Mechanisms of hormone-dependent Rho activation

激素依赖性 Rho 激活机制

• 批准号: 7039095
• 负责人: ROBERT E WARD
• 金额: $ 24.89万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039095
• 关键词: Drosophilidae; actins; biological signal transduction; cytoskeleton; ecdysone; guanine nucleotide binding protein; guanosinetriphosphatases; histogenesis; hormone regulation /control mechanism; imaginal disc; invertebrate embryology; leg; metastasis; microarray technology; neoplastic process; posttranslational modifications

DESCRIPTION (provided by applicant): Precise temporal and spatial control over cell shape changes and cell rearrangements are essential for the development of all metazoans. Endocrine signaling provides a critical level of temporal control that additionally aids in the coordination of morphogenetic events. The elongation and eversion of Drosophila leg imaginal discs provide an ideal system for defining the molecular mechanisms of hormone-regulated tissue morphogenesis. A pulse of the steroid hormone ecdysone triggers the transformation of an epithelial sac into an immature adult leg through coordinated changes in cell shape. Previous studies indicate that ecdysone-dependent leg morphogenesis requires signaling through the Rho 1 small GTPase. Although the direct effects that Rho 1 signaling has on the actin cytoskeleton are well established, little is known about the mechanisms that control Rho 1 activity in a developmental context. Understanding these control mechanisms for Rho 1 signaling are critical since perturbation of Rho activity during vertebrate embryonic development can lead to incomplete neural tube closure and heart defects. Furthermore, dysregulation of Rho signaling at later stages of development may result in tumor progression and metastasis. The overall goal of the proposed research is to define the morphogenetic pathway of leg development in Drosophila, from an initiating signal that provides temporal specificity, through a Rho 1 intracellular signaling cascade, to the molecules that apply chemomechanical forces to the actin cytoskeleton. This will be accomplished through the development of methods to monitor Rho 1 activation in imaginal discs undergoing morphogenesis. These methods will be used to examine the activation of Rho 1 by ecdysone. In addition, whole Drosophila genome microarray chips will be probed to identify genes induced by ecdysone at the onset of leg morphogenesis, and simultaneous genetic screens will be conducted to identify Rho 1-interacting genes. It is expected that these genetic and molecular screens will converge to identify key genes that regulate Rho 1 signaling and leg morphogenesis, providing a foundation for understanding how Rho 1 is regulated during a developmental program in an intact living organism, as well as providing insights into how Rho signaling can be subverted to a pathological state.

描述（由申请人提供）：对细胞形状变化和细胞重排的精确时间和空间控制对于所有后生动物的发育至关重要。内分泌信号提供了关键水平的时间控制，还有助于协调形态发生事件。果蝇腿成虫盘的伸长和外翻为定义激素调节的组​​织形态发生的分子机制提供了理想的系统。类固醇激素蜕皮激素的脉冲通过细胞形状的协调变化触发上皮囊转变为未成熟的成年腿。先前的研究表明，蜕皮激素依赖性腿部形态发生需要通过 Rho 1 小 GTP 酶进行信号传导。尽管 Rho 1 信号传导对肌动蛋白细胞骨架的直接影响已得到充分证实，但人们对发育环境中控制 Rho 1 活性的机制知之甚少。了解 Rho 1 信号传导的这些控制机制至关重要，因为脊椎动物胚胎发育过程中 Rho 活性的扰动可能导致神经管闭合不完全和心脏缺陷。此外，Rho信号在发育后期的失调可能导致肿瘤进展和转移。该研究的总体目标是确定果蝇腿部发育的形态发生途径，从提供时间特异性的起始信号，通过 Rho 1 细胞内信号级联，到向肌动蛋白细胞骨架施加化学机械力的分子。这将通过开发监测正在形态发生的成虫盘中 Rho 1 激活的方法来实现。这些方法将用于检查蜕皮激素对 Rho 1 的激活。此外，将探测整个果蝇基因组微阵列芯片，以鉴定在腿部形态发生开始时由蜕皮激素诱导的基因，并将同时进行遗传筛选以鉴定Rho 1相互作用基因。预计这些遗传和分子筛选将集中识别调节 Rho 1 信号传导和腿部形态发生的关键基因，为了解 Rho 1 在完整活体生物体的发育过程中如何受到调节提供基础，并提供深入了解Rho 信号传导如何被颠覆到病理状态。