PUBLICATION

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Authors
Coffin, A.B., Rubel, E.W., and Raible, D.W.
ID
ZDB-PUB-130710-131
Date
2013
Source
Journal of the Association for Research in Otolaryngology : JARO   14(5): 645-59 (Journal)
Registered Authors
Raible, David
Keywords
aminoglycoside, ototoxicity, neuromast, hearing loss, Danio rerio
MeSH Terms
  • Animals
  • Cell Death/drug effects
  • Cell Death/physiology
  • Female
  • Gene Expression Regulation, Developmental
  • Gentamicins/toxicity
  • Hair Cells, Auditory/pathology*
  • Hair Cells, Auditory/physiology
  • Lateral Line System/embryology
  • Lateral Line System/pathology*
  • Male
  • Neomycin/toxicity
  • Protein Synthesis Inhibitors/toxicity
  • Proto-Oncogene Proteins c-bcl-2/genetics*
  • Proto-Oncogene Proteins c-bcl-2/metabolism
  • Tumor Suppressor Protein p53/genetics*
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • bcl-2-Associated X Protein/genetics*
  • bcl-2-Associated X Protein/metabolism
PubMed
23821348 Full text @ J. Assoc. Res. Otolaryngol.
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.

Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping