Radixin deficiency causes deafness associated with progressive degeneration of cochlear stereocilia

Abstract

Ezrin/radixin/moesin (ERM) proteins cross-link actin filaments to plasma membranes to integrate the function of cortical layers, especially microvilli. We found that in cochlear and vestibular sensory hair cells of adult wild-type mice, radixin was specifically enriched in stereocilia, specially developed giant microvilli, and that radixin-deficient (Rdx − / −) adult mice exhibited deafness but no obvious vestibular dysfunction. Before the age of hearing onset (∼2 wk), in the cochlea and vestibule of Rdx − / − mice, stereocilia developed normally in which ezrin was concentrated. As these Rdx − / − mice grew, ezrin-based cochlear stereocilia progressively degenerated, causing deafness, whereas ezrin-based vestibular stereocilia were maintained normally in adult Rdx − / − mice. Thus, we concluded that radixin is indispensable for the hearing ability in mice through the maintenance of cochlear stereocilia, once developed. In Rdx − / − mice, ezrin appeared to compensate for radixin deficiency in terms of the development of cochlear stereocilia and the development/maintenance of vestibular stereocilia. These findings indicated the existence of complicate functional redundancy in situ among ERM proteins.

Postnatal developmental expression of the PDZ scaffolds Na+-H+ exchanger regulatory factors 1 and 2 in the rat cochlea

“…The temporal restriction of NHERF-1 and NHERF-2 expression in the immature hair cell stereocilia at P8 is consistent with developmental and transient expression in the hair cell stereocilia of other PDZ domain or binding proteins (e.g., ezrin, harmonin, and whirlin), which critically regulate development and morphogenesis (e.g., elongation) of cochlear stereocilia prior to the onset of hearing by binding target proteins such as myosin VIIa, cadherin 23, protocadherin 15, and Sans (Boeda et al 2002;Johnson et al 2003;Mburu et al 2003;Kitajiri et al 2004;Belyantseva et al 2005;Kikkawa et al 2005). The stereocilia are composed of bundles of actin filaments of which radixin is a prominent constituent (Kitajiri et al 2004). After P14, ezrin expression in the stereocilia is replaced by radixin, the deficiency of which causes deafness by the degeneration of stereocilia (Kitajiri et al 2004).…”

“…The stereocilia are composed of bundles of actin filaments of which radixin is a prominent constituent (Kitajiri et al 2004). After P14, ezrin expression in the stereocilia is replaced by radixin, the deficiency of which causes deafness by the degeneration of stereocilia (Kitajiri et al 2004). Therefore, the expression of ezrin correlates with NHERF-1 and NHERF-2 in the stereocilia during early postnatal development.…”

“…The rationale for the current study comes from the finding that the cochlea contains a number of proteins known to interact with NHERFs, plus numerous other proteins that have PDZ domains that could potentially interact with NHERFs. These cochlear proteins include NHE3 (Bond et al 1998), the ERM family (Kitajiri et al 2004), actin (Geal-Dor et al 1993;Nishida et al 1998), myosin (Boeda et al 2002;Johnson et al 2003;Mburu et al 2003;Kitajiri et al 2004;Belyantseva et al 2005;Kikkawa et al 2005), NBC3 (Bok et al 2003), P2Y1 (Teixeira et al 2000), β-adrenergic receptors (Fauser et al 2004), the vacuolar proton pump v-H + -ATPase (Stankovic et al 1997), Na + -K + ATPase (Ichimiya et al 1994;Erichsen et al 1996), growth factor receptors (Pickles and van Heumen 1997), glucocorticoid receptors (Erichsen et al 1996), TASK-1 background K + channels (Kanjhan et al 2004a), inwardly rectifying K + channels Kir1.1 (ROMK1) (Glowatzki et al 1995), Kir4.1 and Kir5.1 (Hibino et al 2004), aquaporin-4 (Mhatre et al 2002), glutamate transporter GLAST (Furness and Lehre 1997), and plasma membrane Ca 2+ -ATPase (Ichimiya et al 1994;Dumont et al 2001). …”

Model membranes to shed light on the biochemical and physical properties of ezrin/radixin/moesin

“…However, mice lacking radixin showed liver damage after 8 weeks [21]. In addition, radixin appeared to be important for the implementation of the architecture of cochlear stereocilia, but its absence was offset by other ERMs, including ezrin [22]. It seems the lack of radixin was compensated by other ERM.…”

Recruitment of Dbl by Ezrin and Dystroglycan Drives Membrane Proximal Cdc42 Activation and Filopodia Formation

“…Antisense knockdown of all three ERM proteins however, led to a decrease in cell surface protrusions and inhibited the ability of the cells to spread, suggesting a defect in the ability of these cells to rearrange their actin cytoskeleton effectively. 54 Interestingly whilst the moesin knockout mouse appeared normal the radixin knockout mouse had a structural defect in the auditory stereocilia 55 and the ezrin knockout shows defects in the retinal microvilli and intestinal villi 56,57 all actin-based protrusions which may have a link to aberrant GTPase regulation. Indeed, in Drosophila, mutation of the single ERM gene, Dmoesin, leads to a lethal phenotype which can be suppressed by halving the level of Rho or mimicked by overexpression of Rho.…”