CDH23

Abstract: Hair cells of the inner ear are so-called because of the hair-like projections, or stereocilia, that protrude from their apical surface. Sound-induced stereocilial motion is thought to be coupled to mechanoelectrical transduction channels via the 'tip links' that connect stereocilia to one another. Kazmierczak et al. now report the composition of mammalian tip links. They are formed by the interaction of two members of the family of calcium-dependent cell adhesion proteins, cadherin and protocadherin 15. Interestingly, mutation of these cadherins causes deafness in humans and one such mutation disrupts the interaction between the two molecules. Hair cells of the inner ear have stereocilia that protrude from their apical surface. Sound-induced stereocilial motion is thought to be coupled to mechanoelectrical transduction channels by means of the 'tip links' that connect stereocilia to one another. This paper reports the composition of mammalian tip links cadherin 23 and protocadherin 15 and show how the two molecules interact. Interestingly, mutation of these cadherins causes deafness in humans. Hair cells of the inner ear are mechanosensors that transduce mechanical forces arising from sound waves and head movement into electrochemical signals to provide our sense of hearing and balance. Each hair cell contains at the apical surface a bundle of stereocilia. Mechanoelectrical transduction takes place close to the tips of stereocilia in proximity to extracellular tip-link filaments that connect the stereocilia and are thought to gate the mechanoelectrical transduction channel1,2,3. Recent reports on the composition4,5,6,7,8, properties and function9,10,11 of tip links are conflicting29. Here we demonstrate that two cadherins that are linked to inherited forms of deafness in humans12,13,14,15 interact to form tip links. Immunohistochemical studies using rodent hair cells show that cadherin 23 (CDH23) and protocadherin 15 (PCDH15) localize to the upper and lower part of tip links, respectively. The amino termini of the two cadherins co-localize on tip-link filaments. Biochemical experiments show that CDH23 homodimers interact in trans with PCDH15 homodimers to form a filament with structural similarity to tip links. Ions that affect tip-link integrity and a mutation in PCDH15 that causes a recessive form of deafness16 disrupt interactions between CDH23 and PCDH15. Our studies define the molecular composition of tip links and provide a conceptual base for exploring the mechanisms of sensory impairment associated with mutations in CDH23 and PCDH15.

Abstract: GENETIC deafness is common, affecting about 1 in 2,000 births1. Many of these show primary abnormalities of the sensory neuro-epithelia of the inner ear, as do several hearing-impaired mouse mutants, suggesting that genes involved in sensory transduction could be affected. Here we report the identification of one such gene, the mouseshaker-1(shl) gene. Shaker-1 homozygotes show hyperactivity, head-tossing and circling due to vestibular dysfunction, together with typical neuroepithelial-type cochlear defects involving dysfunction and progressive degeneration of the organ of Corti2–7. The shl gene encodes an unconventional myosin molecule of the type VII family. Three mutations are described, two mis-sense mutations and a splice acceptor site mutation, all in the region encoding the myosin head. The myosin type VII molecule encoded byshl is the first molecule to be identified that is known, by virtue of its mutations, to be involved in auditory transduction.

Abstract: 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 microfilaments, 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.