The objective of this proposal is to develop comprehensive mutational screening methods to identify dominant visual system mutations in zebrafish. Dominant mutations that cause retinal degeneration have been found in many species. In humans, for example, approximately 40 percent of retinitis pigmentosa (RP, characterized by progressive retinal photoreceptor cell degeneration) are dominantly inherited. We know most about dominant RF where mutations have been found in the photoreceptor cell-specific rhodopsin or peripherin genes. However, it is estimated that at the present time only about half of the dominant RP cases can be accounted for by mutations so far discovered. Thus, our understanding of the genetic mechanisms of dominant RP is still only in its infancy. The best way to discover the remaining RP genes is to apply the mutational approach using other vertebrate organisms. To this end, we developed a behavioral assay, based on the visually mediated escape response of zebrafish to a threatening object, that permits a rapid mutant screening for visual system mutations in adult zebrafish. In a previous screening, we have isolated 7 dominant mutations that cause age-related retinal degeneration. In the years to come, we will extend our studies to screen the F 1 generation of ENU mutagenized zebrafish to isolate 1) retinal-specific dominant mutations, 2) gene alleles of night blindness a and night blindness b mutations, and 3) extragenic gene suppressors of night blindness c mutation. A combination of behavioral, genetic, and molecular screening will be used in these studies.
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