Public Release: 

Clockwork Clues Determined

The Geisel School of Medicine at Dartmouth

Temperature may be a key cue for setting the biological clocks that govern the daily ebb and flow of activity in most animals and plants, Dartmouth Medical School geneticists have found.

Their work, reported in the August 7 issue of Science, advances understanding of how internal clocks keep time over the wide range of environmental conditions living things encounter.

Biological clocks are the cellular basis of the circadian rhythm, the 24-hour light-dark cycle that times behavior and metabolism for most organisms from plants to people. In humans, delayed resetting by the clock is an underlying cause of jet lag, and clock malfunction has been linked to seasonal affective disorder and various sleep and mental disorders.

DMS Researchers, Jay Dunlap, Ph.D., professor of biochemistry, Jennifer Loros, Ph.D., associate professor of biochemistry and postdoctoral fellows Yi Liu and Martha Merrow have demonstrated that temperature may be even more influential than light in regulating the clockwork components that cells use to pace themselves.

Their work offers insight into some fundamental properties common to all biological clocks: how they respond to temperature changes and adapt to control rhythm over a wide span.

Light had previously been thought to be the dominant signal in every organism. These studies suggest that this is almost certainly not the case, and that for many biologically and agriculturally important organisms temperature and temperature cycles may be the most important factor in setting the clock, Dunlap said.

Exploring the biological clock in one of the best-known model systems, the bread mold Neurospora, the researchers have built on their studies of a central cog, known as the Frequency (FRQ) protein. When they compared levels of this protein and its related components under various light and temperature conditions, they found that temperature rather than visible light was the dominant cue for resetting the cellular timekeepers.

The work is supported by the National Institutes of Health (National Institute of General Medical Sciences and the National Institute of Mental Health), the National Science Foundation, and in part by the U.S. Air Force.

Loros and Dunlap have studied the clock signals that tell bread mold when to send out spores, delineating how the clock is assembled and how light resets the biological clock. Watershed studies on the Neurospora clock mechanisms have predicted and presaged subsequent work in mammals by several years, Dunlap noted. What is true for the Neurospora clock has been true in mice and will probably be true in people.

The current work expands investigations of the intricate feedback loop that determines how the circadian clocks operate. The loop relies on levels of the FRQ clock protein that feeds back to shut off activity of the gene that produces it. Visible light and high ambient temperatures, interpreted as dusk (going from light to dark) trigger a delay that lengthens the circadian cycle; low temperature and darkness, read as dawn, drive the clock rhythms in the opposite direction, advancing the clock and shortening the cycle.

To determine the relative strength of the two factors, the investigators forced light and temperature to compete with each other in conditions of cool light and warm darkness. They measured the levels and ratios of the FRQ protein and its related gene components and discovered that contrary to previous assumptions, temperature was more effective than light in triggering the clock rhythms.

Moreover, the relation among the clock components, not the absolute amounts, set the new internal time.

Given the parallels between the bread mold and mammalian systems, the findings have implications for humans, the researchers note. They suggest that in the human brain, a low point for key timekeeper proteins could be just before dawn, corresponding to the temperature nadir for healthy adults. Moreover, the asynchrony between light and temperature cycles may be significant for organisms in temperate regions, particularly in spring or fall when environmental temperature touches the lower boundary of the range the clock to keep running.


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