Motor neuron migration regulated by guidance cues

描述(申请人提供)：本项目的总体目标是确定确定运动神经元细胞体位置的机制，并控制运动轴突出中枢神经系统。运动神经元在胚胎发育的早期形成，它们的细胞体聚集在靠近腹中线的精确位置，即底板。运动神经元胞体的定位对于运动的输入和输出是至关重要的。在带有Robo轴突引导受体突变的小鼠胚胎中，我们发现运动神经元胞体移位到底板。这一变化揭示了运动神经元胞体从神经轴的所有水平广泛迁移的惊人能力。需要检验的假设是，运动神经元的迁移受到来自底板的两组相反的引导信号的调节：排斥的Sit/Robo信号和吸引的Netrin/DCC信号。我们的模型是，这些引导信号具有紧密平衡的效果，将运动神经元困在特定位置形成运动核团，并引导它们的轴突离开中枢神经系统。这一探索性应用将使用一系列方法，包括突变小鼠和运动神经元的体外迁移试验，以确定控制其迁移的基本机制。该项目的目的是测试底板引导信号在控制运动神经元迁移中的功能，特别是相反的缝隙排斥剂和Netrin吸引剂信号，并确定控制迁移反应的细胞机制。一个相关的目标将探索引导线索控制运动轴突出中枢神经系统的位置的机制。我们的实验还将在一组细胞中定义Sit/Robo信号的一种新功能，即边界帽，以防止运动神经元胞体沿运动神经异位迁移。该项目的成果将是开发一种运动神经元分化的新观点，通过定义运动运动神经元细胞体被相对的指导线索之间的平衡限制在静态位置的机制。 与公共健康相关：运动神经元在大脑发育的早期形成，在脑干和脊髓的精确位置上形成簇。该项目将定义如何使用两组分子信号来设置运动神经元的位置，并确定这些信号如何调节运动轴突出中枢神经系统。

DESCRIPTION (provided by applicant): The overall objective of this project is to identify the mechanisms that set the position of motor neuron cell bodies, and to control motor axon exit out of the CNS. Motor neurons form early in embryonic development, and their cell bodies cluster in precise positions near the ventral midline, the floor plate. The positioning of motor neuron cell bodies is of fundamental importance for motor input and output. In mouse embryos with mutations in the Robo axon guidance receptors, we discovered that motor neuron cell bodies shift into the floor plate. This shift reveals a surprising ability of motor neuron cell bodies fro all levels of the neuraxis to migrate extensively. The hypothesis to be tested is that motor neuron migration is regulated by two opposing sets of guidance signals from the floor plate: repellent Slit/Robo signals and attractive Netrin/DCC signals. Our model is that these guidance signals have closely balanced effects, trapping motor neurons in specific positions to form motor nuclei, and also guiding their axons out of the CNS. This exploratory application will use a range of approaches including mutant mice and in vitro migration assays for motor neurons to define the basic mechanisms that control their migration. The aims of the project are to test the function of floor plate guidance signals in controlling motor neuron migration, specifically the opposing Slit repellent and Netrin attractant signals, and to identify the cellular mechanisms that control migration responses to the cues. A related aim will explore the mechanisms of guidance cues in controlling where the motor axons exit the central nervous system. Our experiments will also define a novel function of Slit/Robo signals in a set of cells, the boundary cap, that prevent motor neuron cell bodies from ectopically migrating out along the motor nerve. The outcome of the project will be to develop a new viewpoint of motor neuron differentiation, by defining the mechanisms in which motile motor neuron cell bodies are constrained in static positions by a balance between opposing sets of guidance cues. PUBLIC HEALTH RELEVANCE: Motor neurons form early in brain development as clusters in precise positions in the brain stem and spinal cord. This project will define how two sets of molecular signals are used to set the position of motor neurons, and to determine how these signals also regulate motor axon exit out of the central nervous system.