Myosin VIIA Is Required for Aminoglycoside Accumulation in Cochlear Hair Cells

Richardson, G. P.; Forge, Andrew; Kros, Corné J.; Fleming, J.; Brown, Sdm; Steel, Karen P.

doi:10.1523/jneurosci.17-24-09506.1997

Cited by 151 publications

(120 citation statements)

References 57 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…Hence, it appears unlikely that the SC death is the result of a direct aminoglycoside-induced toxicity to the SCs themselves (Aran et al 1995;Richardson et al 1997Richardson et al , 1999. With our kanamycin-furosemide lesion paradigm, where OHCs are preferentially lost throughout the cochlea, we observed that SCs do not appear to degenerate markedly by 1 to 3 months post-lesion.…”

Section: Support Cell Degeneration After Hc Lossmentioning

confidence: 68%

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

Oesterle

Campbell

Taylor³

et al. 2007

JARO

219

245

View full text Add to dashboard Cite

Inner ear hair cells detect environmental signals associated with hearing, balance, and body orientation. In humans and other mammals, significant hair cell loss leads to irreversible hearing and balance deficits, whereas hair cell loss in nonmammalian vertebrates is repaired by the spontaneous generation of replacement hair cells. Research in mammalian hair cell regeneration is hampered by the lack of in vivo damage models for the adult mouse inner ear and the paucity of cell-type-specific markers for nonsensory cells within the sensory receptor epithelia. The present study delineates a protocol to drug damage the adult mouse auditory epithelium (organ of Corti) in situ and uses this protocol to investigate Sox2 and Jagged1 expression in damaged inner ear sensory epithelia. In other tissues, the transcription factor Sox2 and a ligand member of the Notch signaling pathway, Jagged1, are involved in regenerative processes. Both are involved in early inner ear development and are expressed in developing support cells, but little is known about their expressions in the adult. We describe a nonsurgical technique for inducing hair cell damage in adult mouse organ of Corti by a single high-dose injection of the aminoglycoside kanamycin followed by a single injection of the loop diuretic furosemide. This drug combination causes the rapid death of outer hair cells throughout the cochlea. Using immunocytochemical techniques, Sox2 is shown to be expressed specifically in support cells in normal adult mouse inner ear and is not affected by drug damage. Sox2 is absent from auditory hair cells, but is expressed in a subset of vestibular hair cells. Double-labeling experiments with Sox2 and calbindin suggest Sox2-positive hair cells are Type II. Jagged1 is also expressed in support cells in the adult ear and is not affected by drug damage. Sox2 and Jagged1 may be involved in the maintenance of support cells in adult mouse inner ear.

show abstract

Section: Support Cell Degeneration After Hc Lossmentioning

confidence: 68%

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

Oesterle

Campbell

Taylor³

et al. 2007

JARO

219

245

View full text Add to dashboard Cite

show abstract

“…It is well known in both the zebrafish lateral line and the mammalian inner ear that drugs and genes that interfere with the integrity of the transduction channel reduce or eliminate aminoglycoside ototoxicity (Richardson et al 1997;Gale et al 2001;Seiler and Nicolson 1999;Zheng and Gao 1999). To determine if our candidate drugs reduce neuromast hair cell sensitivity to neomycin by interfering with transduction, we tested the integrity of transduction by examining FM1-43 uptake.…”

Section: Texas-red Conjugated Gentamicin and Fm1-43 Uptake Studiesmentioning

confidence: 99%

Identification of FDA-Approved Drugs and Bioactives that Protect Hair Cells in the Zebrafish (Danio rerio) Lateral Line and Mouse (Mus musculus) Utricle

