Abstract
Stereocilia are actin-based cell protrusions on the apical surface of inner ear hair cells, playing a pivotal role in hearing and balancing sensation. The development and maintenance of stereocilia is tightly regulated and deficits in this process usually lead to hearing or balancing disorders. The Rho GTPase cell division cycle 42 (CDC42) is a key regulator of the actin cytoskeleton. It has been reported to localize in the hair cell stereocilia and play important roles in stereocilia maintenance. In the present work, we utilized hair cell-specific Cdc42 knockout mice and CDC42 inhibitor ML141 to explore the role of CDC42 in stereocilia development. Our data show that stereocilia height and width as well as stereocilia resorption are affected in Cdc42-deficient cochlear hair cells when examined at postnatal day 8 (P8). Moreover, ML141 treatment leads to planar cell polarity (PCP) deficits in neonatal hair cells. We also show that overexpression of a constitutively active mutant CDC42 in cochlear hair cells leads to enhanced stereocilia developmental deficits. In conclusion, the present data suggest that CDC42 plays a pivotal role in regulating hair cell stereocilia development.
Highlights
As the mechanosensitive receptor cells in the inner ear, hair cells are characterized by their hairylooking hair bundles, which consist of hundreds of actin-based stereocilia and one microtubulebased kinocilium on the apical surface of each cell (Flock and Cheung, 1977)
Hair Cell-Specific Cdc42 Inactivation Leads to Stereocilia Development Deficits
At postnatal day 0.5 (P0.5), the morphology of hair bundle is largely indistinguishable between Cdc42 cKO and control cochlear hair cells, with multiple rows of immature stereocilia protruding from the apical surface of hair cells (Figures 1A–C)
Summary
As the mechanosensitive receptor cells in the inner ear, hair cells are characterized by their hairylooking hair bundles, which consist of hundreds of actin-based stereocilia and one microtubulebased kinocilium on the apical surface of each cell (Flock and Cheung, 1977). The kinocilium is important for hair bundle development as well as planar cell polarity (PCP) establishment, while the stereocilia are essential for mechano-electrical transduction (MET), the process that converts mechanical signals into electrical signals (Lindeman et al, 1971; Hudspeth and Jacobs, 1979; Jones et al, 2008). The actin core of stereocilia consists of a bundle of cross-linked actin filaments (F-actin), with their barbed (plus) ends pointing toward the distal tips (Flock and Cheung, 1977; Tilney et al, 1980). The stereocilia start as short apical microvilli and develop into the final mature morphology by increasing the length and numbers of F-actin core Our present data suggest that CDC42 regulates hair cell stereocilia development both in a cell autonomous and nonautonomous manner
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