RESEARCH INTEREST

Genetic and molecular mechanisms underlying circadian rhythms and sleep.


RESEARCH TECHNIQUES

Drosophila genetics; molecular biology; circadian rhythm and sleep assays of fruit flies.


RESEARCH SUMMARY

The overall goal of our research is to understand the molecular basis of behavior. The focus has been on cyclic behavior that occurs with a circadian (~24 hour) periodicity. Using the fruit fly Drosophila melanogaster, we and others have characterized a "molecular clock" that requires products of the period (per) and timeless (tim) genes. Levels of per and tim RNA and protein cycle with a circadian period and the two proteins feedback inhibit the synthesis of both mRNAs,thereby generating an autoregulatory loop. We have shown that cycling of the two proteins is critical for rhythmic rest:activity and can even by maintained in the absence of mRNA cycling, most likely through rhythmic activity of phosphatases. These timekeeping mechanisms, first identified in Drosophila, are found to be conserved in mammals. We have also uncovered mechanisms that synchronize the clock to light, starting with the demonstration that the tim protein (TIM) is degraded in response to light and including the most recent discovery of a protein, jet-lag, that targets TIM for degradation. We have also identified components of the pathway that transmit timekeeping signals from the clock and result in rhythmic rest:activity. The Drosophila homolog of the Neurofibromatosis 1 (NF1) gene is one such output gene. In addition, we have examined the effects of clocks in peripheral (non-brain) tissues on other aspects of physiology.

We also developed the fly as a model system for sleep. We showed that the rest phase in flies is a sleeplike state, and can be used to study not only circadian regulation, but also the homeostatic control of sleep, in other words the essential need for sleep. Using the fly model, we have identified molecular components as well as cellular loci that regulate sleep. An important sleep-regulating locus in the fly is the mushroom body, site of learning and memory in the fly. We have also identified effects of aging upon sleep and circadian rhythms.

KEY WORDS:   circadian rhythms; Drosophila; mutations; timeless.


KEY REFERENCES
Hunter-Ensor, M., Ousley, A. and Sehgal, A. "Regulation of the Drosophila protein timeless suggests a mechanism for resetting the circadian clock by light". Cell 84, 677-686 (1996).

Yang, Z., Emerson, M., Su, H. and Sehgal, A. “Response of the timeless protein to light correlates with behavioral entrainment and suggests a nonvisual pathway for circadian photoreception”, Neuron 21, 215-223 (1998).

Naidoo, N., Song, W., Hunter-Ensor, M. and Sehgal, A., “A role for the proteasome in light-induced degradation of the timeless clock protein.” Science 285, 1737-1741 (1999).

Hendricks, J., Finn, S.M, Panckeri, K.A., Chavkin, J., Williams, J., Sehgal, A. and Pack, A. “Rest in Drosophila is a sleep-like state”, Neuron 25, 129-138 (2000).

Yang, Z. and Sehgal, “Role of molecular oscillations in the Drosophila circadian clock”, Neuron 29, 453-467 (2001).

McNamara, P., Seo, S., Sehgal, A., Chakravarti, D. and FitzGerald, G.A. "Regulation of CLOCK and MOP4 by Nuclear Hormone Receptors in Vascular cells: A Humoral Mechanism to Reset a Peripheral Clock”. Cell 105, 877-890 (2001).

Williams, J., Field, J., Bernards, A. and Sehgal, A. “Neurofibromin 1 signals through the Ras-MAP kinase pathway to control circadian behavioral rhythms in Drosophila”, Science 293, 2251-2256 (2001).

Hendricks, J.C., Williams, J.A., Panckeri, K., Kirk, D., Yin, J.C-P. and Sehgal, A. “A non-circadian role for cAMP signaling and CREB activity in waking and rest homeostasis in Drosophila melanogaster.” Nature Neurosci. 4, 1108-1115 (2001).

Dockendorf, T. Su, H., McBride, S., Yang, Z., Siwicki, K.K., Sehgal, A. and Jongens, T.A. “The Drosophila dFMR mutation produces defects in circadian rhythms and courtship behavior”, Neuron 34: 973-984 (2002).

Myers, E., Yu, J. and Sehgal, A. “Circadian control of eclosion: Interaction between a central and a peripheral clock”, Current Biol 13, 526-533 (2003).

Sathyanarayan, S., Zheng, X., Xiao, R. and Sehgal, A. “Post-translational control of Drosophila PERIOD protein by Protein Phosphatase 2A”, Cell 116, 603-615 (2004).