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

Kelly N Owens; Felipe Santos; Brock Roberts; Tor Linbo; Allison B Coffin; Anna J Knisely; Julian A Simon; Edwin W Rubel; David W Raible

doi:10.1371/journal.pgen.1000020

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

Journal article

Open access

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

Kelly N Owens, Felipe Santos, Brock Roberts, Tor Linbo, Allison B Coffin, Anna J Knisely, Julian A Simon, Edwin W Rubel and David W Raible

PLoS genetics, Vol.4(2), pp.e1000020-e1000020

02/29/2008

DOI: https://doi.org/10.1371/journal.pgen.1000020

Handle:

https://hdl.handle.net/2376/105311

PMCID: PMC2265478

PMID: 18454195

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https://doi.org/10.1371/journal.pgen.1000020View

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Abstract

Zebrafish - anatomy & histology

Codon, Terminator - genetics

Hearing Loss - etiology

Humans

DNA, Complementary - genetics

DNA Primers - genetics

Neomycin - toxicity

Hair Cells, Auditory, Inner - cytology

Hair Cells, Auditory, Inner - drug effects

Cisplatin - toxicity

Cell Death - genetics

Base Sequence

Neomycin - antagonists & inhibitors

Cell Death - drug effects

Drug Evaluation, Preclinical

Aminoglycosides - antagonists & inhibitors

Saccule and Utricle - drug effects

Saccule and Utricle - pathology

Thiophenes - pharmacology

Zebrafish - genetics

Hearing Loss - genetics

Point Mutation

Animals

Aminoglycosides - toxicity

Epistasis, Genetic

Zebrafish - physiology

Mice

Hair Cells, Auditory, Inner - physiology

Thiophenes - chemistry

Hearing Loss - prevention & control

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.

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Title: Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death
Creators: Kelly N Owens - Department of Biological Structure, University of Washington, Seattle, Washington, United States of America
Felipe Santos
Brock Roberts
Tor Linbo
Allison B Coffin
Anna J Knisely
Julian A Simon
Edwin W Rubel
David W Raible
Publication Details: PLoS genetics, Vol.4(2), pp.e1000020-e1000020
Academic Unit: Integrative Physiology and Neuroscience, Department of
Publisher: United States
Grant note: T32 DC000018 / NIDCD NIH HHS DC07244 / NIDCD NIH HHS DC00699 / NIDCD NIH HHS P30 DC004661 / NIDCD NIH HHS DC04661 / NIDCD NIH HHS F32 DC006998 / NIDCD NIH HHS DC0018 / NIDCD NIH HHS F32 DC007244 / NIDCD NIH HHS R01 DC005987 / NIDCD NIH HHS DC05987 / NIDCD NIH HHS
Identifiers: 99900547085101842
Language: English
Resource Type: Journal article