Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
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.
View: Text | PDF
Research Article Otology

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

  • Text
  • PDF
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

×

Figure 6

Morphology of the endolymphatic sac and duct and vestibular aqueduct.

Options: View larger image (or click on image) Download as PowerPoint
Morphology of the endolymphatic sac and duct and vestibular aqueduct.
Sl...
Slc26a4Δ/+ control (A and E), Tg[E];Tg[R];Slc26a4Δ/Δ IE16.5 (B and F), Tg[E];Tg[R];Slc26a4Δ/Δ IE18.5 (C and G), or Slc26a4Δ/Δ control mice (D and H) were sacrificed at P3 for paint-fill analysis (A–D) or between P28 and P109 for cross-sectional histopathologic measurement of the vestibular aqueduct (VA, shaded pink) adjacent to the common crus (CC, shaded blue; E–H). (I) Mean ± SD values are shown for cross-sectional areas of the vestibular aqueduct. Numbers of mice are indicated. Scale bars: 500 μm (A, applies to A–D; E, applies to E–H). Progressive delays of initiation of pendrin expression to E16.5 and E18.5 result in abnormal enlargement of the endolymphatic duct and sac and vestibular aqueduct. ES, endolymphatic sac; ED, endolymphatic duct; S, saccule; CO, cochlea.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts