Tricellulin deficiency affects tight junction architecture and cochlear hair cells
Tricellulin deficiency affects tight junction architecture and cochlear hair cells
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DOI：
10.1172/jci69031
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发表时间：
2013-09-01
影响因子：
15.9
通讯作者：
Riazuddinl, Saima
中科院分区：
文献类型：
--
作者：
Nayak, Gowri;Lee, Sue I.;Riazuddinl, Saima
两种成分不同的细胞外耳蜗液（内淋巴液和外淋巴液）由勾勒出中阶和网状层轮廓的紧密连接分开。 TRIC（也称为 MARVELD2）编码一种称为三纤维素的三细胞紧密连接蛋白，其突变会导致非综合征性听力损失 (DFNB49)。我们培育了一种基因敲入小鼠，其携带与人类 DFNB49 听力损失相关的 TRIC 编码突变同源的突变。突变动物内耳上皮细胞的三细胞连接处不存在三纤维素蛋白，突变动物会出现快速进展的听力损失，并伴有机械感觉耳蜗毛细胞的损失，而血管纹中基于生物素的示踪剂的耳蜗内电位和细胞旁通透性没有改变。冷冻断裂电子显微镜显示，三纤维素蛋白缺陷小鼠内耳上皮细胞中连接双细胞和三细胞连接的膜内颗粒链被破坏。这些超微结构的变化可能选择性地影响离子或小分子的细胞旁通透性，导致耳蜗毛细胞产生有毒的微环境。与这一假设一致的是，当转录因子 Pou3f4 的同时缺失抑制了正常内淋巴的生成时，三纤维素蛋白缺陷小鼠的毛细胞损失得以挽救。最后，全面的表型筛选显示突变小鼠具有更广泛的病理表型，这凸显了三纤维素发挥的非冗余作用。
The two compositionally distinct extracellular cochlear fluids, endolymph and perilymph, are separated by tight junctions that outline the scala media and reticular lamina. Mutations in TRIC (also known as MARVELD2), which encodes a tricellular tight junction protein known as tricellulin, lead to nonsyndromic hearing loss (DFNB49). We generated a knockin mouse that carries a mutation orthologous to the TRIC coding mutation linked to DFNB49 hearing loss in humans. Tricellulin was absent from the tricellular junctions in the inner ear epithelia of the mutant animals, which developed rapidly progressing hearing loss accompanied by loss of mechanosensory cochlear hair cells, while the endocochlear potential and paracellular permeability of a biotin-based tracer in the stria vascularis were unaltered. Freeze-fracture electron microscopy revealed disruption of the strands of intramembrane particles connecting bicellular and tricellular junctions in the inner ear epithelia of tricellulin-deficient mice. These ultrastructural changes may selectively affect the paracellular permeability of ions or small molecules, resulting in a toxic microenvironment for cochlear hair cells. Consistent with this hypothesis, hair cell loss was rescued in tricellulin-deficient mice when generation of normal endolymph was inhibited by a concomitant deletion of the transcription factor, Pou3f4. Finally, comprehensive phenotypic screening showed a broader pathological phenotype in the mutant mice, which highlights the non-redundant roles played by tricellulin.