Genetic Analysis of the Induction and Morphogenesis of the Inner Ear

描述(申请人提供)：当胚胎后脑两侧的两个外胚层区域形成增厚的上皮片时，内耳就开始发育，称为耳状安慰剂。构成膜性内耳的所有细胞类型，包括机械感觉毛细胞和支配它们的神经元，都是耳板细胞的后代。因此，耳道胎盘形成中的任何干扰都可能对内耳的形成和功能产生严重后果。此外，据估计，高达39%的先天性听力和平衡障碍病例与内耳畸形有关。这个项目的长期目标是了解耳道胎盘诱导所需的分子通路，这将加强我们对与内耳畸形相关的先天性听力和平衡障碍的理解。在这里，我们提出了一种遗传学的方法来阐明Sprouty家族受体酪氨酸激酶信号的拮抗剂，包括成纤维细胞生长因子信号，在耳廓胎盘诱导中的作用。本研究的具体目的是：1)分析Spry1和SPRY2基因在耳道胎盘诱导过程中的冗余功能，并验证Spry1和SPRY2基因冗余功能在耳道胎盘诱导过程中限制成纤维细胞生长因子信号范围的假说。目的2)验证Spry1和SPRY2基因在耳源性胎盘诱导早期功能冗余的假说，以及在Spry1和SPRY2基因功能缺失的情况下，参与耳源性胎盘诱导的其他信号通路将被错误调控的假说。目的3)确定单个Spry1和SPRY2基因在耳道胎盘诱导过程中的基因充分性，并验证Spry1和SPRY2的组织特异性表达对耳道胎盘的正确诱导至关重要的假说。

DESCRIPTION (provided by applicant): Development of the inner ear begins when two regions of ectoderm on either side of the embryonic hindbrain form thickened patches of epithelium called the otic placodes. All of the cell types that compose the membranous inner ear, including the mechanosensory hair cells and the neurons that innervate them, are descendents of cells in the otic placode. Consequently, any perturbations in formation of the otic placode can have severe consequences on the formation and function of the inner ear. Furthermore, it is estimated that up to 39% of cases of congenital hearing and balance disorders are associated with malformation of the inner ear. The long-term goal of this project is to understand the molecular pathways required for induction of the otic placode, which should enhance our understanding of those congenital hearing and balance disorders associated with inner ear malformation. Here we propose a genetic approach to elucidate the role of the Sprouty family of antagonists of receptor tyrosine kinase signaling, including Fibroblast Growth Factor (FGF) signaling, in otic placode induction. The specific aims of this proposal are: Aim 1) To analyze the redundant functions of the Spry1 and Spry2 genes during otic placode induction and to test the hypothesis that Spry1 and Spry2 function redundantly to limit the range of FGF signaling during induction of the otic placode. Aim 2) To test the hypothesis that Spry1 and Spry2 function redundantly at an early step in otic placode induction, and that other signaling pathways that contribute to otic placode induction will be misregulated in the absence of both Spry1 and Spry2 gene function. Aim 3) To determine the gene-sufficiency of the individual Spry1 and Spry2 genes during otic placode induction and to test the hypothesis that the tissue-specific expression of Spry1 and Spry2 is critical for proper induction of the otic placode.