PUBLICATION

Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death

Authors
Owens, K.N., Santos, F., Roberts, B., Linbo, T., Coffin, A.B., Knisely, A.J., Simon, J.A., Rubel, E.W., and Raible, D.W.
ID
ZDB-PUB-080506-9
Date
2008
Source
PLoS Genetics   4(2): e1000020 (Journal)
Registered Authors
Linbo, Tor, Owens, Kelly, Raible, David
Keywords
none
MeSH Terms
  • Drug Evaluation, Preclinical
  • Base Sequence
  • Mice
  • Humans
  • Epistasis, Genetic
  • DNA Primers/genetics
  • Thiophenes/chemistry
  • Thiophenes/pharmacology
  • Codon, Terminator/genetics
  • Hearing Loss/etiology
  • Hearing Loss/genetics
  • Hearing Loss/prevention & control
  • Animals
  • Hair Cells, Auditory, Inner/cytology*
  • Hair Cells, Auditory, Inner/drug effects
  • Hair Cells, Auditory, Inner/physiology*
  • DNA, Complementary/genetics
  • Aminoglycosides/antagonists & inhibitors
  • Aminoglycosides/toxicity
  • Cisplatin/toxicity
  • Neomycin/antagonists & inhibitors
  • Neomycin/toxicity
  • Saccule and Utricle/drug effects
  • Saccule and Utricle/pathology
  • Point Mutation
  • Zebrafish/anatomy & histology*
  • Zebrafish/genetics*
  • Zebrafish/physiology
  • Cell Death/drug effects
  • Cell Death/genetics
(all 30)
PubMed
18454195 Full text @ PLoS Genet.
Abstract
Inner ear sensory hair cell death is observed in the majority of hearing and balance disorders, affecting the health of more than 600 million people worldwide. While normal aging is the single greatest contributor, exposure to environmental toxins and therapeutic drugs such as aminoglycoside antibiotics and antineoplastic agents are significant contributors. Genetic variation contributes markedly to differences in normal disease progression during aging and in susceptibility to ototoxic agents. Using the lateral line system of larval zebrafish, we developed an in vivo drug toxicity interaction screen to uncover genetic modulators of antibiotic-induced hair cell death and to identify compounds that confer protection. We have identified 5 mutations that modulate aminoglycoside susceptibility. Further characterization and identification of one protective mutant, sentinel (snl), revealed a novel conserved vertebrate gene. A similar screen identified a new class of drug-like small molecules, benzothiophene carboxamides, that prevent aminoglycoside-induced hair cell death in zebrafish and in mammals. Testing for interaction with the sentinel mutation suggests that the gene and compounds may operate in different pathways. The combination of chemical screening with traditional genetic approaches is a new strategy for identifying drugs and drug targets to attenuate hearing and balance disorders.
Genes / Markers
Figures
Figure Gallery (11 images) / 2
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Expression
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Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
w38
    Point Mutation
    w39
      Point Mutation
      w40
        Point Mutation
        w41
          Unknown
          w42
            Unknown
            1 - 5 of 5
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            No data available
            Fish
            Antibodies
            No data available
            Orthology
            Gene Orthology
            cc2d2a
            1 - 1 of 1
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            Engineered Foreign Genes
            No data available
            Mapping
            Entity Type Entity Symbol Location
            Featurew38Chr: 23 Details
            SSLPz3794Chr: 23 Details
            SSLPz44679Chr: 23 Details
            1 - 3 of 3
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