Cooperative function of Tbx1 and Brn4 in the periotic mesenchyme is necessary for cochlea formation
Cooperative function of Tbx1 and Brn4 in the periotic mesenchyme is necessary for cochlea formation
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DOI：
10.1007/s10162-008-0110-6
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发表时间：
2008-03-01
影响因子：
2.4
通讯作者：
Adams, Joe C.
中科院分区：
文献类型：
--
作者：
Braunstein, Evan M.;Crenshaw, E. Bryan, III;Adams, Joe C.
T-box转录因子TBX 1是导致Velcardicifacial综合征/DiGeorge综合征（VCFS/DGS）的主要基因。传导性听力损失发生在大多数患有这种综合征的患者中，而感音神经性耳聋也在某些情况下被报道。POU结构域转录因子POU 3F 4/BRN 4的突变导致DFN 3，这是一种X连锁的非综合征型耳聋，其特征在于混合传导性和感音神经性听力损失。这些基因的小鼠直系同源物的失活导致与人类中所见的缺陷相似的缺陷，并为内耳发育的研究提供了极好的模型。Tbx 1和Brn 4在耳泡周围的间充质细胞中表达，并已被证明在耳蜗生长中发挥作用。此外，在Tbx 1无效突变体中Brn 4的表达减少，表明这些基因之间可能存在遗传相互作用。为了测试Tbx 1和Brn 4是否在共同途径中起作用，产生了两种基因的小鼠突变体并分析了内耳缺陷。与Brn 4-或Tbx 1 +/-小鼠相比，Brn 4-; Tbx 1 +/-突变体显示出耳蜗匝数的显著减少。此外，Brn 4-; Tbx 1 +/-小鼠在VCFS/DGS或DFN 3患者中发现的指示Mondini发育不良的顶端耳蜗中显示结构缺陷。这些数据建立了与人类疾病相关的Tbx 1和Brn 4之间的遗传相互作用，并表明这些基因在从耳周间充质到耳泡的信号传导中的功能，以指导耳蜗管的正确卷曲。
The T-box transcription factor TBX1 has been identified as the major gene responsible for the etiology of velocardicifacial syndrome/DiGeorge syndrome (VCFS/DGS). Conductive hearing loss occurs in a majority of patients with this syndrome, while sensorineural deafness has also been reported in some cases. Mutations in POU3F4/BRN4, a POU domain transcription factor, cause DFN3, an X-linked non-syndromic form of deafness characterized by mixed conductive and sensorineural hearing loss. Inactivation of the murine orthologues of these genes causes similar defects to those seen in humans and has provided excellent models for the study of inner ear development. Tbx1 and Brn4 are expressed in the mesenchymal cells surrounding the otic vesicle and have been shown to play roles in cochlear outgrowth. Furthermore, expression of Brn4 is reduced in Tbx1 null mutants, suggesting a possible genetic interaction between these genes. To test whether Tbx1 and Brn4 function in a common pathway, mice mutant for both genes were generated and analyzed for inner ear defects. Brn4-;Tbx1+/- mutants displayed a significant reduction in the number of turns of the cochlea compared to Brn4- or Tbx1+/- mice. In addition, Brn4-;Tbx1+/- mice displayed structural defects in the apical cochlea indicative of Mondini dysplasia found in patients with either VCFS/DGS or DFN3. These data establish a genetic interaction between Tbx1 and Brn4 relevant to human disease and indicate a function of these genes in signaling from the periotic mesenchyme to the otic vesicle to direct proper coiling of the cochlear duct.