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S. E. Brockerhoff, N. Wilson, G. Stearns, A. Lewis; A Zebrafish Mutation Identifies Nonclassic Cadherins as Critical Modulators of Outer Retina Physiology. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4799.
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© ARVO (1962-2015); The Authors (2016-present)
We use zebrafish as a model organism to study cone photoreceptor biology with the long term goal of applying information learned to dissecting the molecular basis of human retinal disease. In this study, we describe the characterization of a novel mutation, zvm7.
zvm7 larvae were identified in a three-generation screen for ENU-induced recessive mutations disrupting the optokinetic response (OKR). Positional/candidate cloning methods, electroretinogram (ERG) recordings, in situ hybridization, immunocytochemistry, and live imaging were done using standard published protocols.
The zvm 7 mutation is recessive and lethal. Zebrafish larvae containing the zvm7 mutation die at 8-10 days postfertilization (dpf). The larvae appear morphologically normal until 6 dpf but acquire a curved tail after this stage. Although mutant larvae lack an OKR starting at 4 dpf, the ERG appears normal at 5 dpf. However, at 6dpf a supernormal ERG with a b-wave amplitude approximately twice that of wild type response is consistently observed in mutants. Isolation and analysis of the a-wave using the metabotropic glutamate agonist 2-amino-4-phosphonbutyric acid (APB), reveals a normal a-wave in mutants at 6dpf. Positional cloning identified a stop codon in an ortholog of nonclassic-type cadherins of the flamingo subfamily. RNA and protein localization as well as live imaging studies are underway and will be described.
The zvm7 mutation identifies nonclassic cadherins as critical modulators of signaling in the outer retina. The function of zvm7 has not been previously analyzed in the vertebrate retina. Mutations in this subfamily in mice cause early embryonic lethal phenotypes. We hypothesize that we have uncovered a late stage phenotype for zvm7 because zebrafish develop rapidly and contain maternally transmitted wild type RNA. When maternal RNA is depleted, loss-of-function phenotypes are uncovered. Late stage phenotypes of other genes have also been discovered in zebrafish for this reason. This fortuitous situation provides the opportunity to study the function of the Zvm7 protein in modulating the physiology of the outer retina.
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