The goal of this proposal is to understand the molecular basis of circadian (approx. 24 hour) rhythms. Circadian rhythms are a central component of normal physiology and are displayed by organisms across the phylogenetic tree. This proposal will test the hypothesis that circadian rhythms in Drosophila depend upon the appropriate regulation and interaction of the period (per) and timeless (tim) proteins. Products of the per gene are known to be controlling elements of the central pacemaker in Drosophila. The arrhythmic clock mutation, timeless (tim), eliminates oscillations of per RNA and protein and reduces the overall levels of per protein. We recently isolated the tim gene and demonstrated that the per and tim proteins interact directly with each other. We also determined that the tim gene displays cyclic expression that requires per protein. Available data indicate that the per and tim proteins regulate each other and interactions between them control the phase and the periodicity of behavioral rhythms. Experiments are proposed to: (1) test the effects of the per mutants on tim protein expression, (2) address the mechanisms by which the per and tim proteins regulate each other's expression, (3) test the prediction that interactions between per and tim regulate the periodicity of circadian behavioral rhythms, (4) understand how per and tim proteins mediate the resetting of the circadian clock by light. Our preliminary data show that levels of tim protein are reduced rapidly by a pulse of light, suggesting that tim protein is the light-responsive element of the central pacemaker. This proposal is unique in its emphasis on the interaction between two circadian rhythm proteins. The mechanisms that regulate the per and tim proteins are likely to be conserved across species. Thus far the two organisms that have allowed extensive molecular analysis of circadian rhythms, Drosophila and Neurospora, show remarkable conservation of underlying mechanisms.
|Zheng, Xiangzhong; Sehgal, Amita (2012) Speed control: cogs and gears that drive the circadian clock. Trends Neurosci 35:574-85|
|Kumar, Shailesh; Chen, Dechun; Sehgal, Amita (2012) Dopamine acts through Cryptochrome to promote acute arousal in Drosophila. Genes Dev 26:1224-34|
|Luo, Wenyu; Sehgal, Amita (2012) Regulation of circadian behavioral output via a MicroRNA-JAK/STAT circuit. Cell 148:765-79|
|Hendricks, Joan C; Lu, Sumei; Kume, Kazuhiko et al. (2003) Gender dimorphism in the role of cycle (BMAL1) in rest, rest regulation, and longevity in Drosophila melanogaster. J Biol Rhythms 18:12-25|
|Wang, G K; Ousley, A; Darlington, T K et al. (2001) Regulation of the cycling of timeless (tim) RNA. J Neurobiol 47:161-75|
|Schotland, P; Hunter-Ensor, M; Lawrence, T et al. (2000) Altered entrainment and feedback loop function effected by a mutant period protein. J Neurosci 20:958-68|
|Ousley, A; Zafarullah, K; Chen, Y et al. (1998) Conserved regions of the timeless (tim) clock gene in Drosophila analyzed through phylogenetic and functional studies. Genetics 148:815-25|