The circadian system regulates a multitude of essential rhythmic physiological processes in organisms ranging from cyanobacteria to humans. Studies during the past 10 years have demonstrated a remarkable conservation of the cellular mechanisms governing circadian periodicity in insects and mammals. This renewal application proposes studies of two Drosophila RNA-binding proteins, LARK and dFMRP, that have a role in the circadian control of behavior. Preliminary studies have identified potential target RNAs for the LARK and dFMRP proteins and certain proposed experiments will use molecular and genetic strategies to determine which targets are relevant, in vivo, for circadian functions. Most LARK target RNAs contain a novel A-rich consensus sequence element in the 3'UTR, and other experiments will test the hypothesis that LARK binds to this element to regulate the stability of targets. Such a function would provide a useful mechanism for the dynamic, clock-regulated control of RNAs encoding factors important for circadian control. It is hypothesized that LARK functions in a circadian output pathway, and genetic approaches will be employed to identify additional elements of this pathway that function with the RNA-binding protein to regulate rhythmic behaviors. The cellular requirements for LARK and dFMRP, with regard to circadian functions, have not been elucidated. Therefore, in a final set of proposed experiments, cell type-specific expression methods, together with RNA interference techniques, will be employed to perturb function and determine the neuronal sites of action for these RNA-binding proteins. Altogether, these proposed studies will contribute to a better understanding of how circadian clocks control organismal physiology. These proposed studies of circadian control mechanisms have considerable significance for an understanding of normal human physiology and for the etiology of pathophysiological conditions, such as jetlag and certain sleep/wake disorders that result from environmental or genetic perturbations of the circadian system. As one of the premier eukaryotic genetic models, Drosophila is an excellent experimental organism for conducting molecular genetic investigations of the circadian system. It is anticipated that the results of studies in Drosophila will provide important and general insights about the molecular mechanisms mediating circadian control.
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