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Updated: May 10, 2026
An Assay for Lateral Line Regeneration in Adult Zebrafish
Published on: April 8, 2014
Bax, Bcl2, and p53 differentially regulate neomycin- and gentamicin-induced hair cell death in the zebrafish lateral
Allison B Coffin1, Edwin W Rubel, David W Raible
1Virginia Merrill Bloedel Hearing Research Center, University of Washington, Box 357923, Seattle, WA, 98195, USA, Allison.coffin@wsu.edu.
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.
Insights
Aminoglycoside antibiotics can cause hearing loss by damaging inner ear hair cells. Mitochondrial p53 activity appears to promote this hair cell death, offering a potential therapeutic target.
Area of Science:
- Ototoxicity research
- Cellular biology
- Molecular mechanisms of hearing loss
Background:
- Sensorineural hearing loss, often age-related, stems from factors like noise and ototoxic drugs (e.g., aminoglycosides).
- Inner ear hair cell death is a primary cause of hearing loss, but the specific cell death pathways remain unclear.
- Aminoglycosides like neomycin and gentamicin trigger overlapping cell death pathways in aquatic vertebrate lateral line hair cells.
Purpose of the Study:
- To investigate the roles of p53, Bax, and Bcl2 in zebrafish lateral line hair cell death induced by neomycin and gentamicin.
- To determine if inhibiting specific proteins or pathways can protect hair cells from aminoglycoside-induced toxicity.
Main Methods:
- Utilized pharmacologic inhibitors and genetic manipulations in zebrafish.
- Assessed the impact of inhibiting p53, Bax, and Bcl2 on hair cell survival.
- Investigated the role of mitochondrial-specific p53 activity in aminoglycoside-induced hair cell death.
Main Results:
- Bax inhibition protected against neomycin but not gentamicin.
- Bcl2 overexpression protected against gentamicin but not neomycin.
- p53 inhibition, particularly targeting mitochondrial p53, protected hair cells from both neomycin and gentamicin, suggesting a role upstream of Bax and Bcl2.
Conclusions:
- Mitochondrial p53 activity plays a significant role in promoting hair cell death following aminoglycoside exposure.
- The interplay between Bax and Bcl2 is differentially affected by neomycin and gentamicin.
- Targeting mitochondrial p53 presents a potential strategy for preventing aminoglycoside-induced hearing loss.
