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WhatFruitFliesCanTellUsAboutHumanSleepandCircadianDisorders

Society for Women's Health Research
Society for Women's Health Research Society for Women's Health Research
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What Fruit Flies Can Tell Us About Human Sleep and Circadian Disorders

By Amita Sehgal, PhD, University of Pennsylvania, SWHR Interdisciplinary Network on Sleep Member and Paula Haynes, PhD, University of Pennsylvania

Patients visit sleep clinics seeking both treatment and the solace of understanding that accompanies a clinical diagnosis: knowing that their sleep problems are not their fault, but are due to physiology and genetics. When people are unable to fall asleep or wake up at normal times, they may have a circadian rhythm disorder caused by a disruption in the body’s internal clock [1, 2]. Surprisingly, much of the basic biology of the body’s internal clock has been discovered by working on the tiny kitchen pest, the fruit fly. The fruit fly, known to researchers as Drosophila melanogaster, is oddly enough a perfect model for scientists to study the genetic basis of seemingly complex behaviors.

Some people may wake up spontaneously in the morning, but those who do not get quite enough sleep might be awoken at exactly the same time every day by an alarm, the voices of young children, or a hungry pet. In fact, people and most animals possess an internal time-keeping mechanism that tells us when it is time to wake up and when it is time to go to sleep, keeping us synchronized to the day/night cycle. This internal time-keeping mechanism is called our circadian clock, derived from the Latin ‘circa’ [about] ‘dian’ [a day], and, just like a wall clock, runs on a daily cycle of 24 hours.

Just like people, fruit flies also have an internal circadian clock. In the 1960’s, Ron Konopka, a student working with the famous Drosophila geneticist, Seymour Benzer began genetic studies of circadian rhythms in flies. Although Benzer was skeptical that specific genes would underlie daily behavioral rhythms, Konopka devised a way to identify mutant flies with disrupted circadian rhythms. Knowing that flies tend to emerge from their pupal cases at dawn, Konopka collected and bred the flies that emerged at inappropriate times. Konopka’s mutant flies were found to have a mutation in a single gene, which was named period [3,4].

Years later, other genes affecting circadian rhythms, such as timeless [5,6], Clock [7], cycle [8], Doubletime [9] and Jetlag [10], were discovered in flies, with many of these genes functioning similarly in mice and humans. Indeed, scientists also studied these genes in families that exhibit unusual sleep-timing patterns, such as one in which many members fall asleep between 6 to 8pm and wake up between 1 to 3am. Thanks to work on flies, scientists considered the period genes in humans as possible culprits and sure enough, traced the “earliness” to a mutation in the Period2 gene [11].

Following the successful use of fruit flies in understanding circadian rhythms, researchers now use flies to figure out what makes us sleepy [12,13]. Just as with circadian timing, the genes that drive sleep in fruit flies and humans are likely to be similar as well. In fact, caffeine keeps flies awake, just as it does people [14]. We have also discovered other genes, named sleepless [15] and redeye [16], which are needed to maintain sleep in flies, and others have found similar genes in mammals [17,18, 19]. Moving forward, scientists hope to use the humble fruit fly to uncover even greater mysteries, including understanding why we sleep at all.

The Society for Women’s Health Research Interdisciplinary Network on Sleep is committed to promoting awareness of sex and gender differences in sleep and circadian rhythms across the lifespan, and the impact they have on health and well-being. Learn more about the Sleep Network here.

References

  1. Sehgal, A. & Mignot, E. Genetics of sleep and sleep disorders. Cell 146, 194–207 (2011).
  2. Jones, C. R., Huang, A. L., Ptáček, L. J. & Fu, Y.-H. Genetic basis of human circadian rhythm disorders. Exp. Neurol.243, 28–33 (2013).
  3. Bargiello, T. A., Jackson, F. R. & Young, M. W. Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312, 752–754 (1984).
  4. Zehring, W. A. et al. P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster. Cell 39, 369–76 (1984).
  5. Sehgal, A. et al. Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation. Science 270, 808–10 (1995).
  6. Sehgal, A., Price, J. L., Man, B. & Young, M. W. Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless. Science 263, 1603–6 (1994).
  7. Allada, R., White, N. E., So, W. V, Hall, J. C. & Rosbash, M. A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 93, 791–804 (1998).
  8. Rutila, J. E. et al. CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93, 805–14 (1998).
  9. Kloss, B. et al. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon. Cell 94, 97–107 (1998).
  10. Koh, K., Zheng, X. & Sehgal, A. JETLAG resets the Drosophila circadian clock by promoting light-induced degradation of TIMELESS. Science 312, 1809–12 (2006).
  11. Toh, K. L. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–3 (2001).
  12. Shaw, P. J., Cirelli, C., Greenspan, R. J. & Tononi, G. Correlates of sleep and waking in Drosophila melanogaster. Science 287, 1834–7 (2000).
  13. Hendricks, J. C. et al. Rest in Drosophila is a sleep-like state. Neuron 25, 129–38 (2000).
  14. Nall, A. H. et al. Caffeine promotes wakefulness via dopamine signaling in Drosophila. Sci. Rep. 6, 20938 (2016).
  15. Koh, K. et al. Identification of SLEEPLESS, a sleep-promoting factor. Science 321, 372–6 (2008).
  16. Shi, M., Yue, Z., Kuryatov, A., Lindstrom, J. M. & Sehgal, A. Identification of Redeye, a new sleep-regulating protein whose expression is modulated by sleep amount. Elife 3, e01473 (2014).
  17. Ni, K.-M. et al. Selectively driving cholinergic fibers optically in the thalamic reticular nucleus promotes sleep. Elife 5, 745–752 (2016).
  18. Puddifoot, C. A., Wu, M., Sung, R.-J. & Joiner, W. J. Ly6h Regulates Trafficking of Alpha7 Nicotinic Acetylcholine Receptors and Nicotine-Induced Potentiation of Glutamatergic Signaling. J. Neurosci. 35, (2015).
  19. Wu, M., Puddifoot, C. A., Taylor, P. & Joiner, W. J. Mechanisms of inhibition and potentiation of α4β2 nicotinic acetylcholine receptors by members of the Ly6 protein family. J. Biol. Chem. 290, 24509–18 (2015).

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Society for Women's Health Research
Society for Women's Health Research

The Society for Women’s Health Research (SWHR ®) is a national non-profit based in Washington D.C. that is widely recognized as the thought-leader in promoting research on biological differences in disease and is dedicated to transforming women’s health through science, advocacy, and education.

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