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是发育中的神经系统轴突引导的必要条件。细胞间相互作用在几乎所有的实验模型中都被证明是轴突引导的关键，但要充分理解这一点，不仅需要了解神经元之间相互作用的细胞和分子基础，还需要了解胶质神经元之间相互作用的细胞和分子基础。本研究的重点是在嗅觉通路发育过程中，神经胶质细胞与神经元之间的相互作用是嗅觉轴突分类的基础，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，嗅觉受体神经元（orn）的轴突必须摆脱它们在周围建立的轴突联系，形成新的气味反应特异性关系。在Manduca sexta飞蛾中，ORN轴突在从感觉上皮延伸到大脑的神经中一个离散的、高度可接近的、富含胶质的区域进行分类。发育由ORN轴突发起；后来到达的轴突一旦进入这个“分拣区”，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，才能在嗅叶的肾小球中正确地分类成束。因此，Manduca的分选区是研究轴突分选和束状形成背后的神经胶质-轴突信号机制的一个特别有利的准备。这些研究采用平行的体内和体外方法来验证神经胶质细胞调节引导ORN轴突分选的特定阳性（例如，促进生长或粘附）和阴性（例如，抑制生长或排斥）信号平衡的假设。EM，共聚焦和活细胞显微镜将用于分析细胞粘附分子fasiclin II和Neuroglian，受体酪氨酸激酶EGFR和FGFR，以及EphR/ephrin信号系统对轴突分选的贡献。Manduca的嗅觉系统具有足够的复杂性和与哺乳动物系统的相似性，可以作为研究分类的有用模型。相关性：长期目标是阐明神经胶质-神经元相互作用的机制，这可能是嗅觉发育和许多其他中枢神经系统通路发育的共同机制。了解这些神经元-神经胶质相互作用将有助于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.