Genetic Dissection of Auditory Circuit Assembly

描述（由申请人提供）：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听觉信息从毛细胞到中枢神经系统的唯一通道。听觉神经元的丧失是对损伤、肿瘤或毛细胞变性的反应，这些都是人类先天性和年龄相关性耳聋的常见原因。耳聋最有效的治疗方法是人工耳蜗植入，它通过直接刺激螺旋神经节神经元起作用，强调需要在耳朵和大脑之间保持适当的有线连接。了解听觉神经元在发育过程中是如何形成模式和连接的，将为设计保护内耳神经元免于变性的疗法和开发基于干细胞的神经元替代方法提供重要基础。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对声音感知特异的特性。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共同神经源区域内。精确连接的听觉回路通过一系列事件形成，包括向毛细胞延伸的过程，耳蜗核中投射的分叉，以及与脑干中的靶神经元形成专门的突触。通过与前庭神经节神经元的比较，这些事件中的许多事件都得到了强调，前庭神经节神经元是平衡感知的基础，因此在相同的局部环境中做出了一系列不同的布线决定。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。基于其在其他发育系统中作为主调节器的活性，GATA 3被假设为协调螺旋神经节神经元发育的神经特异性程序。有三个目标：1）比较高度纯化的螺旋神经节和前庭神经节神经元中的基因表达谱，以确定特定布线事件背后的电路组装的神经系统特异性程序; 2）通过产生和分析条件性敲除小鼠来理解GATA 3如何对早期和晚期布线事件施加不同的影响;和3）鉴定作用于GATA 3下游以调节回路形成的多个阶段的神经特异性基因。这些实验的结果将为听觉神经元独特的细胞和分子特性提供关键的见解，并可能揭示与甲状旁腺功能减退，感觉神经性耳聋和肾异常（HDR）相关的耳聋的病因，这是由GATA 3突变引起的。声音是由耳朵收集的，但我们之所以能意识到声音，是因为连接耳朵和大脑的复杂神经元网络的活动。听觉神经元可能由于创伤性损伤或由于耳朵的其他部分不能正常工作而死亡。耳聋的一种有效治疗方法是人工耳蜗植入，它通过直接刺激听觉神经元来代替耳蜗。了解特定的神经元如何变得独特地适合于感知声音是改进人工耳蜗技术的关键一步，并且可以帮助确定保持神经元存活的新方法，或者用新的神经元替换受损的神经元，从而重建耳朵和大脑之间的精确连接。

DESCRIPTION (provided by applicant): 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. Sounds are collected by the ear, but we only become aware of sounds because of the activity of complex networks of neurons that connect the ear to the brain. Auditory neurons can die due to traumatic injury or because other parts of the ear do not function properly. An effective treatment for deafness is the cochlear implant, which replaces the cochlea by directly stimulating auditory neurons. Understanding how specific sets of neurons become uniquely suited for the perception of sound is a crucial step towards improved cochlear implant technology, and could help identify new ways to keep neurons alive or to replace damaged neurons with new neurons that can re-establish precise connections between the ear and the brain.