Jin Zhe, Ulfendahl Mats, Järlebark Leif
Center for Hearing and Communication Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Eur J Neurosci. 2008 Jan;27(1):145-54. doi: 10.1111/j.1460-9568.2007.05994.x. Epub 2007 Dec 17.
Genetic deafness is one of the most common human genetic birth defects. To understand the molecular mechanisms underlying human hereditary deafness, deaf animal strains have proved to be invaluable models. The German waltzing guinea pig is a new strain of animals with unidentified gene mutation(s), displaying recessively inherited cochleovestibular impairment. Histological investigations of the homozygous animals (gw/gw) revealed a collapse of the endolymphatic compartment and malformation of stria vascularis. RT-PCR showed a significant reduction in expression of the strial intermediate cell-specific gene Dct and the tight-junction gene Cldn11 in the embryonic day (E)40 and adult gw/gw cochlear lateral wall. Immunohistochemical analysis of the gw/gw cochlea showed loss of the tight junction protein CLDN11 in strial basal cells from E40, loss of the potassium channel subunit KCNJ10 in strial intermediate cells from E50, and loss of the Na-K-Cl cotransporter SLC12A2 in strial marginal cells from E50. In addition, a temporary loss of the gap junction protein GJB2 (connexin 26) between fibrocytes in the spiral ligament of the E50 gw/gw cochlea was observed. The barrier composed of tight junctions between strial basal cells was disrupted in the gw/gw cochlea as indicated by a biotin tracer permeability assay. In conclusion, spatiotemporal loss of K+ transport proteins in the cochlear lateral wall is caused by malformation of the stria vascularis in the developing German waltzing guinea pig inner ear. This new animal strain may serve as a good model for studying human genetic deafness due to disruption of inner ear ion homeostasis.
遗传性耳聋是人类最常见的遗传性出生缺陷之一。为了了解人类遗传性耳聋的分子机制，耳聋动物品系已被证明是非常有价值的模型。德国华尔兹豚鼠是一种基因突变不明的新型动物品系，表现出隐性遗传的耳蜗前庭损伤。对纯合动物（gw/gw）的组织学研究显示内淋巴腔塌陷和血管纹畸形。逆转录聚合酶链反应（RT-PCR）表明，在胚胎期（E）40和成年gw/gw耳蜗外侧壁中，血管纹中间细胞特异性基因Dct和紧密连接基因Cldn11的表达显著降低。对gw/gw耳蜗的免疫组织化学分析显示，从E40开始，血管纹基底细胞中的紧密连接蛋白CLDN11缺失，从E50开始，血管纹中间细胞中的钾通道亚基KCNJ10缺失，从E50开始，血管纹边缘细胞中的钠-钾-氯共转运蛋白SLC12A2缺失。此外，在E50 gw/gw耳蜗螺旋韧带中的纤维细胞之间观察到缝隙连接蛋白GJB2（连接蛋白26）暂时缺失。生物素示踪剂通透性测定表明，gw/gw耳蜗中由血管纹基底细胞之间的紧密连接组成的屏障被破坏。总之，发育中的德国华尔兹豚鼠内耳血管纹畸形导致耳蜗外侧壁钾离子转运蛋白的时空缺失。这种新的动物品系可能是研究由于内耳离子稳态破坏导致的人类遗传性耳聋的良好模型。
