Our goal is to understand the role of light-dark cycles and a photoreceptor circadian clock in the control of overt rhythmic physiology in the retina. This application capitalizes on the recent discovery that Period genes are critical to circadian rhythmicity and to light responses of the circadian clock. We will study the role of a light- and dopamine-responsive period gene (xPer2) in rhythmic retinal physiology. The model underlying the application is that xPer2 plays an important role in coordinating the effects of light-dark cycles with an endogenous clock. We will study (1) light- and dopamine-induced up-regulation of xPer2 in relationship to expression of other clock genes, (2) the consequences of over-expression of xPer2 in the photoreceptor-RPE complex using Xenopus transgenesis, and (3) transcriptional regulation of the xPer2 gene using nuclear run-on assays. A central hypothesis is that the protein product of the xPer2 gene interacts with other cycling components of the retinal circadian clock to mediate the phase resetting effects of light and dopamine. Disruption of these interactions in constant light is proposed to account for disruption of circadian rhythms and for known alterations in photoreceptor membrane turnover.
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