MECHANISMS THAT GUIDE MOTOR AXON PATHFINDING

引导运动轴突寻路的机制

• 批准号: 6538944
• 负责人: CATHERINE Ellen KRULL
• 金额: $ 12.62万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6538944
• 关键词: agglutinins; developmental neurobiology; glycoproteins; growth cones; membrane proteins; motor neurons; neuronal guidance; protein tyrosine kinase; receptor binding; time resolved data; tissue /cell culture; transfection; video microscopy

DESCRIPTION (Verbatim from the Applicant's Abstract): During neural development, neuronal growth cones navigate long distances to their target regions. The mechanisms and molecules that guide growing neurons to their final destinations are the central focus of our laboratory research. We have chosen to study this issue in the developing avian peripheral nervous system because of a rich literature detailing the tissue interactions that influence the pathfinding of motor axons. Our long-term goal is to dissect apart the key molecular mechanisms that influence motor axons as they extend from the ventral neural tube to their muscle targets. The proposed studies focus on the patterning of motor axons in a portion of their pathway, the somitic mesoderm. We will take loss- of-function and gain-or-function approaches to examine the roles of two sets of candidate guidance cues: 1) the Eph family of receptor tyrosine kinases (RTKs) and their ligands, the ephrins, and 2) two glycoproteins that bind the lectin peanut agglutinin. The specific aims of our studies are as follows: 1) Analyze the effects of blocking Eph RTK-ligand interaction on the segmental patterning of motor axons; 2) Examine effects of ectopic expression of ephrin-B1 on axon outgrowth in vivo; 3) Analyze the function of PNA-binding molecules in patterning motor axons. We will take advantage of a novel whole embryo explant system where we can perturb guidance cues and examine the subsequent effects on motor axons using time- lapse videomicroscopy. Avian-specific retroviruses will be used to misexpress ephrins in ectopic regions, a gain-of-function approach to analyze the roles of these guidance cues in axon pathfinding. The results of these studies will provide critical insights about the positive and negative factors that sculpt patterns of neural architecture during development and may have important implications for neural regeneration in response to injury or disease.

描述（逐字化申请人摘要）：在神经发育期间，神经元生长锥导航到其目标区域。指导成长神经元到最终目的地的机制和分子是我们实验室研究的中心重点。我们选择在发展中的禽神经系统中研究此问题，因为有丰富的文献详细介绍了影响运动轴突探路的组织相互作用。我们的长期目标是剖析影响运动轴突从腹侧神经管延伸到肌肉靶标的关键分子机制。拟议的研究集中于在其途径的一部分躯体中胚层中运动轴突的图案。我们将采用功能和增益或功能的方法来检查两组候选引导提示的作用：1）EPH受体酪氨酸激酶（RTKS）及其配体的EPH家族，Ephrins，Ephrins和2）两种糖蛋白结合了凝集素Peanut peanut凝集凝集素。我们研究的具体目的如下：1）分析阻断EPH RTK-配体相互作用对运动轴突节段图案的影响； 2）检查晶状体-B1异位表达对体内轴突生长的影响； 3）分析PNA结合分子在模式运动轴突中的功能。我们将利用一种新型的整个胚胎外植体系统，在该系统中我们可以使用时间流逝的视频显微镜检查对运动轴突的后续作用。禽类特异性逆转录病毒将用于异位区域中的misexpress ephrins，这是一种分析这些引导线索在轴突途径中的作用的功能获得的方法。这些研究的结果将提供有关开发过程中神经建筑模式的正面和负面因素的关键见解，并且可能对响应损伤或疾病的神经再生具有重要意义。