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

The University of Sheffield, United Kingdom
PLoS Biology (Impact Factor: 9.34). 06/2013; 11(6):e1001583. DOI: 10.1371/journal.pbio.1001583
Source: PubMed


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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    • "Moreover, the reduction in the total fluorescence intensity observed for the clarin-1 MOs and clarin-1 morpholinos + cRNACT (Fig. 4 I) was not caused by a reduction in the number of hair cells per neuromast (Fig. 4 J) but rather in their ability to incorporate the dye (Fig. 4 K), which is consistent with a defect associated with the mechanotransduction machinery. Two closely related pcdh15 genes have been identified in zebrafish (Seiler et al., 2005), with Pcdh15a involved in hearing and vestibular functions presumably through the formation of the tip links that gate the mechanotransduction channels, as is the case in mammalian hair cells (Kazmierczak et al., 2007; Indzhykulian et al., 2013). We generated Pcdh15a MOs and tested them for dye uptake impairment. "
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    The Journal of General Physiology 11/2014; 207(3). DOI:10.1083/jcb.201404016 · 4.79 Impact Factor
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    PLoS Biology 06/2013; 11(6):e1001584. DOI:10.1371/journal.pbio.1001584 · 9.34 Impact Factor
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