Abstract
SUMMARYMutations in human GRXCR2, which encodes a protein of undetermined function, cause hearing loss by unknown mechanisms. We found that mouse GRXCR2 localizes to the base of the stereocilia, which are actin-based mechanosensing organelles in cochlear hair cells that convert sound-induced vibrations into electrical signals. The stereocilia base also contains taperin, another protein of unknown function required for human hearing. We show that taperin and GRXCR2 form a complex and that taperin is diffused throughout the stereocilia length in Grxcr2-deficient hair cells. Stereocilia lacking GRXCR2 are longer than normal and disorganized due to the mislocalization of taperin, which could modulate the actin cytoskeleton in stereocilia. Remarkably, reducing taperin expression levels could rescue the morphological defects of stereocilia and restore the hearing of Grxcr2-deficient mice. Thus, our findings suggest that GRXCR2 is critical for the morphogenesis of stereocilia and auditory perception by restricting taperin to the stereocilia base.
Highlights
Human sensorineural hearing loss, the most common form of deafness, is often caused by defects in stereocilia (Barr-Gillespie, 2015; Richardson et al, 2011)
GRXCR2 Is Concentrated at the Base of the Stereocilia, and Grxcr2-Deficient Mice Are Deaf GRXCR2 mutation has been linked to hearing loss in humans (Imtiaz et al, 2014)
By 1 month of age, most Grxcr2D46/D46taperinIn103/+ hair cells had a classical V-shaped hair bundle, while occasional hair cell loss occurred in Grxcr2D46/D46taperinIn103/In103 mice (Figure 6B). These results demonstrate that stereocilia defects in the Grxcr2 mutant are caused by the mislocalization of taperin because reducing taperin expression rescued stereocilia morphology
Summary
The most common form of deafness, is often caused by defects in stereocilia (Barr-Gillespie, 2015; Richardson et al, 2011). Found on sensory hair cells in the inner ear, stereocilia are the mechanically sensitive, actin-based protrusions responsible for converting force from sound waves into electrical signals (Fettiplace and Kim, 2014; Gillespie and Mu€ller, 2009; Hudspeth, 2008). This function depends on the organization and morphology of stereocilia. Several stereocilia form a bundle organized into rows of decreasing height. Stereocilia are stiff due to a core of tightly cross-linked actin filaments, but they can flex at the base where the structure narrows in a taper region that is anchored by rootlet filaments (Figure 1A) (Barr-Gillespie, 2015)
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