Inoshita A, Iizuka T, Okamura H-O, Minekawa A, Kojima K, Furukawa M, Kusunoki T, Ikeda K
Department of Otorhinolaryngology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Neuroscience. 2008 Oct 28;156(4):1039-47. doi: 10.1016/j.neuroscience.2008.08.027. Epub 2008 Aug 22.
Hereditary hearing loss is one of the most prevalent inherited human birth defects, affecting one in 2000. A strikingly high proportion (50%) of congenital bilateral nonsyndromic sensorineural deafness cases have been linked to mutations in the GJB2 coding for the connexin26. It has been hypothesized that gap junctions in the cochlea, especially connexin26, provide an intercellular passage by which K(+) are transported to maintain high levels of the endocochlear potential essential for sensory hair cell excitation. We previously reported the generation of a mouse model carrying human connexin26 with R75W mutation (R75W+ mice). The present study attempted to evaluate postnatal development of the organ of Corti in the R75W+ mice. R75W+ mice have never shown auditory brainstem response waveforms throughout postnatal development, indicating the disturbance of auditory organ development. Histological observations at postnatal days (P) 5-14 were characterized by i) absence of tunnel of Corti, Nuel's space, or spaces surrounding the outer hair cells, ii) significantly small numbers of microtubules in inner pillar cells, iii) shortening of height of the organ of Corti, and iv) increase of the cross-sectional area of the cells of the organ of Corti. Thus, morphological observations confirmed that a dominant-negative Gjb2 mutation showed incomplete development of the cochlear supporting cells. On the other hand, the development of the sensory hair cells, at least from P5 to P12, was not affected. The present study suggests that Gjb2 is indispensable in the postnatal development of the organ of Corti and normal hearing.
遗传性听力损失是最常见的人类遗传性出生缺陷之一，每2000人中就有1人受影响。在先天性双侧非综合征性感音神经性耳聋病例中，高达50%的病例与编码连接蛋白26的GJB2基因突变有关。据推测，耳蜗中的缝隙连接，尤其是连接蛋白26，提供了一个细胞间通道，钾离子通过该通道运输，以维持对感觉毛细胞兴奋至关重要的内淋巴电位的高水平。我们之前报道了携带R75W突变的人连接蛋白26的小鼠模型（R75W+小鼠）的产生。本研究试图评估R75W+小鼠中柯蒂氏器的出生后发育情况。R75W+小鼠在整个出生后发育过程中从未显示出听觉脑干反应波形，表明听觉器官发育受到干扰。出生后第5 - 14天的组织学观察结果的特征为：i）缺乏柯蒂氏隧道、内尔间隙或外毛细胞周围的间隙；ii）内柱细胞中的微管数量显著减少；iii）柯蒂氏器高度缩短；iv）柯蒂氏器细胞的横截面积增加。因此，形态学观察证实，显性负性Gjb2突变显示耳蜗支持细胞发育不完全。另一方面，感觉毛细胞的发育，至少从出生后第5天到第12天，没有受到影响。本研究表明，Gjb2在柯蒂氏器的出生后发育和正常听力中是不可或缺的。
