Cellular and Molecular Mechanisms of Myotube Guidance

肌管引导的细胞和分子机制

• 批准号: 10659818
• 负责人: AARON N JOHNSON
• 金额: $ 41.15万
• 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: 2016-09-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659818
• 关键词: Actins; Anatomy; Biosensor; Cell Shape; Cell physiology; Cells; Code; Collaborations; Complement; Complex; Cytoskeleton; Disease; Drosophila genus; Embryo; Embryonic Development; Ensure; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Genes; Genetic; Genetic Screening; Genetic Transcription; Genomics; Guanosine Triphosphate Phosphohydrolases; In Vitro; Ligands; Modeling; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Morphology; Movement; Muscle; Muscle Development; Muscle Fibers; Musculoskeletal; Musculoskeletal Diseases; Mutation Analysis; Myoblasts; Myopathy; Pathway interactions; Pattern; Polymers; Population Heterogeneity; Protein Family; Regulator Genes; Role; Semaphorins; Signal Transduction; Site; Skeletal Muscle; Specific qualifier value; Structural Congenital Anomalies; System; Techniques; Tendon structure; Work; axon guidance; differential expression; functional genomics; gene regulatory network; genetic approach; human disease; imaging approach; imaging study; in vivo; insight; migration; myogenesis; plexin; polymerization; programs; protein function; protein protein interaction; receptor; response; reverse genetics; single cell sequencing; tool; transcription factor; transcriptomics

PROJECT SUMMARY The mechanisms that regulate skeletal muscle topography and perfectly align muscle morphology with the overall body plan remain poorly understood. During embryonic development, muscle precursors known as myotubes undergo a dramatic morphogenesis in which the myotube leading edges elongate, navigate to tendons, and then choose pre-determined sites for muscle attachment. Myotube guidance refers to the combined cellular processes of leading edge navigation and targeting decisions that connect muscles with the correct tendons. We have used myogenesis in the Drosophila embryo as an entry point to identify the cellular and molecular mechanisms of myotube guidance. Using forward genetic screens and genomics-based reverse genetics, we identified multiple navigational signals that direct myotube leading edge migration, and uncovered transcription factors that direct muscle morphogenesis. Our live imaging approaches revealed that myotubes actively choose the correct muscle attachment site through a putative contact-dependent mechanism with tendon cells. We hypothesize that the integrated actions of short-range navigational signals, morphogenetic gene regulatory networks, and contact-dependent cell recognition programs direct myotube guidance to ensure muscle topography perfectly complements the body plan. To achieve a comprehensive understanding of myotube guidance, we will investigate the interplay between navigation, cell recognition, and gene regulatory modules. We propose (1) to investigate how multiple navigational signals co-regulate the cytoskeleton to direct myotube leading edge migration, (2) to use functional genomics to understand how a morphogenetic gene regulatory network modulates responses to navigational signals and directs contact-dependent cell recognition, and (3) to uncover the heterophilic protein- protein interactions between myotubes and tendon cells that establish a myotendinuos code. We expect the foundational work proposed in this study will be a necessary first step toward understanding how navigational, cell recognition, and gene regulatory modules cooperate to direct myogenesis in more complex systems and human disease.

项目摘要 调节骨骼肌拓扑结构并使肌肉形态与骨骼肌形态完全一致的机制是： 总体身体计划仍然知之甚少。在胚胎发育期间，肌肉前体被称为 肌管经历了一个戏剧性的形态发生，其中肌管前缘伸长， 肌腱，然后选择预先确定的肌肉附着部位。肌管引导是指 结合细胞过程的前沿导航和目标的决定，连接肌肉与 正确的肌腱 我们以果蝇胚胎中的肌细胞发生为切入点， 肌管引导的机制。使用正向遗传筛选和基于基因组学的反向遗传学，我们 鉴定了指导肌管前缘迁移的多种导航信号， 影响肌肉形态发生的因素。我们的实时成像方法显示，肌管积极地 通过与肌腱细胞的假定接触依赖机制选择正确的肌肉附着部位。 我们假设，短距离导航信号、形态发生基因调控和基因调控的综合作用， 网络和接触依赖性细胞识别程序直接肌管指导，以确保肌肉 地形完美地补充了身体的计划。 为了全面了解肌管引导，我们将研究 导航、细胞识别和基因调控模块。我们建议（1）调查多个 导航信号共同调节细胞骨架以指导肌管前缘迁移，（2）使用 功能基因组学，以了解形态发生基因调控网络如何调节对 导航信号并指导接触依赖性细胞识别，以及（3）揭示嗜异性蛋白- 肌管和腱细胞之间的蛋白质相互作用，建立了肌腱密码。我们预计 这项研究中提出的基础工作将是理解如何导航， 细胞识别和基因调控模块合作指导更复杂系统中的肌生成， 人类疾病