Cunningham

Francis

et al. 2009

JARO

106

105

View full text Add to dashboard Cite

The hair cells of the larval zebrafish lateral line provide a useful preparation in which to study hair cell death and to screen for genes and small molecules that modulate hair cell toxicity. We recently reported preliminary results from screening a small-molecule library for compounds that inhibit aminoglycoside-induced hair cell death. To potentially reduce the time required for development of drugs and drug combinations that can be clinically useful, we screened a library of 1,040 FDA-approved drugs and bioactive compounds (NINDS Custom Collection II). Seven compounds that protect against neomycin-induced hair cell death were identified. Four of the seven drugs inhibited aminoglycoside uptake, based on Texas-Red-conjugated gentamicin uptake. The activities of two of the remaining three drugs were evaluated using an in vitro adult mouse utricle preparation. One drug, 9-amino-1,2,3,4-tetrahydroacridine (tacrine) demonstrated conserved protective effects in the mouse utricle. These results demonstrate that the zebrafish lateral line can be used to screen successfully for drugs within a library of FDA-approved drugs and bioactives that inhibit hair cell death in the mammalian inner ear and identify tacrine as a promising protective drug for future studies.

show abstract

“…To examine whether transduction-channel closure prevents Myo1c binding in our in situ binding assay, we examined the ability of Myo1c-T701 to bind to the stereocilia in cochleas from Myo7a 6J mice, which harbor a mutation in myosin VIIa resulting in bundle abnormalities and transduction channels that are closed at rest (Richardson et al, 1997;Self et al, 1998;Gale et al, 2001;Kros et al, 2002). Cochlear hair cells from heterozygous Myo7a 6J animals exhibit normal bundle morphology; however, those from homozygous Myo7a 6J mice have severely disorganized hair bundles that are fragmented into several smaller units each comprised of variable numbers of individual stereocilia (Fig.…”

Section: Myo7amentioning

confidence: 99%

Stereociliary Myosin-1c Receptors Are Sensitive to Calcium Chelation and Absent from Cadherin 23 Mutant Mice

Phillips

Tong²,

Goodyear³

et al. 2006

J. Neurosci.

Self Cite

View full text Add to dashboard Cite

The identities of some of the constituents of the hair-cell transduction apparatus have been elucidated only recently. The molecular motor myosin-1c (Myo1c) functions in adaptation of the hair-cell response to sustained mechanical stimuli and is therefore an integral part of the transduction complex. Recent data indicate that Myo1c interacts in vitro with two other molecules proposed to be important for transduction: cadherin 23 (Cdh23), a candidate for the stereociliary tip link, and phosphatidylinositol 4,5-bisphosphate (PIP 2 ), which is abundant in the membranes of hair-cell stereocilia. It is not known, however, whether these interactions occur in hair cells. Using an in situ binding assay on saccular hair cells, we demonstrated previously that Myo1c interacts with molecules at stereociliary tips, the site of transduction, through sequences contained within its calmodulin (CaM)-binding neck domain, which can bind up to four CaM molecules. In the current study, we identify the second CaM-binding IQ domain as a region of Myo1c that mediates CaM-sensitive binding to stereociliary tips and to PIP 2 immobilized on a solid support. Binding of Myo1c to stereociliary tips of cochlear and vestibular hair cells is disrupted by treatments that break tip links. In addition, Myo1c does not bind to stereocilia from mice whose hair cells lack Cdh23 protein despite the presence of PIP 2 in the stereociliary membranes. Collectively, our data suggest that Myo1c and Cdh23 interact at the tips of hair-cell stereocilia and that this interaction is modulated by CaM.

show abstract

Myosin VIIA Is Required for Aminoglycoside Accumulation in Cochlear Hair Cells

Cited by 151 publications

References 57 publications

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

Identification of FDA-Approved Drugs and Bioactives that Protect Hair Cells in the Zebrafish (Danio rerio) Lateral Line and Mouse (Mus musculus) Utricle

Stereociliary Myosin-1c Receptors Are Sensitive to Calcium Chelation and Absent from Cadherin 23 Mutant Mice

Contact Info

Product

Resources

About