Investigating the Role of Tbx1 in Ear Development

描述（由申请人提供）：T-box转录因子TBX1最近被确定为导致22q11缺失综合征（22q11DS）病因的基因。传导性听力损失发生在大多数患者的这种综合征，而感音神经性耳聋也有报道在一些情况下。小鼠同源基因Tbx1的突变已被证明是这种疾病的极好模型。没有Tbx1基因的小鼠不能发育出外耳和中耳，而内耳的发育从未超过耳泡期。此外，耳蜗前庭神经节（CVG）由耳囊形成，在Tbx1胚胎中复制。上皮细胞和间充质细胞的相互作用被认为在耳蜗和前庭系统的发育中起重要作用，然而许多控制内耳发育的信号通路尚不清楚。Tbx1在耳小泡上皮和周围的周间质（POM）中均有表达。我们假设POM中的Tbx1信号通过与转录因子Brn4的遗传相互作用是耳蜗发育所必需的。对于Specific Aim 1，将使用Cre/loxP系统使Tbx1在POM中失活，以创建条件小鼠突变体，从而分离Tbx1在该组织中的作用。在Specific Aim 2中，将通过生成两个基因的小鼠突变体来测试POM中Brn4和Tbx1之间的相互作用。Tbx1或Brn4的杂合零突变不会产生内耳畸形。同时携带两个基因突变的复合杂合小鼠将被分析内耳缺陷。这些具体目标的实现将进一步深入了解Tbx1在内耳发育中的作用及其发挥作用的遗传途径。耳聋是一个重大的公共卫生问题，耳聋的遗传原因仍然知之甚少。TBX1是导致22q11变性的许多症状的基因，包括听力丧失。了解这种基因如何促进正常的耳部发育，对于更好地了解先天性耳聋的病因至关重要，并将有助于改进对这种疾病的检测。

DESCRIPTION (provided by applicant): The T-box transcription factor TBX1 was recently identified as the gene responsible for the etiology of 22q11 deletion syndrome (22q11DS). Conductive hearing loss occurs in a majority of patients with this syndrome, while sensorineural deafness has also been reported in some cases. Mutation of the murine orthologue, Tbx1, has proven to be an excellent model for this disease. Mice null for Tbx1 fail to develop an outer and middle ear, while the inner ear never develops beyond the otic vesicle stage. In addition, the cochleovestibular ganglion (CVG), which forms from the otic vesicle, is duplicated in Tbx1 null embryos. Epithelial and mesenchymal interactions are thought to play an important role in the development of the both the cochlea and vestibular system, however many of the signaling pathways that control inner ear development are not known. Tbx1 is expressed both in the otic vesicle epithelium and the surrounding periotic mesenchyme (POM). We hypothesize that Tbx1 signaling in the POM is required for cochlear development via a genetic interaction with the transcription factor Brn4. For Specific Aim 1, Tbx1 will be inactivated in the POM using the Cre/loxP system to create a conditional mouse mutant, enabling the isolation of the role of Tbx1 in this tissue. In Specific Aim 2, the interaction between Brn4 and Tbx1 in the POM will be tested by generating mice mutant for both genes. Heterozygous null mutations in either Tbx1 or Brn4 do not produce inner ear malformation. Compound heterozygous mice harboring mutations for both genes will be analyzed for inner ear defects. Achievement of these specific aims will provide a further insight into the role of Tbx1 in inner ear development and the genetic pathways in which it functions. Deafness is a major public health issue, and the genetic causes of deafness are still poorly understood. TBX1 is the gene responsible for many of the symptoms of 22q11 DS, including hearing loss. Understanding of how this gene contributes to normal ear development is crucial to gaining a better knowledge of the causes of congenital deafness and will lead to improved detection of this disease.