Deafness in mice lacking the T-box transcription factor Tbx18 in otic fibrocytes
Deafness in mice lacking the T-box transcription factor Tbx18 in otic fibrocytes
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DOI：
10.1242/dev.014043
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发表时间：
2008-05-01
期刊：
影响因子：
4.6
通讯作者：
Kispert, Andreas
中科院分区：
文献类型：
--
作者：
Trowe, Mark-Oliver;Maier, Hannes;Kispert, Andreas
在耳蜗中，纤维细胞发挥着重要的生理作用，包括维持内淋巴的离子组成。人类耳聋对纤维细胞的改变证明了它们对听力的关键作用。我们证明了眼部成纤维细胞的分化需要T-box转录因子基因TBX18。在内耳发育期间，TBX18的表达仅限于耳间充质亚区，该亚区注定要分化为纤维细胞。我们通过转基因方法挽救了导致TBX18突变小鼠围产期死亡的躯体缺陷，并测量了听觉脑干反应。成年的TBX18基因缺陷小鼠表现出严重的耳聋和耳蜗内电位的完全破坏，这是感觉性毛细胞转导声音所必需的。螺旋韧带成纤维细胞分化严重受损。侧壁血管纹的组织结构被破坏，表现为几乎完全没有基底细胞层，中间细胞和边缘细胞分别减少和改变。血管纹缺陷是由于TBX18突变的纤维细胞不能通过间充质-上皮细胞转变而产生基底层。耳廓成纤维细胞分化缺陷可能与TBX18在耳廓间充质早期区划中的主要作用有关，因为突变体严重影响耳廓成纤维细胞与周围耳囊之间的谱系限制和边界形成。我们的研究揭示了耳间充质形成和分化的遗传控制，揭示了血管纹形成的不同步骤，并阐明了非上皮源性耳细胞类型对正常听力和耳聋病因的重要性。
In the cochlea, fibrocytes play important physiological roles, including the maintenance of the ionic composition of the endolymph. Human deafness upon fibrocyte alterations witnesses their crucial role for hearing. We demonstrate that differentiation of otic fibrocytes requires the T-box transcription factor gene Tbx18. Tbx18 expression during inner ear development is restricted to the sub-region of otic mesenchyme that is fated to differentiate into fibrocytes. We rescued the somitic defect that underlies the perinatal lethality of Tbx18-mutant mice by a transgenic approach, and measured auditory brainstem responses. Adult Tbx18-deficient mice showed profound deafness and a complete disruption of the endocochlear potential that is essential for the transduction of sound by sensory hair cells. The differentiation of otic fibrocytes of the spiral ligament was severely compromised. Tissue architecture of the stria vascularis of the lateral wall was disrupted, exhibiting an almost complete absence of the basal cell layer, and a reduction and changes of intermediate and marginal cells, respectively. Stria vascularis defects resulted from the failure of Tbx18-mutant otic fibrocytes to generate the basal cell layer by a mesenchymal-epithelial transition. Defects in otic fibrocyte differentiation may be subordinate to a primary role of Tbx18 in early compartmentalization of the otic mesenchyme, as lineage restriction and boundary formation between otic fibrocytes and the surrounding otic capsule were severely affected in the mutant. Our study sheds light on the genetic control of patterning and differentiation of the otic mesenchyme, uncovers distinct steps of stria vascularis formation and illuminates the importance of non-epithelially-derived otic cell types for normal hearing and the etiology of deafness.