Cellular and Molecular Mechanisms of Myotube Pathfinding

肌管寻路的细胞和分子机制

• 批准号: 9770532
• 负责人: AARON N JOHNSON
• 金额: $ 33.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770532
• 关键词: Actins; Actomyosin; Alleles; Area; Behavior; Biochemical; Biological Assay; Biology; Cells; Chemotaxis; Collection; Cues; Data; Defect; Development; Disease; Drosophila genus; Embryo; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Filopodia; Gene Expression Profiling; Genes; Genetic; Genetic Screening; Human; Image; Knowledge; Molecular; Morphogenesis; Muscle; Muscle Development; Muscle Fibers; Muscle hypotonia; Mutation; Myoblasts; Myopathy; Names; Notch and Wnt Signaling Pathway; Outcome; Pathway interactions; Patients; Phosphotransferases; Protein Kinase; Protein-Serine-Threonine Kinases; Publishing; Regulatory Pathway; Role; Sarcomeres; Signal Transduction; Site; Site-Directed Mutagenesis; Skeletal Muscle; Techniques; Tendon structure; Testing; Transgenic Organisms; Tropomyosin; Wasps; Work; clinical phenotype; congenital myopathy; early onset; extracellular; genetic regulatory protein; in vivo; insight; mutant; myogenesis; novel; protein function; public health relevance; receptor; respiratory; tool

Project Summary Congenital myopathies (CM) are a heterogeneous collection of disorders defined by early onset hypotonia. Some myopathies can progress to extreme conditions in which patients develop respiratory complications and even require assistance for mobility. Mutations in genes associated with actin dynamics have been identified in patients with CMs, including Tropomyosins. We found that Drosophila Tropomyosin 2 (Tm2) directs embryonic skeletal muscle development by promoting myoblast fusion, myotube elongation, and sarcomere assembly. These surprising results argue that defects in myofiber development contribute to the clinical phenotypes associated with CMs. There remain critical knowledge gaps in our understanding of skeletal muscle development. In particular, nascent myotubes must elongate and attach to the appropriate tendon cells to form a functional contractile unit. However, the molecules that guide myotubes to their muscle attachment sites remain largely unknown. In addition, the mechanisms by which myotubes respond to chemotactic signals are unclear. We have used forward genetic screens and cutting edge transcriptional profiling to identify myotube guidance molecules and intracellular effectors of myotube elongation. Our preliminary work has generated unique genetic tools and novel mechanistic insights that will allow us to characterize the central pathways and mechanisms that direct myotube elongation. The overall hypothesis for this application is that filopodia are the key effectors of myotube pathfinding, and that filopodial behavior is dictated by external pathfinding cues, intracellular protein kinases, and actin regulatory proteins. This project will achieve the following aims: (1) define the cellular pathways by which Tropomyosin regulates myogenesis, (2) characterize novel intracellular effectors of myotube pathfinding, and (3) characterize chemotactic mechanisms that direct myotube pathfinding. These studies will make substantial inroads into an emerging area of muscle biology that has the potential to uncover novel mechanisms that contribute to muscle disease.

项目摘要 先天性肌病（CM）是一种异质性疾病的集合， 张力减退一些肌病可以进展到极端条件下，患者发展 呼吸系统并发症，甚至需要帮助移动。相关基因突变 与肌动蛋白动力学的关系，包括原肌球蛋白。我们发现 果蝇原肌球蛋白2（Tm2）通过促进胚胎骨骼肌的发育， 成肌细胞融合、肌管伸长和肌节组装。这些惊人的结果表明， 肌纤维发育缺陷导致与CM相关的临床表型。 在我们对骨骼肌发育的理解中仍然存在关键的知识差距。在 特别是，新生肌管必须伸长并附着在适当的肌腱细胞上，以形成一个 功能性收缩单位然而，引导肌管附着在肌肉上的分子 网站仍然基本上未知。此外，肌管对 趋化信号不清楚。我们使用了基因筛查和尖端技术 用于鉴定肌管引导分子和肌管的细胞内效应物的转录谱分析 伸长率我们的初步工作已经产生了独特的遗传工具和新颖的机制见解 这将使我们能够描述控制肌管的中枢通路和机制， 伸长率本申请的总体假设是，丝状伪足是 肌管寻路，丝状伪足的行为是由外部寻路线索，细胞内 蛋白激酶和肌动蛋白调节蛋白。该项目将实现以下目标：（1）定义 原肌球蛋白调节肌生成的细胞途径，（2）表征新的 肌管寻路的细胞内效应物，和（3）表征趋化机制， 直接肌管寻路。这些研究将在一个新兴领域取得实质性进展， 肌肉生物学有可能揭示导致肌肉疾病的新机制。