Abstract
The hair bundle of cochlear hair cells is the site of auditory mechanoelectrical transduction. It is formed by three rows of stiff microvilli-like protrusions of graduated heights, the short, middle-sized, and tall stereocilia. In developing and mature sensory hair cells, stereocilia are connected to each other by various types of fibrous links. Two unconventional cadherins, protocadherin-15 (PCDH15) and cadherin-23 (CDH23), form the tip-links, whose tension gates the hair cell mechanoelectrical transduction channels. These proteins also form transient lateral links connecting neighboring stereocilia during hair bundle morphogenesis. The proteins involved in anchoring these diverse links to the stereocilia dense actin cytoskeleton remain largely unknown. We show that the long isoform of whirlin (L-whirlin), a PDZ domain-containing submembrane scaffold protein, is present at the tips of the tall stereocilia in mature hair cells, together with PCDH15 isoforms CD1 and CD2; L-whirlin localization to the ankle-link region in developing hair bundles moreover depends on the presence of PCDH15-CD1 also localizing there. We further demonstrate that L-whirlin binds to PCDH15 and CDH23 with moderate-to-high affinities in vitro. From these results, we suggest that L-whirlin is part of the molecular complexes bridging PCDH15-, and possibly CDH23-containing lateral links to the cytoskeleton in immature and mature stereocilia.
Highlights
The hair bundle of cochlear hair cells is the site of auditory mechanoelectrical transduction
Another group, combining observations made by structured illumination microscopy in wild-type mice and in L-whirlin-null mutant mice with several antibodies recognizing both the L- and S-isoforms, concluded that L-whirlin is restricted to a position midway along the middle-sized stereocilia of both inner hair cells (IHCs) and outer hair cells (OHCs) on P 1025
It is unclear whether this discordance was due to the different epitopes recognized by the antibodies used, or to differences between the developmental stages analyzed. We addressed this issue by producing a new antibody directed against the N-terminal region of L-whirlin (L-whirlin NTR; see Materials and methods)
Summary
The hair bundle of cochlear hair cells is the site of auditory mechanoelectrical transduction It is formed by three rows of stiff microvilli-like protrusions of graduated heights, the short, middle-sized, and tall stereocilia. Protocadherin-15 (PCDH15) and cadherin-23 (CDH23), form the tip-links, whose tension gates the hair cell mechanoelectrical transduction channels These proteins form transient lateral links connecting neighboring stereocilia during hair bundle morphogenesis. The sensory cells of the cochlea (inner and outer hair cells) convert acoustic waves into receptor potentials by the process of mechanoelectrical transduction (MET)[1,2] This process takes place in the hair bundle, a mechanosensitive antenna formed by thick and stiff microvilli-like protrusions called stereocilia, organized in three rows of graduated height (i.e., short, middle-sized, and tall stereocilia) at the apical surface of the hair cells.
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