Size-control of the hair-cell bundle for frequency-selective auditory detection – HAIRBUNDLEMORPH

Our ability to communicate with speech or enjoy music relies on acute frequency discrimination over a broad range of sound frequencies. To cope with this requirement, the auditory sensory organ of the ear –the cochlea– is endowed with cellular microphones –the hair cells– that are each tuned to be most sensitive at a characteristic frequency of sound-evoked mechanical vibration and are spatially distributed according to a frequency map of mechanosensitivity. Despite its critical importance for hearing, the mechanism that specifies the characteristic frequency of a given hair cell and its regulation among hair cells to cover the entire auditory range is largely unknown. In this proposal, we focus on an intrinsic contribution to frequency tuning: the size of the hair-cell bundle. Each hair cell is adorned with a tuft of cylindrical protrusions called stereocilia that works as a mechanosensory antenna. Sound evokes deflections of the hair bundle to which the hair cell responds by producing an electrical signal that is transmitted by neurons to the brain. The hair bundle provides a striking example of an organelle where morphology is tightly linked to function. Along the longitudinal axis of the cochlear tube, the size of the hair bundle varies monotically from the high-frequency base (short bundles with many stereocilia) to the low-frequency apex (longer bundles with fewer stereocilia) of the organ. This suggests that the hair-cell bundle’s morphology is tightly regulated to allow this organelle to operate as a (living) tuning fork for which size helps select the preferred frequency of vibration. In this project, we aim at clarifying the mechanism of size control in the mature hair-cell bundle with respect to characteristic frequency of the hair cell.

Each stereocilium is supported by a para-crystalline array of parallel actin filaments that is ensheathed in the plasma membrane of the hair cell. The mechanism by which a stereocilium controls its length has remained elusive, but recent efforts to assay the function of proteins coded by deafness genes implicate the tip links that interconnect neighboring stereocilia near their tips and mediate mechano-sensitivity. In conditional knock-out mice for which the gene coding for the tip- link constituent cadherin-23 or protocadherin-15 is deleted after the normal development of the hair bundle, most stereocilia progressively decrease in length until they disappear almost completely. Our working hypothesis is that the tip link provides both mechanical and biochemical clues to regulate the local or global dynamics of the actin core of the stereocilia. Specifically, we propose to experimentally probe the role that tip-link tension, as well as the molecular connection between the tip link and actin, can have on stereociliary length. Within this framework, it then becomes important to determine the molecular mechanism of tension homeostasis, which likely implicates molecular motors and feedback from the Ca2+ influx through the transduction channels. To address these fundamental questions, our project combines biophysical tools, in particular a novel method of magnetic force application to the stereociliary membrane, with genetic and physiological approaches.

Defects in the morphology of the hair-cell bundle result in severe hearing deficits. By better understanding how the morphology of the hair-cell bundle is tuned according to its function as a frequency-selective mechanosensor, as well as by finding the origin of its deterioration in deaf animals, we hope to lay the groundwork for some future therapeutic approaches of deafness of genetic or environmental origin.