Tbx1 Functions in Ear Development

描述（申请人提供）：Tbx1是一种高度保守的t -box编码转录因子。Tbxl在小鼠中的功能丧失与外耳、中耳和内耳的严重发育缺陷以及其他发育异常有关。TBX1被认为是de122qll/DiGeorge综合征（DGS）发病机制中的关键基因。外耳形态异常和听力障碍（传导性或感音神经性）影响大多数患者。小鼠模型外耳和中耳缺损符合Tbxl对咽弓发育的要求，内耳缺损来源不明。初步数据强调了Tbxl对耳囊肿生长和耳蜗导管和半规管形成的要求。由于受影响的发育过程的根本重要性，我们提出了内耳Tbxl功能的遗传解剖。该项目的第一个目标是建立Tbxl功能丧失阻碍耳囊肿形态发生的机制。我们假设这是由于耳部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个假设。第二个目的是了解Tbxl是否需要在耳上皮、周间质或两者中表达。我们假设Tbxl在耳上皮中是细胞自主需要的，我们将利用该基因的组织特异性突变从间质中可能的非细胞自主作用来剖析这种功能。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，我们将使用一个次形的Tbxl等位基因来验证这一假设。特别是，我们想了解Tbxl的剂量减少是否会导致听力障碍，这是DGS患者常见的临床发现。

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.