University of Virginia Health System

My laboratory studies the regulation of genes in retinal photoreceptors, with a focus on the genes involved in the many changes that occur in the retina in response to the time of day. This ability to temporally regulate physiology is not simply a response to light and dark, but is controlled by a circadian clock, an intrinsic component of vertebrate retinas. Although the molecular mechanism of circadian timing is not known, a common theme to clock function seems to be regulation at the level of gene expression. I have chosen to focus my research on the clock located in retinal photoreceptors in the African clawed frog, Xenopus laevis. These animals are particularly well suited to cellular and molecular analyses of retinal function. We have techniques for culturing Xenopus retinas such that the circadian clock remains functional and entrainable for many days in vitro. As part of a screen for rhythmic gene products, we recently identified a novel gene that is expressed specifically in Xenopus photoreceptors. This gene is transcriptionally active for only a few hours in the early night, producing peak mRNA levels at around 4 hours after dusk. This rhythmic expression occurs independently of the presence of light/dark cycles which indicates that it is transcriptionally regulated by an intrinsic circadian clock. This gene encodes a protein that we have named "nocturnin." The protein sequence is novel, but it contains a leucine zipper-like motif and a large region of similarity to a yeast transcription factor called CCR4. Based on this sequence analysis, our current hypothesis is that nocturnin may be dimerizing with another protein through its leucine zipper and functioning as a photoreceptor-specific transcription factor. We are currently studying both the function of the nocturnin protein within the retina and the mechanism by which the circadian clock regulates the expression of this gene to produce such striking rhythmicity. We are also studying the development of the photoreceptor clock in embryonic Xenopus and are currently working to generate transgenic Xenopus embryos to study the function and expression of nocturnin and other rhythmic gene products. Generation of transgenic lines expressing rhythmic reporters will further extend our studies by allowing real time analysis of gene expression in living embryos.

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http://www.med.virginia.edu/ed-programs/neuroscience/