Regulation of sensory cell specification in the developing cochlea

描述（由申请人提供）：Corti器官的发育是一个严格调控的过程，其中耳蜗管的小“前感觉”域被分选为各种类型的毛细胞和支持细胞。虽然已知细胞间信号，如Notch和FGF，在耳蜗发育的几个步骤中是必需的，但它们在感觉细胞特化阶段的确切作用和关系尚不清楚。在过去的一年中，我们发现FGF 20是感觉细胞特化所必需的。FGF 20的抑制或FGF受体的抑制导致Atoh 1表达的丧失。我们还发现，在耳蜗发育的早期阶段，在外植体培养物中抑制Notch信号传导导致感觉细胞发育的阻滞。这些发现导致了一个工作模型，其中前感觉Notch信号导致Fgf 20的表达，然后激活感觉细胞中的Atoh 1。在此提交，我们提出了几条线的调查，旨在测试特定的假设的分子机制的感觉细胞规格。我们的建议有以下具体目标：1.确定Notch的前感觉作用是否由FGF 20介导; 2.确定Notch对FGF 20表达的作用是否是直接的; 3.确定Ets结构域转录因子是否是感觉细胞特化所必需和/或充分的。更好地了解调节正常发育的分子途径将是至关重要的合理策略，毛细胞的替代和再生成人发病耳聋。 公共卫生相关性：了解内耳的感觉细胞是如何被指定的是设计合理的修复策略的非常重要的第一步，用于耳毒性或噪音损伤后。这个建议是为了阐明感觉细胞和相关分子发育的关键步骤。一旦建立了分子途径及其使用顺序，就可以测试在受损组织中激活或抑制这些途径的化合物，以评估它们对再生的影响。

DESCRIPTION (provided by applicant): The development of the organ of Corti is a tightly regulated process, in which a small "prosensory" domain of the cochlear duct is sorted into various types of hair cells and support cells. While it known that intercellular signals, like Notch and FGF, are required at several steps in cochlear development, their precise roles and relationship at the stage of sensory cell specification are not clear. In the past year, we have found that FGF20 is necessary for sensory cell specification. Inhibition of FGF20 or inhibition of the FGF receptors leads to a loss in Atoh1 expression. We have also found that inhibition of Notch signaling in explant cultures at early stages of cochlear development leads to a block in sensory cell development. These findings have led to a working model in which the prosensory Notch signal leads to the expression of Fgf20, which then activates Atoh1 in the sensory cells. In this submission, we propose several lines of investigation aimed at testing specific hypotheses about the molecular mechanisms of sensory cell specification. Our proposal has the following specific aims: 1. To determine whether the prosensory action of Notch is mediated by FGF20; 2. To determine whether the action of Notch on FGF20 expression is direct; 3. To determine whether Ets domain transcription factors are necessary and/or sufficient for sensory cell specification. A better understanding of the molecular pathways regulating normal development will be critical for rational strategies for hair cell replacement and regeneration in adult onset deafness. PUBLIC HEALTH RELEVANCE: Understanding how the sensory cells of the inner ear are specified is a very important first step towards designing rational repair strategies for use after damage due to ototoxicity or noise. This proposal is geared towards elucidating the key steps in development of the sensory cells and the molecules involved. Once the molecular pathways, and the order in which they are used, are established it would allow for testing of compounds that activate or inhibit these pathways in damaged tissue to assess their influence on regeneration.