Mechanisms Underlying Muscle Development in Drosophila

果蝇肌肉发育的机制

• 批准号: 9116040
• 负责人: Erika Rae Geisbrecht
• 金额: $ 33.13万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116040
• 关键词: Actins; Address; Binding Proteins; Biochemical; Biochemical Genetics; Biological Assay; Cell Adhesion; Cells; Cities; Complex; Cytoskeleton; Data; Defect; Development; Disease; Drosophila genus; Drosophila melanogaster; Extracellular Matrix; Fluorescence Resonance Energy Transfer; Genes; Genetic; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Human; Image; Importins; Invertebrates; Lead; Life; Maintenance; Mechanical Stress; Mediating; Membrane; Microscopy; Mission; Mitochondria; Modeling; Monomeric GTP-Binding Proteins; Muscle; Muscle Cells; Muscle Contraction; Muscle Development; Muscle Weakness; Myoblasts; Myopathy; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Organelles; Organism; Phenotype; Process; Proteins; Recruitment Activity; Regulation; Resistance; Role; Series; Signal Transduction; Site; Skeletal Muscle; Structure; Tendon structure; Testing; Vertebrates; base; fly; genetic approach; insight; integrin-linked kinase; intercellular communication; mutant; myogenesis; novel; protein complex; protein function; research study; transmission process

DESCRIPTION (provided by applicant): The myotendinous junction (MTJ) is the primary site for force transmission from the interior of the muscle cell, across its membrane, and to the extracellular matrix (ECM). In healthy muscle tissue, the MTJ provides resistance against the mechanical stress generated during muscle contraction, and it is now known that any decrease in MTJ stability leads to muscle detachment in diverse organisms. Most significantly, it is this detachment phenotype that typifies a series of congenital, progressive myopathies in humans. While many features concerning MTJ formation, structure, and function are conserved between both vertebrates and invertebrates, studies in the genetically tractable organism Drosophila melanogaster have proven instrumental in uncovering many proteins essential for MTJ assembly and function and muscle development as a whole. Therefore, the overall goal of this application is to use the fly model to better understand MTJ formation and how defects in MTJ stability may lead to the onset and progression of myopathies. The evolutionarily conserved Elmo-Myoblast city (Mbc) complex activates the small GTPase Rac during Drosophila muscle development. While the primary role of Rac lies in regulation of the actin cytoskeleton, other signaling components that function in Elmo-mediated myogensis - including the signals that initiate and regulate Elmo- Mbc activity - have remained elusive. This proposal expands upon preliminary data which show that (i) Elmo is also required for proper muscle-tendon attachment in the fly, and that (ii) there exist two new Elmo-binding proteins, both of which are required for muscle attachment at the MTJ. The role(s) of these Elmo-containing complexes will be examined using the mature Drosophila MTJ as a model for both muscle-tendon signaling and subsequent force transmission generated upon muscle contraction. To test our overall hypothesis that these new Elmo protein complexes function to mediate cytoskeletal rearrangement during Drosophila muscle attachment, we will use a powerful combination of genetic, biochemical, and imaging approaches to pursue the following specific aims: (1) dissect the role of Elmo in MTJ formation and/or Rac activation; (2) identify the mechanism by which Elmo and associated proteins function to maintain stable MTJs; and (3) understand the function of Elmo complexes in mitochondrial localization during muscle attachment.

描述（由申请人提供）：肌齿状连接（MTJ）是从肌肉细胞内部，膜穿过膜和细胞外基质（ECM）的力量传播的主要位点。在健康的肌肉组织中，MTJ具有抵抗肌肉收缩过程中产生的机械应力的抗性，现在众所周知，MTJ稳定性的任何降低都会导致各种生物体的肌肉脱离。最重要的是，这种分离表型代表了人类中一系列先天性的，进行性肌病。尽管有关MTJ形成，结构和功能的许多特征在脊椎动物和无脊椎动物之间都是保守的，但在遗传上可牵引的有机体果蝇的研究已经证明，已证明对MTJ组装和功能和肌肉发育至关重要。因此，该应用程序的总体目标是使用飞行模型更好地了解MTJ形成以及MTJ稳定性中的缺陷如何导致肌病的发作和进展。进化保守的Elmo-Myoblast City（MBC）复合物在果蝇肌肉发育过程中激活了小的GTPase RAC。尽管RAC的主要作用在于调节肌动蛋白细胞骨架，但在ELMO介导的肌动物中起作用的其他信号成分（包括启动和调节Elmo -MBC活性的信号）仍然难以捉摸。该提案扩展了初步数据，这些数据表明（i）eLmo在即时进行适当的肌肉刺激附件也需要，并且（ii）存在两个新的Elmo结合蛋白，这两种蛋白都需要 MTJ的肌肉附着。这些含ELMO的复合物的作用将使用成熟的果蝇MTJ作为肌肉刺信信号传导和随后在肌肉收缩时产生的力传播的模型进行检查。为了检验我们的总体假设，即这些新的Elmo蛋白复合物在果蝇肌肉附着过程中介导细胞骨架重排的功能，我们将使用遗传，生化和成像方法的强大组合来追求以下特定目的：（1）Elmo在MTJ形成和/或种族中的作用； （2）确定Elmo和相关蛋白质保持稳定MTJ的机制； （3）了解Elmo复合物在肌肉附着过程中线粒体定位中的功能。