Regulation of sensory cell specification in the developing cochlea

描述（由申请人提供）：Corti器官的发育是一个受到严格调控的过程，在这个过程中，耳蜗导管的一个小的“前感觉”区域被分类为各种类型的毛细胞和支持细胞。虽然已知Notch和FGF等细胞间信号在耳蜗发育的几个阶段都是必需的，但它们在感觉细胞分化阶段的确切作用和关系尚不清楚。在过去的一年里，我们发现FGF20对于感觉细胞的规格是必要的。抑制FGF20或抑制FGF受体导致Atoh1表达缺失。我们还发现，在耳蜗发育的早期阶段，外植体培养中Notch信号的抑制会导致感觉细胞发育受阻。这些发现导致了一个工作模型，在这个模型中，前感觉Notch信号导致Fgf20的表达，然后Fgf20激活感觉细胞中的Atoh1。在这篇文章中，我们提出了几条研究路线，旨在测试关于感觉细胞特化的分子机制的特定假设。我们的建议有以下具体目的：确定Notch的前感觉作用是否由FGF20介导；2. 确定Notch对FGF20表达的作用是否直接；3. 确定Ets结构域转录因子对感觉细胞的特异性是否必要和/或充分。更好地了解调节正常发育的分子途径将对成人耳聋毛细胞替换和再生的合理策略至关重要。

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.