Forward genetic analysis of visual behavior in zebrafish.
The visual system converts the distribution and wavelengths of photons entering the eye into patterns of neuronal activity, which then drive motor and endocrine behavioral responses. The gene products important for visual processing by a living and behaving vertebrate animal have not been identified in an unbiased fashion. Likewise, the genes that affect development of the nervous system to shape visual function later in life are largely unknown. Here we have set out to close this gap in our understanding by using a forward genetic approach in zebrafish. Moving stimuli evoke two innate reflexes in zebrafish larvae, the optomotor and the optokinetic response, providing two rapid and quantitative tests to assess visual function in wild-type (WT) and mutant animals. These behavioral assays were used in a high-throughput screen, encompassing over half a million fish. In almost 2,000 F2 families mutagenized with ethylnitrosourea, we discovered 53 recessive mutations in 41 genes. These new mutations have generated a broad spectrum of phenotypes, which vary in specificity and severity, but can be placed into only a handful of classes. Developmental phenotypes include complete absence or abnormal morphogenesis of photoreceptors, and deficits in ganglion cell differentiation or axon targeting. Other mutations evidently leave neuronal circuits intact, but disrupt phototransduction, light adaptation, or behavior-specific responses. Almost all of the mutants are morphologically indistinguishable from WT, and many survive to adulthood. Genetic linkage mapping and initial molecular analyses show that our approach was effective in identifying genes with functions specific to the visual system. This collection of zebrafish behavioral mutants provides a novel resource for the study of normal vision and its genetic disorders.
Muto
Akira
A
Department of Physiology, Programs in Neuroscience, Genetics, and Developmental Biology, Center for Human Genetics, University of California, San Francisco, California, United States of America.
Orger
Michael B
MB
Wehman
Ann M
AM
Smear
Matthew C
MC
Kay
Jeremy N
JN
Page-McCaw
Patrick S
PS
Gahtan
Ethan
E
Xiao
Tong
T
Nevin
Linda M
LM
Gosse
Nathan J
NJ
Staub
Wendy
W
Finger-Baier
Karin
K
Baier
Herwig
H
D000818:Animals; D001369:Axons; D001522:Behavior, Animal; D005038:Ethylnitrosourea / Q000494:pharmacology; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D005821:Genetic Techniques; D016296:Mutagenesis; D009799:Ocular Physiological Phenomena; D010641:Phenotype; D010786:Photoreceptor Cells; D014785:Vision, Ocular; D015027:Zebrafish
D005038:Ethylnitrosourea