, 2005, Andretic et al , 2008 and Crocker and Sehgal, 2010) Perh

, 2005, Andretic et al., 2008 and Crocker and Sehgal, 2010). Perhaps the greatest potential of Drosophila for understanding the regulation and function of sleep, however, resides Tyrosine Kinase Inhibitor Library in vitro in employing forward genetic screens to identify genes that regulate sleep and wakefulness. Previous screens have led to the isolation of mutations

in the voltage-gated potassium channel encoded by Shaker ( Cirelli et al., 2005), and in sleepless ( Koh et al., 2008), which encodes an extracellular membrane-linked peptide that physically associates with the Shaker channel and regulates its abundance and activity ( Koh et al., 2008 and Wu et al., 2010). Hyperkinetic, which encodes the cytoplasmic beta-subunit of the Shaker channel, has also been shown to regulate sleep ( Bushey et al., 2007). In addition to sharply reducing sleep, loss-of-function mutations in each of these genes are associated with reduced longevity, suggesting a link between decreased sleep and lifespan ( Cirelli et al., 2005, Koh et al., 2008 and Bushey et al., 2010). Here, we describe the molecular cloning and characterization of insomniac, a mutant isolated in a forward genetic screen for altered sleep-wake behavior. insomniac animals exhibit severely reduced sleep, shortened sleep bouts, and decreased sleep consolidation. insomniac expression

does not oscillate in a circadian manner, and the circadian clock is intact in insomniac animals, suggesting a function in pathways distinct from the circadian clock. Neuronally restricted depletion Selumetinib price of insomniac mimics the phenotype of insomniac mutants, indicating that insomniac is required in the nervous system for the proper regulation of sleep and wakefulness. Conversely,

restoration of insomniac expression to the brains of insomniac animals is largely sufficient to rescue normal sleep-wake behavior. insomniac encodes a protein of the BTB/POZ superfamily. Closely related members of this superfamily function as adaptors for the Cullin-3 (Cul3) ubiquitin ligase complex and thus contribute to protein degradation pathways. Consistent with the hypothesis that Insomniac may function as a Cul3 adaptor, we show that Insomniac can physically interact with Cul3, and that neuronal RNAi directed against Cul3 recapitulates the insomniac phenotype. To identify mutations altering sleep, second we selected a Canton-S (CS) strain exhibiting well consolidated sleep and subjected it to chemical mutagenesis with ethyl methanesulfonate. The screening regimen we employed, in which F2 males are screened, enriches for X chromosome mutations. Over 20,800 animals, representing 3,550 lines, were screened in alternating 12 hr light-12 hr dark (LD) cycles using an automated locomotor activity monitoring system. Three mutant lines exhibiting severe X-linked sleep defects were characterized further. Two of the lines shake under ether anesthesia and fail to complement the sleep defect of Shaker mutants ( Cirelli et al.

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