Tbx1 Functions in Ear Development

描述(申请人提供)：TBX1是一个高度保守的编码T盒的转录因子。小鼠Tbx1功能的丧失与外耳、中耳和内耳的严重发育缺陷以及其他发育异常有关。Tbx1基因被认为是de122qll/DiGeorge综合征(DGS)发病机制中的关键基因。外耳的形态异常和听力障碍(传导性或感觉神经性)影响大多数患者。小鼠模型的外耳和中耳缺陷符合Tbx1对咽弓发育的要求，而内耳缺陷的来源不明。初步数据表明，Tbx1对耳囊的生长以及耳蜗管和半规管的形成是必需的。由于受影响的发育过程的基本重要性，我们建议对Tbx1在内耳中的功能进行遗传解剖。该项目的第一个目标是建立Tbx1功能丧失阻碍耳囊形态发生的机制。我们推测这是由于眼球上皮细胞亚群的生长失败、死亡或命运改变所致。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Tbx1在耳廓上皮、骨膜间充质或两者中是否需要表达。我们假设Tbx1在耳廓上皮细胞中是细胞自主所必需的，我们将使用该基因的组织特异性突变从间质中可能的非细胞自主角色中剖析这一功能。第三个目的是确定Tbx1 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Tbx1在内耳发育中的作用是剂量依赖的，我们将使用一个亚形的Tbx1等位基因来检验这一假设。特别是，我们想了解减少Tbx1剂量是否会导致听力障碍，这在DGS患者中是常见的临床发现。

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.