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As different as night and day

In biology, sunlight is just one distinction between night and day. Some animals, like horses, hares and humans, are active during days -- even cloudy ones -- while mice, raccoons and skunks prefer skulking in moonlight and starlight.

Plants churn out more chlorophyll during daytime. Even in a lowly blue-green alga, cell division, nitrogen fixation, photosynthesis and respiration all reflect time of day or night.

In fact, creatures have apparently been responding to light and darkness ever since multi-cellular organisms appeared about 700 million years ago.

Over the past 40 years, researchers looking into circadian ("roughly day-length") rhythms found that in mammals, the unpronounceable suprachiasmatic nucleus (SCN) serves as the master clock in the brain.

The idea that mammals had a built-in clock once seemed exotic enough. Now it's clear that mammals, plants, many fungi and even blue-green algae also have separate clocks in most of their cells. (And you thought digital clocks were getting shrimpy...)

Evidence for this astonishing proposition comes from circadian changes in the output of messenger RNA -- the template upon which proteins are built -- within cells. If you grow rat fibroblasts -- primitive cells that can form cells of skin or connective tissue -- in culture and treat them for an hour or two with high concentrations of blood serum, gene expression will follow circadian rhythms for several days, says Ulie Schibler, a molecular biologist who studies these rhythms at the University of Geneva.

Likewise, research groups lead by Michael Menaker at the University of Virginia and Hajime Tei at the University of Tokyo have shown that circadian oscillations continue for a few days in slices of rat liver or lung grown in tissue culture.

Only a matter of time
Cells from the master clock in the SCN, however, obey circadian rhythms for weeks on end. How does the master clock communicate with the subservient "slave" clocks so an organism can adapt to changing day length and keep its billions of clocks synchronous?

In new research, Schibler's group has fingered glucocorticoid hormone as one messenger for this essential job. This hormone is produced rhythmically by the adrenal gland upon signals from the pituitary gland, the hypothalamus, and the SCN.

While glucocorticoid can reset the slave clocks, Schibler believes it does so in collaboration with other chemical signals in the blood.

Before starting the present research project, Schibler knew that glucocorticoid receptors were common in most body cells, but absent from the SCN. He also knew that the clocks in rat fibroblasts respond to glucocorticoid.

To test whether glucocorticoid hormone would signal individual cells, Schibler's group injected dexamethasone, a drug often substituted for glucocorticoid in experiments, into mice. Then they measured the output of genes involved in circadian timing.

All in the timing
Glucocorticoid not only affected the timing genes, but it did so in a manner that, helpfully enough, would adjust slave clocks to changing day length. The hormone replacement had no effect when given during the mouse's daytime. When given at night, the effect depended on timing. "When you measure the curve of gene expression, you find that it is delayed or advanced, depending on when you inject dexamethasone," says Schibler.

By delaying or advancing the formation of various proteins, the cell would enter "day" or "night" mode at different times, thus adapting to changing seasons. The change, Schibler says, also helps the cells compensate for errors in their clocks.

Unlike the peripheral cells, the master clock does not respond to glucocorticoid. That also makes sense, since chaos might result if the SCN were to reset itself. "If you have to be reset by the central pacemaker, you should always listen," says Schibler, "but the central pacemaker should not listen to itself."

How does it work?
While artificial clocks work by counting brief oscillations like the swing of a pendulum or the vibration of atoms in an atomic clock, the cellular clock uses a negative feedback mechanism. Jay Dunlap, professor of genetics at Dartmouth College, says, "There are proteins that work together to turn on a gene, and the gene product blocks their activity."

If the right delays are built in to the system, so it takes a while to turn on the gene, then it takes a while for the gene to make protein and feed back, "you have an oscillator" that can keep approximate time, he adds.

Obviously, cellular clocks play a critical role in determining sleep-wake cycles, Schibler says, although they also reflect our need for sleep at a particular time.

But circadian timing is also crucial in influencing body temperature, blood pressure and heartbeat. It even tells the kidneys to slack off during the night. So if you fly to Europe, don't be surprised if one element of jet lag is a pressing need to visit the loo all night long...

-- David Tenenbaum


Resetting of Circadian Time in Peripheral Tissues by Glucocorticoid Signaling, Aurelio Balsalobre et al, Science, 29 September 2000, pp. 2344-7,

Molecular Bases for Circadian Clocks (review), Jay Dunlap, Cell, Jan. 1999, pp. 271-90.

Source: The Why Files. September 29, 2000.

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