Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition

被引:85
|
作者
Choi, Byung Yoon [2 ]
Kim, Hyoung-Mi [3 ]
Ito, Taku [1 ]
Lee, Kyu-Yup [1 ]
Li, Xiangming [3 ]
Monahan, Kelly [1 ]
Wen, Yaqing [1 ]
Wilson, Elizabeth [2 ]
Kurima, Kiyoto [1 ]
Saunders, Thomas L. [4 ]
Petralia, Ronald S. [5 ]
Wangemann, Philine [3 ]
Friedman, Thomas B. [2 ]
Griffith, Andrew J. [1 ]
机构
[1] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, Rockville, MD 20850 USA
[2] Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Rockville, MD 20850 USA
[3] Kansas State Univ, Dept Anat & Physiol, Manhattan, KS 66506 USA
[4] Univ Michigan, Sch Med, Ann Arbor, MI USA
[5] Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD USA
来源
JOURNAL OF CLINICAL INVESTIGATION | 2011年 / 121卷 / 11期
关键词
GENOTYPE-PHENOTYPE CORRELATION; KCNJ10 PROTEIN EXPRESSION; PENDRED-SYNDROME; INNER-EAR; CAUSES DEAFNESS; MUTATIONS; INSIGHT; CELLS;
D O I
10.1172/JCI59353
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:4516 / 4525
页数:10
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