Journal article
Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line
Journal of the Association for Research in Otolaryngology, Vol.14(5), pp.645-659
10/2013
Handle:
https://hdl.handle.net/2376/105563
PMCID: PMC3767879
PMID: 23821348
Abstract
Sensorineural hearing loss is a normal consequence of aging and results from a variety of extrinsic challenges such as excessive noise exposure and certain therapeutic drugs, including the aminoglycoside antibiotics. The proximal cause of hearing loss is often death of inner ear hair cells. The signaling pathways necessary for hair cell death are not fully understood and may be specific for each type of insult. In the lateral line, the closely related aminoglycoside antibiotics neomycin and gentamicin appear to kill hair cells by activating a partially overlapping suite of cell death pathways. The lateral line is a system of hair cell-containing sense organs found on the head and body of aquatic vertebrates. In the present study, we use a combination of pharmacologic and genetic manipulations to assess the contributions of p53, Bax, and Bcl2 in the death of zebrafish lateral line hair cells. Bax inhibition significantly protects hair cells from neomycin but not from gentamicin toxicity. Conversely, transgenic overexpression of Bcl2 attenuates hair cell death due to gentamicin but not neomycin, suggesting a complex interplay of pro-death and pro-survival proteins in drug-treated hair cells. p53 inhibition protects hair cells from damage due to either aminoglycoside, with more robust protection seen against gentamicin. Further experiments evaluating p53 suggest that inhibition of mitochondrial-specific p53 activity confers significant hair cell protection from either aminoglycoside. These results suggest a role for mitochondrial p53 activity in promoting hair cell death due to aminoglycosides, likely upstream of Bax and Bcl2.
Metrics
5 Record Views
Details
- Title
- Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line
- Creators
- Allison B Coffin - Virginia Merrill Bloedel Hearing Research Center, University of Washington, Box 357923, Seattle, WA 98195 USAEdwin W Rubel - Virginia Merrill Bloedel Hearing Research Center, University of Washington, Box 357923, Seattle, WA 98195 USADavid W Raible - Virginia Merrill Bloedel Hearing Research Center, University of Washington, Box 357923, Seattle, WA 98195 USA
- Publication Details
- Journal of the Association for Research in Otolaryngology, Vol.14(5), pp.645-659
- Academic Unit
- Integrative Physiology and Neuroscience, Department of
- Publisher
- Springer US; Boston
- Identifiers
- 99900546788101842
- Language
- English
- Resource Type
- Journal article