Genetic Regulation of Inner, Middle and Outer Ear Development

内耳、中耳和外耳发育的遗传调控

基本信息

批准号：
10293609
负责人：
Andrew K Groves
金额：
$ 52.15万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-22 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10293609
关键词：
ATAC-seq Affect Alleles Auditory Biochemical Bioinformatics Branchial arch structure Cell Death Cell Differentiation process Cell model Cells Cephalic ChIP-seq Chick Chick Embryo Child Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Conductive hearing loss Congenital Abnormality Data Defect Development ES Cell Line Ear Ear ossicles Ectoderm Embryo Embryonic Development Endoderm Epidermis Epigenetic Process External Ear FGF8 gene Failure Family Funding Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Goals Head Hearing Homeobox Genes Hour Human Knock-in Mouse Knockout Mice Labyrinth Light Maps Mesenchyme Modeling Molecular Molecular Analysis Molecular Genetics Mus Mutagenesis Mutant Strains Mice Mutate Mutation Neural Crest Neural Crest Cell Neuraxis Nuclear Localization Signal Otic Placodes Pathogenicity Patients Pattern Phenotype Regulation Role Series Signal Transduction Structure Switzerland Testing Time Tissues Up-Regulation Variant Work craniofacial critical period deep sequencing ear development embryonic stem cell experimental study forkhead protein gastrulation gene function genetic variant genomic locus hereditary hearing loss inner ear development interest loss of function microtia middle ear mouse model mutant neural plate novel overexpression progenitor response single-cell RNA sequencing transcription factor

项目摘要

PROJECT SUMMARY 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 work 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 external ear begins to form in Foxi3 mutants, but rapidly succumbs to massive cell death. Moreover, we have recently identified human patients with Foxi3 variants that have a variety of defects in their hearing apparatus 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. Our data 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 and external ear – here we will both study the effects of loss of Foxi3 in mice, but also create mouse mutants that recapitulate the genetic variants seen in some of our human patients.

项目概要哺乳动物的内耳、中耳和外耳具有不同的胚胎起源，但发育听觉器官的每个组成部分必须在空间和时间上精确同步。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我们已经确定了叉头。转录因子 Foxi3，在 Foxi3 小鼠胚胎头部的早期阶段表达。我们实验室制造的突变体缺乏内耳、中耳和外耳的所有组成部分。耳诱导的第一步——耳基板的形成——在 Foxi3 突变体中不会发生。此外，产生中耳小骨的第一和第二鳃弓的间质和 Foxi3 突变体中的外耳开始形成，但很快就会导致大量细胞死亡。最近发现携带 Foxi3 变体的人类患者存在多种听力缺陷设备据我们所知，Foxi3 是唯一导致大脑发育完全失败的哺乳动物基因。因此，我们对自身突变时的整个内耳、中耳和外耳非常感兴趣。了解 Foxi3 如何在细胞和分子层面协调听觉器官的发育我们的数据表明 Foxi3 可能充当“先锋”转录因子——它的主要功能除了启动转录是通过表观遗传方式组织包含耳特异性基因的基因组位点我们的前两个目标将决定 Foxi3 的功能和机制。使用基因敲除小鼠、鸡胚操作和最先进的 ES 细胞进行内耳发育我们的最终目标集中在 Foxi3 基因的功能。中耳和外耳的发育——在这里我们将研究 Foxi3 缺失对小鼠的影响，还创造了小鼠突变体，重现了我们在一些人类患者身上看到的基因变异。