Tbx1 Functions in Ear Development

描述（由申请人提供）：Tbx 1是一种高度保守的编码T-box的转录因子。小鼠中Tbxl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相关。TBX 1基因被认为是de 122 qll/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（传导性或感觉神经性）影响大多数患者。小鼠模型中的外耳和中耳缺损与Tbxl对咽弓发育的要求一致，但内耳缺损的原因不明。初步数据强调了Tbxl对耳囊生长以及耳蜗管和半规管形成的需求。由于受影响的发展过程的根本重要性，我们提出了一个遗传解剖的功能Tbxl在内耳。该项目的第一个目的是建立Tbxl功能丧失阻断耳囊形态发生的机制。我们推测这是由于耳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表达是否需要在耳上皮、耳周间充质或两者中。我们假设，Tbxl是需要细胞自主的耳上皮，我们将解剖这种功能，从一个可能的非细胞自主的作用，在间充质中使用组织特异性突变的基因。第三个目的是确定Tbxl RNA信使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，并且我们将使用亚型Tbxl等位基因来检验这一假设。特别地，我们想了解Tbxl剂量减少是否会导致听力损伤，这是DGS患者中常见的临床发现。

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.