Molecular Clocks Throb Throughout Fruit Flies

November 27, 1997

A fruit fly's brain may have little edge over its leg bristles when it comes to telling what time it is. Clocks independently regulated by light abound throughout a fruit fly's body, report National Institute of Mental Health (NIMH) -funded researchers in the November 28 issue of Science. By making them glow like the dials of their mechanical namesakes, the researchers graphically demonstrated that these tiny timepieces can indeed "take a lickin' and keep on tickin'."

The scientific team, led by Steve Kay, Ph.D., Scripps Research Institute, took apart fruit flies to find out if, without any help from their heads, other body parts would respond to changes in the light/dark cycle. Strikingly, clock genes, named period, in each separately cultured segment, turned on and off in unison, according to rhythms set by environmental light manipulations.

"Under alternating light/dark conditions, the waxing and waning of clock gene expression was virtually the same in the head, thorax and abdomen," said Kay. "Our findings confirm that body clocks run independently in many tissues outside the brain, implying that cells harbor novel photoreceptors that aren't involved in vision."

NIMH Director Steven Hyman, M.D., noted that "circadian rhythms, which we share with all living organisms, influence many human problems, from adjusting to shift work, to clinical depression, to the timing of cancer chemotherapy. Using molecular biology to study these rhythms and how they respond to environmental events, we have recently seen that clock genes are ubiquitous in mice, and possibly other mammals, including humans. Seeing the clock genes expressed in fruit flies is a breakthrough."

Kay explained that his team "borrowed a trick from a jellyfish to see where period was expressed and a trick from a firefly to see when." The researchers made the clocks glow by engineering transgenic strains of flies in which the same genes that illuminate a jellyfish and a firefly's tail are attached to period. The gene for luciferase, the enzyme that glows intermittently in fireflies, was expressed along with period to reveal when the clock protein was being produced. Flies were also molecularly altered to brightly mark the clock sites with Green Fluorescent Protein, which glows constantly in jellyfish.

The resulting eerie green/yellow photos of the glowing clock gene expression, produced by co-investigator Jeffrey Plautz of Scripps, are published on the cover of Science and on the web (http://www.scripps.edu/~jplautz/images.html).

Period expression was especially conspicuous in chemosensory cells at the base of hairs on the legs and wings and on the antennae and beak, prompting the researchers to speculate that circadian rhythms may regulate a fruit fly's sensitivity to smell.

Rhythms are known to influence sensitivity to light and pain in mammals. A variant of period and another similar gene, clock, have recently been found throughout the bodies of mice. And, there is recent evidence that variants also exist in humans. Hence, the researchers suggest that even in higher animals, light itself, rather than the brain, could serve as the "master oscillator" that coordinates rhythms throughout the organism.

Yet the brain still retains a certain distinction -- even in a fruit fly. In tissues outside the brain, period gradually dimmed and went out of sync under conditions of constant darkness, although its normal rhythmicity recovered after light was reintroduced. Only within the brain did period stay in sync in the prolonged absence of light. And period in the head has previously been shown to play a pivotal role in regulating a fruit fly's behavior.

Also participating in the research were Maki Kaneko and Jeffrey Hall, Ph.D., of the National Science Foundation (NSF) Center for Biological Timing at Brandeis University. The study was also supported in part by NSF.

NIMH is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services.
-end-
Researcher Steve Kay, Ph.D. (stevek@scripps.edu), can be reached by contacting Robin Goldsmith, Scripps Research Institute (rgoldsmi@scripps.edu), 619-784-8134, or directly at 609-784-2360.

NIH/National Institute of Mental Health

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