Oculomotor axon guidance and neuron migration

 描述(由申请人提供)：本项目的总体目标是确定控制动眼神经引导的分子机制。动眼神经支配六块眼肌中的四块。神经线如何连接到每块肌肉，对运动信号的精确计时和协调至关重要，并驱动视觉所需的一组复杂的眼部运动。眼球运动系统非常容易受到发育错误的影响，导致2-5%的人类婴儿眼球运动或排列不齐。然而，动眼神经如何导航到眼睛并瞄准特定肌肉的基本机制在很大程度上仍不清楚。我们的初步研究发现，Sit/Robo排斥引导线索系统是动眼运动发育中几个步骤的关键调节因子，包括轴突向眼睛的投射，轴突与肌肉前体的相互作用，以及独特的运动神经元细胞体跨越中脑中线的迁移。在拟议的项目中，我们将使用一系列补充方法，包括研究突变小鼠的动眼神经发育，培养中的轴突反应，以及转录分析，以确定新的标记和候选的指导调节因子。该项目的目标将是：1)确定Sit/Robo信号在引导动眼神经到达眼肌中的作用；2)确定另一个引导系统--Semaphorin/Neuropilin信号--如何引导动眼神经，以及这些信号与Sit/Robo信号如何相互作用。3)确定Sit/Robo排斥力如何控制特定动眼神经元子集的中线迁移。总之，这项研究将定义一个新的实验模型，以了解神经肌肉靶向的分子基础，并确定眼动系统发展的新机制。

 DESCRIPTION (provided by applicant): The overall goal of this project is to identify molecular mechanisms that control the guidance of the oculomotor nerve. The oculomotor nerve innervates four of the six eye muscles. How the nerve wires up to each muscle is fundamental to the precise timing and coordination of motor signals, and drive the sophisticated set of eye movements required for vision. The oculomotor system is highly susceptible to developmental errors, causing eye movements or alignment in 2-5% of human infants. However, the basic mechanisms of how the oculomotor nerve navigates to the eye and targets specific muscles remain largely unknown. Our preliminary studies have identified the Slit/Robo repulsive guidance cues system as key regulators of several steps in oculomotor development, including axon projections to the eye, axon interactions with muscle precursors, and a unique motor neuron cell body migration across the midline of the midbrain. In the proposed project, we will use a range of complementary approaches, including studies of oculomotor nerve development in mutant mice, axon responses in culture, and transcriptomic analysis to identify new markers and candidate regulators of guidance. The aims of the project will be: 1) Determine the role of Slit/Robo signals in guiding the oculomotor nerve to the eye muscles; 2) Determine how another guidance system, the Semaphorin/Neuropilin signals, guide the oculomotor nerve, and how these signals interact with Slit/Robo signals. 3) Determine how Slit/Robo repulsion controls the midline migration of a specific subset of oculomotor neurons. Overall, this study will define a new experimental model for understanding the molecular basis for neuromuscular targeting, and identify novel mechanisms for the development of the oculomotor system