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Molecular Remodeling of Tip Links Underlies Mechanosensory Regeneration in Auditory Hair Cells

Authors
Journal
PLoS Biology
1544-9173
Publisher
Public Library of Science
Publication Date
Volume
11
Issue
6
Identifiers
DOI: 10.1371/journal.pbio.1001583
Source
Legacy
Keywords
  • Research Article
  • Biology
  • Neuroscience
  • Sensory Systems
  • Auditory System

Abstract

Author Summary The inner ear detects sound when stereocilia, the mechanosensory projections on the apical surface of the hair cells, are deflected and tug on tiny extracellular tip links. These links interconnect stereocilia and convey forces to the mechanosensitive transduction channels. Current models postulate a static composition of the tip link with protocadherin 15 (PCDH15) at the link's bottom end and cadherin 23 (CDH23) at the upper end. Tip links are subjected to substantial sound-induced forces. Although hair cells can renew (regenerate) disrupted tip links and restore hearing, the molecular details of this process are unknown. Our study provides mechanistic insight into tip link regeneration. We used backscatter scanning electron microscopy to monitor the distribution of immuno-gold labeled molecular components of the tip links during their re-formation and a conventional whole-cell patch-clamp technique to follow the concomitant recovery of mechano-electrical transduction. According to our data, the mechanotransduction machinery is initially re-established by the formation of functional (mechanotransduction-mediating) links of a previously unknown composition, PCDH15–PCDH15. Transition to the PCDH15–CDH23 composition underlies final maturation of mechanotransduction. This two-step mechanism of tip link regeneration was unexpected. As tip links are continuously stressed by loud sounds and regenerated throughout an organism's life, we provide a plausible molecular mechanism for the life-long maintenance of mechanosensory function in nonregenerating cochlear hair cells.

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