Inhibition of caspases prevents ototoxic and ongoing hair cell death.
Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.
Matsui
Jonathan I
JI
Central Institute for the Deaf, Fay and Carl Simons Center for Biology of Hearing and Deafness, Washington University School of Medicine, St. Louis, Missouri 63110, USA. jmatsui@cid.wustl.edu
Ogilvie
Judith M
JM
Warchol
Mark E
ME
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D017209:Apoptosis; D064032:Calbindin 2; D061945:Caspase Inhibitors; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002645:Chickens; D002843:Chromatin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D009355:Neomycin / Q000494:pharmacology; D009924:Organ Culture Techniques; D011500:Protein Synthesis Inhibitors / Q000633:toxicity; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D012444:Saccule and Utricle / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D000590:Amino Acid Chloromethyl Ketones; D000900:Anti-Bacterial Agents; D064032:Calbindin 2; D061945:Caspase Inhibitors; D002843:Chromatin; D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; D064030:S100 Calcium Binding Protein G; C103192:butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone; D009355:Neomycin