 Decapentaplegic、Hedgehog、FGF、EGF、Wg、Notch-Delta 和 Bicoid 形态发生素信号蛋白。 论文的主题是，将这些蛋白质从其来源转移并将其分配到目标的机制 涉及细胞机器和细胞器，其行为精确地调节蛋白质运动。 确定了介导组织和胚胎中形态发生素信号蛋白运动的新过程， 该提案描述了我们将采取的方法来进一步描述这些过程和 驱动它们的机器和细胞器。 这项工作源于两项独立的调查。第一项调查始于对角色和角色的分析。 与大多数脊椎动物一样，果蝇胚胎经历了 engrailed (en) 分割基因的功能。 原肠胚形成之前的囊胚中期转变（MBT），但果蝇发育的早期阶段 不寻常的特征 - 13 次同步、快速的核分裂，没有胞质分裂，尽管这是教条。 合子基因组对 MBT 前的发育没有贡献，我们发现合子基因 我们发现核周期 2 胚胎中的表达对于正常发育至关重要。 核周期 2 胚胎中重要的合子 en 表达，并鉴定了一小群表达的基因 我们还发现组织 Bicoid 浓度梯度。 胚胎 A/P 轴由第 14 期卵母细胞中产生的蛋白质形成，并在核周期 7 之前发挥作用。 这些发现是拟议项目的基础，该项目研究早期胚胎的模式，并且 已经表明，我们对这一早期关键发展阶段的理解必须彻底改变。 第二个始于我们对细胞线的发现，细胞线是参与细胞间信号传导的特殊丝状伪足。 这一发现使我们提出信号蛋白在细胞之间移动的方式类似于 神经递质在突触前细胞和突触后细胞之间交换——通过在信号细胞之间传递 我们的工作已经确定，突触存在于果蝇翼成虫盘中的以下位置： 细胞因子接触，它们涉及先前已被证明具有功能并且需要的蛋白质 神经元突触，并且它们对于非神经元细胞之间的旁分泌信号传导至关重要。 还获得了强有力的实验证据表明细胞线在生产和生产之间转运信号蛋白 接受细胞，我们已经确定了细胞因子的几个意想不到的特性，这些特性具有显着的意义 我们所从事的工作开发了新的工具。 用于细胞因子成像，并根据我们之前的发现确定其作用、组成和功能 这些非凡的细胞器和这种令人着迷的基于接触的信号传导机制。