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

Cisplatin/toxicity
DNA Primers/genetics
Cell Death/drug effects
Cell Death/genetics
Aminoglycosides/antagonists & inhibitors
Aminoglycosides/toxicity
Animals
Hair Cells, Auditory, Inner/cytology*
Hair Cells, Auditory, Inner/drug effects
Hair Cells, Auditory, Inner/physiology*
Humans
Hearing Loss/etiology
Hearing Loss/genetics
Hearing Loss/prevention & control
Point Mutation
Drug Evaluation, Preclinical
Zebrafish/anatomy & histology*
Zebrafish/genetics*
Zebrafish/physiology
Epistasis, Genetic
Mice
DNA, Complementary/genetics
Codon, Terminator/genetics
Base Sequence
Saccule and Utricle/drug effects
Saccule and Utricle/pathology
Neomycin/antagonists & inhibitors
Neomycin/toxicity
Thiophenes/chemistry
Thiophenes/pharmacology

(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

Show all Figures

Expression

Gene	Antibody	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
cc2d2a		AB	standard conditions	Pec-fin		whole organism	ISH	Fig. S2
cc2d2a		cc2d2a^w38/w38 (AB)	standard conditions	Pec-fin		whole organism	ISH	Fig. S2

1 - 2 of 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment: cisplatin	Day 5	neuromast hair cell decreased amount, abnormal	Fig. 9
AB	chemical treatment: drug, chemical treatment: cisplatin	Day 5	neuromast hair cell decreased amount, abnormal	Fig. 9
AB	chemical treatment: neomycin	Day 5	neuromast hair cell decreased amount, abnormal	Fig. S1
AB	chemical treatment: neomycin	Day 5	neuromast hair cell decreased amount, abnormal	Fig. 3
AB	chemical treatment: neomycin	Day 5	neuromast hair cell decreased amount, abnormal	Fig. 7
AB	chemical treatment: neomycin	Day 5	neuromast hair cell decreased amount, abnormal	Fig. 4
AB	chemical treatment: neomycin	Day 5	neuromast hair cell decreased amount, abnormal	Fig. 5
AB	chemical treatment: neomycin	Days 7-13	neuromast hair cell decreased amount, abnormal	Fig. S1
AB	chemical treatment: neomycin, chemical treatment: drug	Day 5	neuromast hair cell amount, ameliorated	Fig. 7
bne^w41/w41 (AB)	chemical treatment: neomycin	Day 5	neuromast hair cell amount, ameliorated	Fig. 4

1 - 10 of 25

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Mutations / Transgenics

Allele	Type	Affected Genomic Region
w38	Point Mutation	cc2d2a
w39	Point Mutation	slc4a1b
w40	Point Mutation	gcm2
w41	Unknown	bne
w42	Unknown	tmn

Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
AB
bne^w41/w41 (AB)
cc2d2a^w38/w38 (AB)
gcm2^w40/w40 (AB)
slc4a1b^w39/w39 (AB)
tmn^w42/w42 (AB)
WT

Antibodies

Orthology

Gene	Orthology
cc2d2a

Engineered Foreign Genes

Mapping

Entity Type	Entity Symbol	Location
Feature	w38	Chr: 23 Details
SSLP	z3794	Chr: 23 Details
SSLP	z44679	Chr: 23 Details

Owens et al., 2008 ZDB-PUB-080506-9 PMID:18454195

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

Owens et al., 2008

ZDB-PUB-080506-9
PMID:18454195