Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle

Abstract

contributed equally to this work Deaf-blindness in three distinct genetic forms of Usher type I syndrome (USH1) is caused by defects in myosin VIIa, harmonin and cadherin 23. Despite being critical for hearing, the functions of these proteins in the inner ear remain elusive. Here we show that harmonin, a PDZ domain-containing protein, and cadherin 23 are both present in the growing stereocilia and that they bind to each other. Moreover, we demonstrate that harmonin b is an F-actin-bundling protein, which is thus likely to anchor cadherin 23 to the stereocilia micro®laments, thereby identifying a novel anchorage mode of the cadherins to the actin cytoskeleton. Moreover, harmonin b interacts directly with myosin VIIa, and is absent from the disorganized hair bundles of myosin VIIa mutant mice, suggesting that myosin VIIa conveys harmonin b along the actin core of the developing stereocilia. We propose that the shaping of the hair bundle relies on a functional unit composed of myosin VIIa, harmonin b and cadherin 23 that is essential to ensure the cohesion of the stereocilia.

Progressive Hearing Loss and Increased Susceptibility to Noise-Induced Hearing Loss in Mice Carrying a Cdh23 but not a Myo7a Mutation

“…However, we do detect a phenotypic effect of a presumed 50% reduction in the amount of functional Cdh23 in the adult cochlea. It may be that Cdh23 elsewhere in the hair cell mediates the effects we see or that only small amounts of Cdh23 protein are present in mature stereocilia, below the detection limits of the technique used by Boeda et al (2002). Alternatively, in Cdh23 v heterozygotes, the stereocilia bundle may not attain maximum strength because of the proposed transient links being compromised during development.…”

“…These links are thought to be important in holding the stereocilia bundle together. Boeda et al (2002) recently reported that Cdh23 could not be detected in stereocilia of mice older than post natal day 30, suggesting that Cdh23 could be involved in crosslinking only developing stereocilia. However, we do detect a phenotypic effect of a presumed 50% reduction in the amount of functional Cdh23 in the adult cochlea.…”

“…Recently, Myo7a has been shown to interact with harmonin which in turn interacts with Cdh23 (Boeda et al 2002;Siemens et al 2002). All three proteins are present in the stereocilia, thus potentially placing Cdh23 and Myo7a in the same functional complex (Hasson et al 1997a;Boeda et al 2002).…”

“…Both genes have also been shown to underlie nonsyndromic forms of deafness (Liu et al 1997a,b;Weil et al 1997;Bork et al 2001). Recently, Myo7a and Cdh23 were both shown to bind to harmonin suggesting that these molecules form a functional complex within the stereocilia (Boeda et al 2002). Cdh23 may form links between adjacent stereocilia, with Myo7a anchoring the whole complex to the actin core (Di Palma et al 2001;Kros et al 2002).…”

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

“…In addition to the proteins directly involved in ion transport, there is increasing evidence that protein scaffolds play important roles in cochlear function (Verpy et al 2000;Davies et al 2001;Boeda et al 2002;Mburu et al 2003;Bao et al 2004;Belyantseva et al 2005;Kikkawa et al 2005). For example, the postsynaptic density of the 95-kDa-disc large-zona occludens-1 (PDZ) domain protein harmonin has been shown to anchor cadherin 23 to the stereocilia microfilaments and is thought to contribute to shaping the hair bundle (Boeda et al 2002).…”