Top, an entire bundle with a staircase pattern of stereociliary organization. (D) A hair bundle shown by scanning electron microscopy. βIII tubulin (red) labels calyx afferents of type I hair cells. Phalloidin signal (green) indicates actin bundles in stereocilia. (C) Type I (I) and type II (II) hair cells in the murine utricular extrastriola shown by immunofluorescence. The organ of Corti has one row of inner hair cells (IHCs) and three rows of outer hair cells (OHCs). (B) Top view of the murine organ of Corti shown by scanning electron microscopy. The vestibular system includes the utricle, saccule and semicircular canal ampullae (Right). It contains the cochlea and vestibular system. The inner ear is the most inner part of the ear (Left). (A) The position and structure of the inner ear. Inner ear anatomy and mechanoelectrical transduction (MET). Influx of cations leads to membrane potential changes, thereby converting the mechanical stimuli into electrical responses ( Figure 1E), a process referred to as mechanoelectrical transduction (MET). Responding to sound, movement or gravity, the hair bundle deflects in the excitatory direction toward the longest stereocilia, which induces the opening of ion channels at the tip of shorter stereocilia. Each hair bundle consists of well-organized, actin-based stereocilia graded in lengths and a long microtubule-based kinocilium, although the latter is missing in mature mammalian cochlear hair cells. In both cochlear and vestibular systems, hair cells are neurons possessing a specialized mechanosensitive structure, the hair bundle, on their cellular apices ( Figure 1D). Two types of hair cells, named I and II, exist in these vestibular sensory organs ( Figure 1C). The vestibular system includes the utricle and saccule for detection of linear acceleration as well as semicircular canal ampullae for detection of angular acceleration ( Figure 1A).
OHCs receive and amplify sound-evoked vibrations of the sensory epithelium, whereas IHCs convert the amplified mechanical signals into electrical responses. In the cochlea, the organ of Corti, the main sound-sensitive structure, has three rows of outer hair cells (OHCs) and one row of inner hair cells (IHCs) ( Figure 1B). The inner ear contains the cochlea and vestibular system for sensing sounds and position changes, respectively ( Figure 1A). In mammals, the inner ear and retina are the two sensory organs responsible for hearing, balance and vision. In this review, we focus on the most recent discoveries in the field with an emphasis on USH genes, protein complexes and functions in various tissues as well as progress toward therapeutic development for USH. Despite the unavailability of a cure, progress has been made to develop effective treatments for this disease. Although their exact functions remain enigmatic in the retina, USH proteins are required for the development, maintenance and function of hair bundles, which are the primary mechanosensitive structure of inner ear hair cells. Studies on the proteins encoded by these USH genes suggest that USH proteins interact among one another and function in multiprotein complexes in vivo. Among them, twelve have been identified as causative genes and one as a modifier gene. Sixteen loci have been reported to be involved in the occurrence of USH and atypical USH. USH is classified into three types, based on the hearing and vestibular symptoms observed in patients. Usher syndrome (USH), clinically and genetically heterogeneous, is the leading genetic cause of combined hearing and vision loss.
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