Genetic regulation of Inner and Middle Ear Development

描述（申请人提供）：哺乳动物的内耳、中耳和外耳具有不同的胚胎起源，但听觉器官的每个组成部分的发育必须在空间和时间上精确同步。了解调节和协调这些结构发育的机制对于理解影响听力的许多出生缺陷的基础至关重要。我们已经确定了叉头转录因子Foxi3，它在胚胎头的早期阶段就表达了。我们实验室制造的fox3小鼠突变体缺乏内耳、中耳和外耳的所有组成部分。我们的初步证据表明，耳部诱导的第一步——耳位的形成——并没有发生在Foxi3突变体中。此外，在fox3突变体中，产生中耳小骨和耳廓的第一和第二鳃弓的间质开始形成，但迅速屈服于大量细胞死亡。据我们所知，Foxi3是唯一一个单独突变时导致整个内耳、中耳和外耳发育完全失败的哺乳动物基因。因此，我们非常有兴趣了解Foxi3如何在细胞和分子水平上协调听觉器官的发育。初步证据表明，Foxi3可能是一个“先锋”转录因子——除了启动转录外，它的主要功能是在表观遗传上组织含有耳朵特异性基因的基因组位点，使其处于转录能力状态。我们的前两个目标是通过敲除小鼠、鸡胚胎操作和最先进的胚胎干细胞模型、深度测序和生物信息学分析来确定fox3在内耳发育过程中的功能和机制。我们的最终目标是关注fox3基因在中耳发育中的作用。

DESCRIPTION (provided by applicant): The mammalian inner, middle and outer ears have different embryonic origins, yet the development of each component of the auditory apparatus must be precisely synchronized in space and time. Understanding the mechanisms that regulate and co-ordinate the development of these structures is of central importance in understanding the basis of the many birth defects that affect hearing. We have identified a Forkhead transcription factor, Foxi3, that is expressed at very early stages in the embryonic head. Foxi3 mouse mutants made in our lab lack all components of the inner, middle and external ears. Our preliminary evidence suggests that one of the first steps in ear induction - the formation of the otic placode - does not occur in Foxi3 mutants. Moreover, the mesenchyme of the first and second branchial arches that generate the middle ear ossicles and the pinna begins to form in Foxi3 mutants, but rapidly succumbs to massive cell death. To our knowledge, Foxi3 is the only mammalian gene that causes a complete developmental failure of the entire inner, middle and outer ears when mutated by itself. We are therefore extremely interested to understand how Foxi3 orchestrates development of the auditory apparatus at both the cellular and molecular levels. Preliminary evidence suggests that Foxi3 may act as a "pioneer" transcription factor - its main function in addition to initiating transcription is to epigenetically organize genomic loci containing ear-specific genes in a transcriptionally competent state. Our first two aims will determine the function and mechanism of Foxi3 during development of the inner ear using knockout mice, chick embryo manipulations and state-of-the-art ES cell models, deep sequencing and bioinformatic analysis. Our final aim focuses on the function the Foxi3 gene in the development of the middle ear.