Genetic Dissection of Auditory Circuit Assembly

6.项目总结/摘要 听力始于内耳耳蜗中的毛细胞对声音的检测。螺旋神经节 神经元提供了从毛细胞到中枢神经系统的听觉信息的唯一管道。损失 听觉神经元的发生是对损伤、肿瘤或毛细胞变性的反应，这些都是常见的原因 人类先天性耳聋和与年龄相关的耳聋。耳聋最有效的治疗方法是耳蜗 植入物，其工作原理是直接刺激螺旋神经节神经元，强调需要保持适当的 耳朵和大脑之间的有线连接了解听觉神经元是如何形成模式的， 在发展过程中的有线将提供一个重要的基础设计的治疗，以保护内耳 研究人员还致力于研究神经元的变性，以及开发基于干细胞的神经元替代方法。 听觉神经科学中的一个中心问题是螺旋神经节神经元如何获得特定的特性 来感知声音。螺旋神经节神经元与前庭神经节神经元一起起源于 耳泡的一个常见的神经原区域。听觉回路通过一系列 事件，包括向毛细胞延伸的过程，耳蜗中投射的分叉 核，并与脑干中的靶神经元形成专门的突触。许多这些 通过与前庭神经节神经元的比较，突出了事件，前庭神经节神经元是感知的基础。 平衡，并因此在相同的本地环境中做出一系列不同的布线决策。的 转录因子GATA 3在听觉神经元中产生，但在前庭神经元中不产生。根据其作为主节点的活动 在其他发展中的系统中，GATA 3被假设为协调特定的药物程序， 螺旋神经节神经元的发育。有三个目标：1）比较基因表达谱， 高度纯化的螺旋神经节和前庭神经节神经元，以确定神经元特异性回路程序 组装潜在的特定布线事件2）了解GATA 3如何对早期和 通过产生和分析条件性基因敲除小鼠的晚期连接事件;和3）鉴定神经特异性的 作用于GATA 3下游以调节回路形成的多个阶段的基因。从这些 实验将提供听觉神经元独特的细胞和分子特性的关键见解， 可能揭示与甲状旁腺功能减退、感音神经性耳聋和 肾脏异常（HDR），这是由GATA 3突变引起的。

6. Project Summary/Abstract Hearing begins with the detection of sound by hair cells in the cochlea of the inner ear. Spiral ganglion neurons provide the sole conduit for auditory information from hair cells to the central nervous system. Loss of auditory neurons occurs in response to injury, tumors, or hair cell degeneration, which are all common causes of human congenital and age-related deafness. The most effective treatment for deafness is the cochlear implant, which works by directly stimulating spiral ganglion neurons, emphasizing the need to maintain properly wired connections between the ear and the brain. Understanding how auditory neurons are patterned and wired during development will provide an important foundation for the design of therapies to protect inner ear neurons from degeneration and for the development of stem-cell based methods for neuronal replacement. A central question in auditory neuroscience is how spiral ganglion neurons acquire properties that are specific for the perception of sound. Spiral ganglion neurons originate together with vestibular ganglion neurons within a common neurogenic region of the otic vesicle. Precisely wired auditory circuits form through a series of events, including the extension of processes towards hair cells, bifurcation of projections in the cochlear nucleus, and the formation of specialized synapses with target neurons in the brainstem. Many of these events are highlighted by comparison with vestibular ganglion neurons, which underlie the perception of balance and therefore make a distinct series of wiring decisions within the same local environment. The transcription factor GATA3 is produced in auditory but not vestibular neurons. Based on its activity as a master regulator in other developing systems, GATA3 is hypothesized to coordinate auditory-specific programs of development in spiral ganglion neurons. There are three goals: 1) to compare gene expression profiles in highly purified spiral and vestibular ganglion neurons in order to define the auditory-specific programs of circuit assembly underlying specific wiring events 2) to understand how GATA3 exerts distinct effects on early and late wiring events by generating and analyzing conditional knock-out mice; and 3) to identify auditory-specific genes that act downstream of GATA3 to regulate multiple stages of circuit formation. Results from these experiments will provide key insights into the unique cellular and molecular properties of auditory neurons, and may shed light on the etiology of deafness associated with hypoparathyroidism, sensorineural deafness, and renal anomalies (HDR), which is caused by mutations in GATA3.