Genetic regulation of Inner and Middle Ear Development

内耳和中耳发育的基因调控

• 批准号: 8478254
• 负责人: Andrew K Groves
• 金额: $ 45.11万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-22 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478254
• 关键词: Address; Affect; Auditory; Binding; Binding Sites; Bioinformatics; Branchial arch structure; Cell Death; Cell Survival; Cell division; Cell model; Cephalic; Cessation of life; Chick Embryo; Child; Chromatin Remodeling Factor; Chromatin Structure; Collaborations; Congenital Abnormality; DNA; DNA Binding Domain; DNA Methylation; Defect; Development; Ear; Ear ossicles; Ectoderm; Ectoderm Cell; Electroporation; Embryo; Endoderm; Enhancers; External Ear; FGF8 gene; Failure; Fibroblast Growth Factor; Genes; Genetic; Genetic Transcription; Genomics; Head; Hearing; Histones; Human; Inherited; Knockout Mice; Labyrinth; Light; Mesenchyme; Molecular; Mus; Mutant Strains Mice; Mutate; Neural Crest; Neural Crest Cell; Organ; Otic Placodes; Output; Pattern; Production; Property; Proteins; Regulation; Sensory; Signal Transduction; Source; Staging; Structure; Technology; Testing; Time; Tissues; Universities; Work; base; craniofacial; deep sequencing; embryonic stem cell; external ear auricle; forkhead protein; gene function; hearing impairment; histone modification; interest; loss of function; middle ear; mutant; placodal ectoderm; progenitor; public health relevance; research study; response; transcription factor

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.

描述（由申请人提供）：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了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，Foxi 3，这是在胚胎头部的非常早期阶段表达。我们实验室制造的Foxi 3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，在耳朵诱导的第一步-耳基板的形成-不发生在Foxi 3突变体。此外，产生中耳小骨和耳廓的第一和第二鳃弓的间充质在Foxi 3突变体中开始形成，但迅速地屈服于大量细胞死亡。据我们所知，Foxi 3是唯一一个在自身突变时导致整个内耳、中耳和外耳完全发育失败的哺乳动物基因。因此，我们非常有兴趣了解Foxi 3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，Foxi 3可能作为一个“先锋”转录因子-其主要功能除了启动转录是表观遗传组织基因组位点含有耳特异性基因在转录能力状态。我们的前两个目标将使用敲除小鼠，鸡胚操作和最先进的ES细胞模型，深度测序和生物信息学分析来确定Foxi 3在内耳发育过程中的功能和机制。我们的最终目的是集中在功能Foxi 3基因在中耳的发展。