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Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition
Byung Yoon Choi, … , Thomas B. Friedman, Andrew J. Griffith
Byung Yoon Choi, … , Thomas B. Friedman, Andrew J. Griffith
Published October 3, 2011
Citation Information: J Clin Invest. 2011;121(11):4516-4525. https://doi.org/10.1172/JCI59353.
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Research Article Otology

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

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Abstract

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 hearing loss.

Authors

Byung Yoon Choi, Hyoung-Mi Kim, Taku Ito, Kyu-Yup Lee, Xiangming Li, Kelly Monahan, Yaqing Wen, Elizabeth Wilson, Kiyoto Kurima, Thomas L. Saunders, Ronald S. Petralia, Philine Wangemann, Thomas B. Friedman, Andrew J. Griffith

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Figure 7

Morphology of the cochlear duct and organ of Corti at P25 to P35.

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Morphology of the cochlear duct and organ of Corti at P25 to P35.
(A–D) ...
(A–D) Light microscopic images of plastic-embedded sections of the middle cochlear turn stained with toluidine blue. (E–H) Scanning electron micrographs of the organ of Corti from the middle cochlear turn. Scale bars: 100 μm (A, applies to A–C); 200 μm (D); and 10 μm (E, applies to E–H). Note the different scale bar in D for the enlarged cochlear duct of Slc26a4Δ/Δ mice. SLm, spiral limbus; TM, tectorial membrane; SLg, spiral ligament; OHC, 3 rows of outer hair cells; IHC, single row of inner hair cells. The Reissner membrane of Tg[E];Tg[R];Slc26a4Δ/Δ IE18.5 ears is collapsed onto the spiral limbus and tectorial membrane. The spiral ganglion, stria vascularis, organ of Corti hair cells and other structures of the cochlear ducts of Tg[E];Tg[R];Slc26a4Δ/Δ IE18.5 and DE17.5 mice look similar to those of Slc26a4Δ/+ controls.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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