Tbx1 Functions in Ear Development

Tbx1 在耳朵发育中的功能

基本信息

批准号：
7223803
负责人：
ANTONIO BALDINI
金额：
$ 18.1万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7223803
关键词：
cell population study cell proliferation congenital deafness congenital ear disorder developmental genetics epithelium gene dosage gene expression gene mutation growth /development histogenesis laboratory mouse labyrinth mammalian embryology mesenchyme otocyst /otolith transcription factor

项目摘要

DESCRIPTION (provided by applicant): Tbx1 is a highly conserved T-box-encoding transcription factor. Loss of function of Tbxl in mice is associated with severe developmental defects of the external, middle and inner ear, as well as other developmental abnormalities. TBX1 is thought to be a critical gene in the pathogenesis of de122qll/DiGeorge syndrome (DGS). Morphological abnormalities of the external ear and hearing impairment (conductive or sensorineural) affect the majority of patients. The external and middle ear defects in the mouse model are consistent with the requirement of Tbxl for the development of the pharyngeal arches but the inner ear defects are of unknown origin. Preliminary data underline the requirement of Tbxl for the growth of the otocyst and for the formation of the cochlear duct and semicircular canals. Because of the fundamental importance of the affected developmental processes, we propose a genetic dissection of the function of Tbxl in the inner ear. The first aim of the project is to establish the mechanism by which Tbxl loss of function blocks otocyst morphogenesis. We hypothesize that this is due to growth failure, death or fate change of a subpopulation of otic epithelial cells. We will use chimera and cell fate analyses to address this hypothesis. The second aim is to understand whether Tbxl expression is required in the otic epithelium, periotic mesenchyme or both. We hypothesize that Tbxl is required cell-autonomously in the otic epithelium and we will dissect this function from a possible non-cell autonomous role in the mesenchyme using tissue-specific mutation of the gene. The third aim is to establish whether quantitative reduction of Tbxl RNA message can cause morphological, molecular and/or functional abnormalities of the inner ear. We hypothesize that the function of Tbxl in inner ear development is dosage-dependent and we will use a hypomorphic Tbxl allele to test this hypothesis. In particular, we would like to understand whether Tbxl dosage reduction could cause hearing impairment, a common clinical finding in DGS patients.

描述（由申请人提供）：TBX1是高度保守的T盒编码转录因子。 TBXL在小鼠中的功能丧失与外耳中，内耳和内耳以及其他发育异常的严重发育缺陷有关。 TBX1被认为是DE122QLL/Digeorge综合征（DGS）发病机理中的关键基因。外耳和听力障碍（导电或感觉神经性）的形态异常会影响大多数患者。小鼠模型中的外耳和中耳缺陷与TBXL对咽弓的开发的要求一致，但内耳缺陷是未知来源的。初步数据强调了TBXL对耳囊的生长以及对耳蜗管和半圆形管的形成的需求。由于受影响的发育过程的基本重要性，我们提出了对内耳中TBXL功能的遗传解剖。该项目的第一个目的是建立TBXL功能丧失阻碍耳囊形态发生的机制。我们假设这是由于生长衰竭，死亡或命运的变化，使耳细胞的亚群变化。我们将使用嵌合体和细胞命运分析来解决这一假设。第二个目的是了解在耳朵上皮，毛毛间质还是两者中是否需要TBXL表达。我们假设在眼膜上皮中需要细胞自主，我们将使用基因的组织特异性突变从间质中可能的非细胞自主作用剖析该功能。第三个目的是确定TBXL RNA信息的定量减少是否会导致内耳的形态，分子和/或功能异常。我们假设TBXL在内耳发育中的功能是剂量依赖性的，我们将使用型型TBXL等位基因来检验这一假设。特别是，我们想了解降低TBXL剂量是否会导致听力障碍，这是DGS患者的常见临床发现。