Mechanisms of Sympathetic Axon Pruning

描述（由申请人提供）：成熟神经通路的重塑包括轴突生长以建立新的连接和轴突退化从而消除终止。在没有细胞死亡的情况下，轴突末端被消除或修剪的机制尚不清楚。外周交感神经支配是研究正常生理和病理生理条件下轴突修剪的一个特别容易处理的模型。初生子宫交感轴突密度在发情周期波动迅速，雌激素水平升高时终端轴突退化，雌激素水平下降时再生。我们已经表明，雌激素升高子宫脑源性神经营养因子，并假设这有助于交感神经轴突变性。我们假设脑源性神经营养因子激活p75神经营养受体，刺激轴突内神经酰胺的形成。这通过膜通透性和肌动蛋白解聚的异常增加促进终端轴突变性。本研究探讨的机制，即目标引发选择性末端轴突修剪。第一个目的是评估p75NTR激活在生理条件下诱导交感轴突变性的假设。在目标2中，我们探讨了p75NTR激活通过增加轴突膜的渗透性和促进肌动蛋白细胞骨架的不稳定而产生轴突变性的假设。在目标3中，我们研究了由目标产生的引起轴突退化的配体的性质。具体来说，我们将评估BDNF、pro-NGF和neurotrimin的作用。这些研究使用易于处理的体内和体外方法来探索目标衍生配体，神经受体和信号转导途径之间的关系，并将提供关于在生理和病理生理条件下如何完成选择性末端轴突变性的新信息。研究结果将有助于理解与正常神经系统可塑性相关的组织原理，以及某些疾病状态下神经支配的紊乱。

DESCRIPTION (provided by applicant): Remodeling of mature neural pathways involves both axonal outgrowth to establish new connections and axonal degeneration whereby terminations are eliminated. Mechanisms by which axon terminations are eliminated, or pruned, in the absence of cell death are poorly understood. Peripheral sympathetic innervation presents an especially tractable model for studying axon pruning under normal physiological and pathophysiological conditions. Sympathetic axon density in the virgin rodent uterus fluctuates rapidly during the estrous cycle, with terminal axons degenerating when estrogen levels rise and regenerating when they decline. We have shown that estrogen elevates uterine brain derived neurotrophic factor, and hypothesize that this contributes to sympathetic axon degeneration. We hypothesize that brain derived neurotrophic factor activates the p75 neurotrophin receptor, which stimulates intra-axonal ceramide formation. This promotes terminal axon degeneration through abnormal increases in membrane permeability and actin depolymerization. The present study investigates mechanisms whereby targets elicit selective terminal axon pruning. The first aim evaluates the hypothesis that p75NTR activation is responsible for inducing sympathetic axon degeneration under physiological conditions. In aim 2, we explore the hypothesis that p75NTR activation produces axon degeneration by increasing permeability of axonal membranes, and by promoting destabilization of the actin cytoskeleton. In aim 3, we investigate the nature of ligands produced by the target that incur axon degeneration. Specifically, the roles of BDNF, pro-NGF and neurotrimin will be assessed. These studies use tractable in vivo and in vitro approaches to explore relationships among target- derived ligands, neural receptors, and signal transduction pathways, and will provide novel information on how selective terminal axon degeneration is accomplished under physiological and pathophysiological conditions. Findings will be pertinent to understanding both organizing principles related to normal nervous system plasticity, and to disturbances in innervation in certain disease states.