Glial and axonal interactions mediating olfactory receptor axon sorting

描述（由申请人提供）：根据其靶向目的地对轴突进行分类对于发育中的神经系统中的轴突引导至关重要。几乎所有的实验模型都表明，细胞间的相互作用对轴突的导向至关重要，但要全面了解这一点，不仅需要了解神经元-神经元相互作用的细胞和分子基础，还需要了解神经胶质-神经元相互作用的细胞和分子基础。这项建议的重点是互惠胶质神经元的相互作用的基础上的嗅觉轴突的发展过程中的嗅觉通路的排序，特别是神经胶质细胞在调节特定的信号通路的作用。在发育过程中，嗅觉受体神经元（ORN）的轴突必须摆脱它们在外周建立的轴突联系，并形成新的气味反应特异性关系。在天蛾Manduca sexta中，ORN轴突在从感觉上皮延伸到大脑的神经的离散的、高度可接近的、富含胶质的区域中排序。发育是由ORN轴突发起的;后来到达的轴突一旦进入这个“分类区”就突然改变它们的生长模式和它们的关联。重要的是，轴突必须与神经胶质细胞相互作用，才能正确地分类成注定要在嗅叶中形成肾小球的纤维束。因此，Manduca的分选区是一个特别有利的准备问问题的神经胶质轴突信号机制的轴突分选和成束。这些研究使用平行的体内和体外方法来测试神经胶质细胞调节特异性阳性细胞（例如，生长促进剂或粘合剂）和阴性（例如，生长抑制或排斥）的线索，指导ORN轴突的分类。将使用EM、共聚焦和活细胞显微镜来测定细胞粘附分子Fasciclin II和Neuroglian、受体酪氨酸激酶EGFR和FGFR以及EphR/ephrin信号传导系统对轴突分选的贡献。曼杜卡的嗅觉系统有足够的复杂性和相似性的哺乳动物系统是一个有用的模型，研究排序。相关性：长期的目标是阐明胶质细胞-神经元相互作用的机制，这可能是共同的嗅觉发育和许多其他中枢神经系统途径的发展。了解这些相互的神经元-胶质细胞相互作用将有助于克服神经系统的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.