R Allada

..Future studies of pacemaker mechanisms and their control of physiology and behavior will likely continue to rely on forward genetics...

..These studies reveal a remarkable complexity to circadian pathways in this "simple" model organism...

..The finding of a dual function of CK2 in clocks and in UV responses supports the notion that clocks evolved to assist organisms in avoiding the mutagenic effects of daily sunlight...

..Taken together, these studies suggest an ancient origin for sleep and raise the possibility that model organism genetics may reveal the molecular mechanisms that guide sleep and wake...

..In this issue of Cell Metabolism, Xu et al. (2008) explore the fruit fly as a model system to examine the links between clocks, feeding, and metabolism...

..These effects are probably direct, as CK2alpha specifically phosphorylates Per in vitro. We propose that CK2 is an evolutionary link between the divergent circadian systems of animals, plants and fungi...

..The period lengthening effects in Tik heterozygotes are reduced in a tim(UL) mutant that disrupts a putative CK2 phosphorylation site. Together, these data indicate that TIM is an important mediator of CK2 effects on circadian rhythms...

..In addition, RDL is detectable most strongly on the large subset of PDF+ pacemaker neurons. These results suggest that GABAergic inhibition of arousal-promoting PDF neurons is an important mode of sleep-wake regulation in vivo...

..To address this question, we expressed a temperature-sensitive, dominant negative allele of the fly homolog of dynamin called shibire(ts1) (shi(ts1)), an active component in membrane vesicle scission...

..While other factors may contribute, these results indicate that persistent Clock induction is uniquely capable of broadly inducing ectopic rhythms even in adults, consistent with a special role at the top of a clock gene hierarchy...

..Molecular analysis suggests that CWO acts, in part, by repressing CLK target genes. We propose that CWO acts as a transcriptional and behavioral rhythm amplifier...

..Chemical ablation of the mushroom bodies also resulted in reduced sleep. These studies highlight a central role for the mushroom bodies in sleep regulation...

..gop is expressed most strongly in the dorsal brain in regions that lie in proximity to PDF-containing nerve terminals. Taken together, these studies implicate GOP as a PDF receptor in Drosophila...

..In na mutants, expression of potassium currents and the key neuropeptide PDF are elevated, the latter consistent with reduced release. These data implicate NA and the pacemaker neural network in controlling phase and rhythmicity...

..In Drosophila, the first loop has been well characterized and controls rhythmic period expression. In this issue of Cell, define a role for a transcriptional activator and a repressor in the second feedback loop...

..In many respects, mutation of these phosphorylation sites phenocopies mutation of the catalytic subunit of CK2. We propose that CK2 phosphorylation at these sites triggers PER nuclear localization...

..On the basis of our findings, we propose that CRY can gate PDF signaling to determine behavioral phase and network hierarchy...

..These studies define a key direct output circuit sufficient for multiple PDF dependent behaviors...

..The fruit fly Drosophila exhibits clock-driven activity increases that anticipate dawn and dusk and free-running rhythms under constant conditions. Flies also respond to the onset of light and dark with acute increases in activity...

..Taken together, these in vivo data implicate a central role of CK2alpha function in timing PER negative feedback in adult circadian neurons...

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..demonstrate that, under certain genetic conditions, a novel cluster of pacemaker neurons can drive rhythmic behavior in constant light. Surprisingly, these neurons are distinct from those thought to drive rhythms in constant darkness...

..Together, these studies suggest that CK2 contributes to repression by Hairy...

..We propose that Clock is uniquely able to induce and organize the core elements of interdependent feedback loops necessary for circadian rhythms...

..Taken together with other data, we propose that Clk makes a major contribution to the strength and amplitude of circadian rhythms...

..Results with the new recessive allele not only support the notion that Clock is an important clock gene but also indicate that it contributes more to the amplitude of the rhythm rather than the period...

..Candidates for this regulation are the E(spl) repressors, the terminal effectors of this pathway...

..Given the potential conservation with humans, this work should provide insight into the mechanisms by which neuropeptides mediate normal and disrupted circadian rhythms in human disease. ..

..Given the conservation of clocks and NA, this proposal should illuminate human daily rhythms and their contribution to disease. ..

..The discovery of a circadian function of CK2 in plants, animals, and fungi suggests these studies will be relevant to many biological systems, including humans. ..