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

Artur A. Indzhykulian, Ruben Stepanyan, Anastasiia Nelina, Kateri J. Spinelli, Zubair M. Ahmed, Inna A. Belyantseva, Thomas B. Friedman, Peter G. Barr-Gillespie, Gregory I. Frolenkov

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Sound detection by inner ear hair cells requires tip links that interconnect mechanosensory stereocilia and convey force to yet unidentified transduction channels. Current models postulate a static composition of the tip link, with protocadherin 15 (PCDH15) at the lower and cadherin 23 (CDH23) at the upper end of the link. In terminally differentiated mammalian auditory hair cells, tip links are subjected to sound-induced forces throughout an organism's life. Although hair cells can regenerate disrupted tip links and restore hearing, the molecular details of this process are unknown. We developed a novel implementation of backscatter electron scanning microscopy to visualize simultaneously immuno-gold particles and stereocilia links, both of only a few nanometers in diameter. We show that functional, mechanotransduction-mediating tip links have at least two molecular compositions, containing either PCDH15/CDH23 or PCDH15/PCDH15. During regeneration, shorter tip links containing nearly equal amounts of PCDH15 at both ends appear first. Whole-cell patch-clamp recordings demonstrate that these transient PCDH15/PCDH15 links mediate mechanotransduction currents of normal amplitude but abnormal Ca2+-dependent decay (adaptation). The mature PCDH15/CDH23 tip link composition is re-established later, concomitant with complete recovery of adaptation. Thus, our findings provide a molecular mechanism for regeneration and maintenance of mechanosensory function in postmitotic auditory hair cells and could help identify elusive components of the mechanotransduction machinery.

Original languageEnglish (US)
Article numbere1001583
JournalPLoS Biology
Volume11
Issue number6
DOIs
StatePublished - Jun 2013

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Indzhykulian, A. A., Stepanyan, R., Nelina, A., Spinelli, K. J., Ahmed, Z. M., Belyantseva, I. A., Friedman, T. B., Barr-Gillespie, P. G., & Frolenkov, G. I. (2013). Molecular Remodeling of Tip Links Underlies Mechanosensory Regeneration in Auditory Hair Cells. PLoS Biology, 11(6), [e1001583]. https://doi.org/10.1371/journal.pbio.1001583