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展的机制对于理解影响听力的许多先天缺陷的基础是至关重要的。我们已经确定了一个叉头转录因子foxI3，它在胚胎头部的非常早期阶段就有表达。我们实验室制造的foxI3小鼠突变体缺乏内、中、外耳的所有成分。我们的初步证据表明，耳朵诱导的第一步之一-耳道胎盘的形成-没有发生在foxI3突变体中。此外，在foxI3突变体中，产生中耳听骨和耳廓的第一和第二鳃弓的间质开始形成，但很快就死于大量细胞死亡。据我们所知，foxI3是唯一一种当自身突变时会导致整个内耳、中耳和外耳完全发育障碍的哺乳动物基因。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可能是一种“先锋”转录因子--除了启动转录外，它的主要功能是以表观遗传学的方式组织包含耳朵特异基因的基因组位点，使其处于转录活性状态。我们的前两个目标将利用基因敲除小鼠、鸡胚胎操作和最先进的ES细胞模型、深度测序和生物信息学分析来确定foxI3在内耳发育过程中的功能和机制。我们的最终目标是研究foxI3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.