Wiring of Spiral Ganglion Neurons and Auditory Hair Cells by Secreted Semaphorins

耳蜗毛细胞与螺旋神经节神经元（SGN）连接的建立和维持 耳蜗对听觉功能至关重要，而这些连接的中断既是一个众所周知的问题， 这是感音神经性听力损失的后果，也是人工耳蜗植入性能下降的原因。 尽管这些连接很重要，但SGN轴突引导和 突触发生在很大程度上是未知的。本研究的长期目标是确定 负责听觉神经系统的发展，因此可以开发出更好的治疗方法来治疗 人类听力损失本申请中概述的研究结果将定义Class-3如何 Semaphorins（Sema 3s），激活神经纤毛蛋白/丛状蛋白（Nrp/Plxn）共受体的分泌因子大家族 对SGN轴突引导决策至关重要。从概念上讲， 这项研究是创新的，因为它将首次深入分析SGN轴突引起的听力损失。 引导缺陷，因为对耳蜗导管内SGN纤维的加工知之甚少 与听力学评估相关。这项研究在技术上是创新的，因为一只老鼠 一个模型，允许标记，可视化和分析的SGN毛细胞的相互作用在真实的时间将是 采用将定义在耳蜗中表达的特定3类信号蛋白的功能。获得功能的腺病毒感染实验和功能丧失的小鼠模型将用于测试 假设Sema 3C吸引SGN，并且Sema 3A对不同的SGN群体进行分类。为了 为了在细胞内传递信号，Nrps必须与丛状蛋白共受体结合。不同的SGN群体 差异表达丛蛋白A3，从而确定丛蛋白A3的功能。使用药理学，小鼠 模型和蛋白质截短实验，假设丛蛋白A3在不同人群中激活 将测试SGN靶向特定毛细胞群体的能力。这项研究的贡献将 因为它将定义第一个分子信号传导途径之一，以促进 哺乳动物听觉系统内复杂传入神经支配模式的发展。

The establishment and maintenance of spiral ganglion neuron (SGN) connections with hair cells in the cochlea is critical to auditory function, and the disruption of these connections is both a well-recognized consequence of sensorineural hearing loss, and a cause of diminished cochlear implant performance. Despite the importance of these connections, the mechanisms required for SGN axon guidance and synaptogenesis are largely unknown. The long-term goal of this research is to define the mechanisms responsible for auditory nervous system development, so that improved therapies can be developed to treat hearing loss in humans. The results from the research outlined in this application will define how class-3 Semaphorins (Sema3s), a large family of secreted factors that activate Neuropilin/Plexin (Nrp/Plxn) coreceptors on growing axons, are essential for SGN axon guidance decisions. Conceptually, the proposed research is innovative because it will provide the first in-depth analysis of hearing loss caused by SGN axon guidance defects, as there is little known about how the elaboration of SGN fibers within the cochlear duct con-elates with audiological assessments. The proposed research is technically innovative because a mouse model that allows the labeling, visualization and analyses of SGN-hair cell interactions in real time will be used. The function of specific class-3 Semaphorins that are expressed in the cochlea will be defined. Gain-of-function adenovirus infection experiments, and loss-of-function mouse models, will be used to test the hypothesis that Sema3C attracts SGNs and that Sema3A sorts different populations of SGNs. In order to transmit a signal intracellularly, Nrps must bind to Plexin co-receptors. Distinct populations of SGNs differentially express PlexinA3, thus the function of PlexlnA3 will be determined. Using pharmacology, mouse models, and protein truncation experiments, the hypothesis that PlexinA3 activation in different populations of SGNs targets them to specific populations of hair cells will be tested. This contribution of this research will be significant because it will define one of the first molecular signaling pathways to contribute to the development of the complex afferent innervation pattern within the mammalian auditory system.