Reduced climbing and increased slipping adaptation in cochlear hair cells of mice with Myo7a mutations

Kros, CJ; Marcotti, Walter; Netten, van Sietse; Self, TJ; Libby, Richard T.; Brown, Sdm; Richardson, G. P.; Steel, KP

doi:10.1038/nn784

Cited by 234 publications

(208 citation statements)

References 45 publications

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“…CDH23, PCDH15, and MYO7A are also expressed in mature hair cells (the mature expression pattern for harmonin and sans has yet to be determined). As tip-link proteins, CDH23 and PCDH15 are thought to gate transduction channels, whereas MYO7A contributes to channel adaptation (45). Missense mutations in the genes for MYO7A and PCDH15, similar to the salsa mutation in CDH23, might also affect tip-link function without effects on hair cell development.…”

Section: Discussionmentioning

confidence: 99%

A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

Schwander

Xiong

Tokita

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Deafness is the most common form of sensory impairment in humans and is frequently caused by single gene mutations. Interestingly, different mutations in a gene can cause syndromic and nonsyndromic forms of deafness, as well as progressive and age-related hearing loss. We provide here an explanation for the phenotypic variability associated with mutations in the cadherin 23 gene (CDH23). CDH23 null alleles cause deaf-blindness (Usher syndrome type 1D; USH1D), whereas missense mutations cause nonsyndromic deafness (DFNB12). In a forward genetic screen, we have identified salsa mice, which suffer from hearing loss due to a Cdh23 missense mutation modeling DFNB12. In contrast to waltzer mice, which carry a CDH23 null allele mimicking USH1D, hair cell development is unaffected in salsa mice. Instead, tip links, which are thought to gate mechanotransduction channels in hair cells, are progressively lost. Our findings suggest that DFNB12 belongs to a new class of disorder that is caused by defects in tip links. We propose that mutations in other genes that cause USH1 and nonsyndromic deafness may also have distinct effects on hair cell development and function.cadherin 23 ͉ Cdh23 ͉ Usher syndrome ͉ progressive hearing loss

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Section: Discussionmentioning

confidence: 99%

A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

Schwander

Xiong

Tokita

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Myosin VIIa is localized throughout the hair bundle and cell body, but its precise role in hair cells remains controversial. Nonetheless, it is clear that myosin VIIa plays a critical role in hair bundle structure and function 44 and probably performs other important tasks elsewhere. Indeed, mutations in myosin VIIa cause both dominant and recessive forms of deafness including, Usher's syndrome type 1B which is characterized by deafness, balance disorders and blindness.…”

Section: Expression Of Deafness Genesmentioning

confidence: 99%

An in vitro model system to study gene therapy in the human inner ear

et al. 2007

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The confined fluid-filled labyrinth of the human inner ear presents an opportunity for introduction of gene therapy reagents designed to treat hearing and balance dysfunction. Here we present a novel model system derived from the sensory epithelia of human vestibular organs and show that the tissue can survive up to 5 days in vitro. We generated organotypic cultures from 26 human sensory epithelia excised at the time of labyrinthectomy for intractable Meniere's disease or vestibular schwannoma. We applied multiply deleted adenoviral vectors at titers between 10 5 and 10 8 viral particles/ml directly to the cultures for 4-24 h and examined the tissue 12-96 h post-transfection. We noted robust expression of the exogenous transgene, green fluorescent protein (GFP), in hair cells and supporting cells suggesting both were targets of adenoviral transfection. We also transfected cultures with a vector that carried the genes for GFP and KCNQ4, a potassium channel subunit that causes dominant-progressive hearing loss when mutated. We noted a positive correlation between GFP fluorescence and KCNQ4 immunolocalization. We conclude that our in vitro model system presents a novel and effective experimental paradigm for evaluation of gene therapy reagents designed to restore cellular function in patients who suffer from inner ear disorders.

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“…Nevertheless, the adaptation motor may play other essential roles besides mediating slow adaptation, including setting the resting tension applied to the transduction channels (Gillespie and Corey 1997; Steyger et al 1998; Gillespie and Walker 2001). Alternatively, maintenance of resting tension may be set in cochlear hair cells by another isozyme, such as myosin-VIIa (Kros et al 2002).…”

Section: Myosin-ic and Adaptationmentioning

confidence: 99%

Myosin-I Isozymes in Neonatal Rodent Auditory and Vestibular Epithelia

Dumont

Zhao

Holt

et al. 2002

JARO - Journal of the Association for Research in Otolaryngolog

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Myosin isozymes are essential for hair cells, the sensory cells of the inner ear. Because a myosin-I subfamily member may mediate adaptation of mechanoelectrical transduction, we examined expression of all eight myosin-I isozymes in rodent auditory and vestibular epithelia. Using RT-PCR, we found prominent expression of three isozymes, Myo1b (also known as myosin-Ia or myr 1), Myo1c (myosin-Ib or myr 2), and Myo1e (myr 3). By contrast, Myo1a (brush-border myosin-I), Myo1d (myosin lc or myr 4), Myo1f, Myo1g, and Myo1h were less readily ampli®ed. Because sequence analysis demonstrated that the RT-PCR products encoded the appropriate isozymes, this represents the ®rst demonstration of expression of all eight mouse myosin-I genes. Using immunocytochemistry with isozyme-selective antibodies, we found that Myo1b was located at apical surfaces of supporting cells that surround hair cells in auditory epithelia of postnatal rats. In vestibular epithelia, Myo1b was present in a ring within the apical pole of the hair cell. In both cases, expression was prominent only immediately after birth. Myo1e was found in hair cells of the auditory and vestibular epithelia; this isozyme was enriched in the cuticular plate, the actin meshwork that anchors the stereocilia. Myo1c was found in hair-cell stereocilia, concentrated towards their tips; we con®rmed this localization by using adenovirus vectors to direct expression of a GFP-Myo1c tail fusion protein; this fusion protein localized to plasma membranes, often concentrating at stereociliary tips. Myo1c therefore remains the myosin isozyme best localized to carry out transducer adaptation.

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Reduced climbing and increased slipping adaptation in cochlear hair cells of mice with Myo7a mutations

Cited by 234 publications

References 45 publications

A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

An in vitro model system to study gene therapy in the human inner ear

Myosin-I Isozymes in Neonatal Rodent Auditory and Vestibular Epithelia

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