Investigating the Role of Tbx1 in Ear Development

描述(申请人提供)：T-box转录因子TBX1最近被确认为22q11缺失综合征(22q11DS)的致病基因。大多数患有这种综合征的患者会发生传导性听力损失，同时也有报道称有些病例是感觉神经性耳聋。小鼠同源基因TBX1的突变已被证明是治疗这种疾病的极好模型。TBX1基因缺失的小鼠无法发育出外耳和中耳，而内耳永远不会发育到耳泡阶段。此外，在TBX1缺失的胚胎中，由耳囊形成的耳蜗前庭神经节(CVG)是复制的。上皮和间充质的相互作用被认为在耳蜗和前庭系统的发育中都起着重要的作用，但许多控制内耳发育的信号通路尚不清楚。TBX1在耳囊上皮和周围的骨膜间充质中均有表达。我们假设，通过与转录因子Brn4的遗传相互作用，POM中的TBX1信号是耳蜗发育所必需的。对于特定的目的1，将使用Cre/loxP系统在POM中灭活TBX1，以创建一个有条件的小鼠突变体，从而能够分离TBX1在该组织中的作用。在特定的目标2中，将通过产生两个基因的突变小鼠来测试POM中Brn4和Tbx1之间的相互作用。Tbx1或Brn4杂合子零突变不会导致内耳畸形。含有这两种基因突变的复合杂合子小鼠将被分析是否有内耳缺陷。这些特定目标的实现将进一步深入了解TBX1在内耳发育中的作用以及它发挥作用的遗传途径。耳聋是一个重大的公共卫生问题，而导致耳聋的遗传原因仍然知之甚少。Tbx1是导致22q11 DS许多症状的基因，包括听力损失。了解这种基因如何促进耳朵的正常发育，对于更好地了解先天性耳聋的原因至关重要，并将导致对这种疾病的更好检测。

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.