Glial and axonal interactions mediating olfactory receptor axon sorting

描述(由申请人提供)：根据轴突的目标目的地对轴突进行分类，对于发育中的神经系统中的轴突指导是必不可少的。在几乎所有的实验模型中，细胞间的相互作用在轴突引导中都被证明是关键的，但全面的理解不仅需要知道神经元-神经元相互作用的细胞和分子基础，而且还需要知道神经胶质细胞-神经元相互作用的细胞和分子基础。这一建议侧重于嗅觉通路发展过程中嗅觉轴突分类的相互作用，特别是神经胶质细胞在调节特定信号通路中的作用。在发育过程中，嗅觉感受器神经元(ON)的轴突必须摆脱它们在外围建立的轴突联系，形成新的气味反应特异性关系。在蛾Manduca sexta中，ORN轴突位于神经的一个离散的、高度可及的、胶质细胞丰富的区域，该区域从感觉上皮延伸到大脑。发育是由ORN轴突启动的；较晚到达的轴突一进入这个“分类区域”，就会突然改变它们的生长模式和它们的联系。重要的是，轴突必须与神经胶质细胞相互作用，才能正确地分类成束状物，送往嗅叶的肾小球。因此，Manduca的分离区是一个特别有利的准备，可以用来询问有关神经胶质-轴突信号机制的问题，这些信号机制是轴突分类和神经束形成的基础。这些研究使用体内和体外平行的方法来检验这一假设，即神经胶质细胞调节指导ORN轴突分类的特定积极(例如，促进生长或粘连)和消极(例如，生长抑制或排斥)信号的平衡。EM、共聚焦和活细胞显微镜将被用来分析细胞黏附分子Fasciclin II和Neuroglian，受体酪氨酸激酶EGFR和FGFR，以及EphR/EPhin信号系统在轴突分类中的作用。Manduca的嗅觉系统与哺乳动物的嗅觉系统具有足够的复杂性和相似性，是研究分类的有用模型。相关性：长期目标是阐明神经胶质细胞-神经元相互作用的机制，这些机制很可能在嗅觉发育和许多其他中枢神经系统通路的发育中是常见的。了解这些神经元-神经胶质细胞的相互作用将有助于为克服神经系统破坏性发育异常和损伤后再生尝试不足所需的基础。

DESCRIPTION (provided by applicant): Sorting of axons according to their target destination is essential for axonal guidance in the developing nervous system. Intercellular interactions have been shown in virtually all experimental models to be critical in axon guidance, but a full understanding requires knowing the cellular and molecular underpinnings not only of neuron-neuron interactions but also of glia-neuron interactions. This proposal focuses on reciprocal glia-neuron interactions underlying the sorting of olfactory axons during development of the olfactory pathway, especially on the role of glial cells in regulating specific signaling pathways. During development, the axons of olfactory receptor neurons (ORNs) must shed the axonal associations they established in the periphery and form new odor response-specific relationships. In the moth Manduca sexta, ORN axons sort in a discrete, highly accessible, glia-rich region of the nerve that extends from the sensory epithelium to the brain. Development is initiated by ORN axons; later arriving axons abruptly change their growth pattern and their associations as soon as they enter this "sorting zone". Importantly, the axons must interact with the glial cells to sort properly into fascicles destined for glomeruli in the olfactory lobe. Thus the sorting zone of Manduca is an especially advantageous preparation to ask questions about glia-axon signaling mechanisms underlying axon sorting and fasciculation. The studies use parallel in vivo and in vitro approaches to test the hypothesis that glial cells regulate the balance of specific positive (e.g., growth-promoting or adhesive) and negative (e.g., growth-inhibiting or repulsive) cues that guides sorting of ORN axons. EM, confocal and live- cell microscopy will be used to assay the contributions of the cell adhesion molecules Fasciclin II and Neuroglian, the receptor tyrosine kinases EGFR and FGFR, and the EphR/ephrin signaling system to axonal sorting. Manduca's olfactory system has sufficient complexity and similarity to the mammalian system to be a useful model in which to study sorting. Relevance : The long term goal is to elucidate the mechanisms of glia-neuron interactions that are likely to be common to olfactory development and development of many other CNS pathways. Understanding these reciprocal neuron-glia interactions will contribute to the foundation needed to conquer devastating developmental abnormalities of the nervous system and inadequate regenerative attempts following injury.