Origin of endocochlear potential studied with mouse model for human heredetary nonsyndromic deafness.

耳蜗管内电位(EP)是在内耳耳蜗管淋巴与邻近鼓阶淋巴液之间观察到的显著静电电位。这种电生理特性是高等脊椎动物，特别是哺乳动物所特有的，对它们的耳蜗功能是必不可少的。然而，关于EP的起源、建立过程和维持方式仍然知之甚少。最近，缝隙连接蛋白26(Cx26)被认为与转录因子BRN-4一样在EP的维持中起着关键作用。Cx26也是人类非综合征性耳聋的应答基因DFNB1和DFNA3。为了更好地了解EP的发生机制，并研究Cx26与BRN-4的联合作用，我们引入了cre-lfcxP系统的条件性基因打靶技术，培育出Cx26-条件性KO小鼠，这些小鼠被认为在体内正常工作，然后以时空依赖的方式诱导Cx26基因的缺失。听性脑干反应检测显示Cx26-Silent-Allele：O/P0-Cre+小鼠为深度耳聋，而Cx26-Silent-Allele：E/PO-Cre+小鼠为正常小鼠。这些结果表明，与人类非综合征性耳聋一样，Cx26基因对小鼠内耳功能是必需的，并提示Cx26-Silent-Allele：E/PO-Cre+小鼠可能是人类DFNB1的模型。

The endocochlear potential (EP) is remarkable electrostatic potential observed between lymph of cochlear duct and that of neighboring duct scala tympani in inner ear. This electro-physiological character is known as specific for higher vertebrate especially in mammalian species and to be essential for their cochlear function. About the origin, the process of establishment, and ways of maintenance of EP, however, are still little known.Recently, Gap junction component connexin 26 (Cx26) is thought to have pivotal role in maintenance of EP as well as transcription factor Brn-4 does. Cx26 is also known as responsive gene for human nonsyndromic deafness DFNB1 and DFNA3. To better understand the mechanism of emergence of EP and to investigate the roles of Cx26 in conjunction with Brn-4, we introduced conditional gene targeting technology using cre-lfcxP system to produce "Cx26-conditional-KO" mice with "silent" alleles of Cx26 those were assumed to work normally in vivo and then induced deletion of Cx26 gene in spatio-temporally dependent manner.By crossing Cx26-conditional-KO mice with PO-Cre transgenic mice, we attempted to eliminate Cx26 gene from whole inner ear tissue cells in their offspring mice of adult age. Auditory brainstem response measurement showed that Cx26-Silent-Allele : O/P0-Cre+ mice were profound deafness whereas Cx26-Silent-Allele:E/PO-Cre+ mice were normal. These results indicate that, like in the case of human nonsyndromic deafness, Cx26 gene is essential for mouse inner ear function and suggest Cx26-Silent-Allele:E/PO-Cre+ mouse could be a model for human DFNB1.