The Role of MYO7A in Tuning Sensory Hair Cell Sensitivity

Hair cells, the sensory receptors of the auditory and vestibular system, transduce mechanical stimuli from sound and head movement into an electrochemical signal. The mechanosensory hair bundle, consisting of an array of elongated microvilli called stereocilia, harbors the mechano-electrical transduction complex (MET). The tip link, an extracellular filament bridging two adjacent stereocilia, connects the MET channel complex at its lower end with the side of the stereocilium in the next tallest row. Deflection of the hair bundle increases tension in the tip links, which opens MET channels at its lower end, leading to the hair cell depolarization of hair cells. Thus, setting up the correct amount of tip-link tension is essential for the sensitivity of and dynamic range of auditory hair cells.
The upper end of the tip link is hypothesized to house a tension-generating element that anchors and pulls the tip link upwards along the F-actin core. Several myosin motors have been proposed to fulfill this function, and one of the candidates is an unconventional myosin - myosin-VIIa (MYO7A). However, functional evidence establishing MYO7A as the tension generator has been challenging to obtain, because hair bundle development is affected in knockout and knockdown mouse models of MYO7A, precluding isolated loss-of-function analyses.
Our study provided evidence that MYO7A is the molecular motor that tensions the MET complex. We further discovered that MYO7A is expressed in two major isoforms with unique N-terminal extensions. These isoforms are differentially expressed in inner and outer hair cells (IHCs and OHCs), correlating with reported differences in tip-link tension. This differential expression pattern of MYO7A isoforms with distinct motor properties might contribute to the tip-link tension variability in different population of hair cells, with potential importance for establishing the remarkable frequency range of mammalian hearing. Last, we identified novel regulatory elements for Myo7a expression, providing the mechanism of the differential expression pattern of MYO7A isoforms in auditory hair cells.