Photoreceptors are highly specialized light-sensitive cells of the retina, essential for visual perception. The loss of photoreceptors in the human eye due to genetic causes is a frequent cause of blindness. Although a lot of effort has been devoted to the studies of the photoreceptor cell, some essential aspects of its differentiaton and function remain poorly understood. In particular, molecular mechanisms that lead to the assembly of the sophisticated features of photoreceptor morphology, such as the photosensitive outer segment, remain to a large extend unknown. Defects of these mechanisms frequently cause photoreceptor death and lead to blindness in humans. A very productive way to gain insight into the genetic causes of photoreceptor degeneration in the human eye is to study animal models of photoreceptor loss. The zebrafish is one of the leading animal models used to study the genetic causes of retinal disease. Using a mutagenesis approach in zebrafish, we have identified and characterized several mutations that lead to photoreceptor death. A newly discovered mutation, jj203, causes a loss of rod photoreceptors and a delay in the differentiation of cone outer segments. We characterized the molecular nature of the jj203 locus and found that it encodes a molecular motor, kinesin. This analysis demonstrated for the first time that kinesins function differently in rods and cones, raising important questions regarding their cargo specificity and the interaction with ciliary transport machinery. We are planning to characterize the role of kinesins in photoreceptor differentiation and survival using chemically-induced mutant alleles recovered both via forward and reverse genetic approaches. We will ask what aspects of photoreceptor phenotype are affected in different kinesin mutants and whether different kinesins can substitute each other. We will also study how kinesins interact with the intraflagellar transport, a process essential for outer segment formation. These studies will provide fundamental insights into the molecular mechanisms that drive photoreceptor differentiation.
We will use animal model, the zebrafish, to study genes responsible for the differentiation of vertebrate, including human, photoreceptor cells. These studies will reveal mechanisms that contribute to photoreceptor degeneration in the human eye, and consequently blindness.
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