Unraveling cadherin 23's role in development and mechanotransduction

The inner ear's sensory cells, the hair cells, mediate mechanotransduction, which enables us to experience sound and movements of the head. Protruding from the apical portion of a hair cell, a hair bundle is formed from actin-rich stereocilia, which are arrayed with increasing length in a staircase formation; mechanical stimuli that deflect the bundle toward the tallest stereocilia open cation-selective transduction channels and initiate mechanotransduction. Integral for the sensing of mechanical tension, a filamentous structure called the tip link spans from the tip of one stereocilium to the side of the next taller one. The molecular identity of the tip link has been hotly debated by the hair-cell field, and the article by Schwander et al. (1) in this issue of PNAS provides a significant step toward a final settlement of this issue. To appreciate the full ramifications of this study and understand the different layers of possible conclusions, it makes sense to step back and recall what we know about tip links. A mechanical stimulus such as sound is transmitted within the inner ear to hair cells and causes the bundle to tilt back and forth. The stereocilia are arranged so that a tilt in the excitatory direction causes the tip links to be pulled taut, at which point transduction channels at the base of the tip link (2) open and allow cations to flow into the hair cell (Fig. 1). Genetic evidence in zebrafish and mouse (3–6), in combination with localization and in vitro interaction studies (7), suggested that 2 extracellular adhesion proteins, cadherin 23 (CDH23) and protocadherin 15 (PCDH15), constitute the tip link. According to this model, …