Oculomotor axon guidance and neuron migration

 描述（由申请人提供）：该项目的总体目标是确定控制眼神经引导的分子机制。眼神经支配六块眼肌中的四块。神经如何连接到每块肌肉是运动信号精确定时和协调的基础，并驱动视觉所需的复杂眼球运动。眼动系统非常容易受到发育错误的影响，导致2-5%的人类婴儿的眼球运动或对齐。然而，眼神经如何导航到眼睛并靶向特定肌肉的基本机制在很大程度上仍然未知。我们的初步研究已经确定了Slit/Robo排斥性引导线索系统作为眼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穿过中脑中线的独特运动神经元细胞体迁移。在拟议的项目中，我们将使用一系列互补的方法，包括突变小鼠的眼神经发育研究，培养中的轴突反应，以及转录组学分析，以确定新的标记物和候选的指导调节剂。该项目的目标将是：1）确定Slit/Robo信号在引导眼神经到眼肌中的作用; 2）确定另一个引导系统Semaphorin/Neuropilin信号如何引导眼神经，以及这些信号如何与Slit/Robo信号相互作用。3)确定Slit/Robo排斥如何控制眼神经元特定子集的中线迁移。总的来说，这项研究将为理解神经肌肉靶向的分子基础定义一个新的实验模型，并确定眼系统发展的新机制。

 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