Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition
Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition
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DOI：
10.1172/jci59353
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发表时间：
2011-11-01
影响因子：
15.9
通讯作者：
Griffith, Andrew J.
中科院分区：
文献类型：
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作者：
Choi, Byung Yoon;Kim, Hyoung-Mi;Griffith, Andrew J.
人SLC 26 A4突变是前庭水管扩大（伊娃）相关听力损失的常见原因。SLC 26 A4编码pendrin，一种在内耳上皮细胞中表达的阴离子交换剂，其将HCO 3-分泌到内淋巴中。对Slc 26 a4缺失小鼠的研究表明，pendrin对内耳发育至关重要，但尚未揭示pendrin是否对体内平衡特别必要。Slc 26 a4基因敲除小鼠是深度耳聋的，具有严重的内耳畸形和退行性变化，其不模拟不太严重的人类表型。在这里，我们描述的研究中，我们产生了一个二元转基因小鼠系，其中Slc 26 a4的表达可以诱导与强力霉素。将转基因杂交到Slc 26 a4-无效背景上，使得所有功能性pendrin均来源于转基因。改变Slc 26 a4的时间表达揭示了E16.5到P2是pendrin获得正常听力所需的关键间隔。在此期间缺乏pendrin导致内淋巴酸化，耳蜗内电位丧失，无法获得正常听力。在E18.5开始使用强力霉素或在E17.5停止使用强力霉素导致部分听力损失，接近人类伊娃听觉表型。这些数据共同提供了对SLC 26 A4突变引起的听力损失的机制性见解，并为进一步研究EVA相关的热损失建立了模型。
Mutations in human SLC26A4 are a common cause of hearing loss associated with enlarged vestibular aqueducts (EVA). SLC26A4 encodes pendrin, an anion-base exchanger expressed in inner ear epithelial cells that secretes HCO3- into endolymph. Studies of Slc26a4-null mice indicate that pendrin is essential for inner ear development, but have not revealed whether pendrin is specifically necessary for homeostasis. Slc26a4-null mice are profoundly deaf, with severe inner ear malformations and degenerative changes that do not model the less severe human phenotype. Here, we describe studies in which we generated a binary transgenic mouse line in which Slc26a4 expression could be induced with doxycycline. The transgenes were crossed onto the Slc26a4-null background so that all functional pendrin was derived from the transgenes. Varying the temporal expression of Slc26a4 revealed that E16.5 to P2 was the critical interval in which pendrin was required for acquisition of normal hearing. Lack of pendrin during this period led to endolymphatic acidification, loss of the endocochlear potential, and failure to acquire normal hearing. Doxycycline initiation at E18.5 or discontinuation at E17.5 resulted in partial hearing loss approximating the human EVA auditory phenotype. These data collectively provide mechanistic insight into hearing loss caused by SLC26A4 mutations and establish a model for further studies of EVA-associated heating loss.