Found: mouse circadian rhythm gene.

Never trust a mouse from Joseph S. Takahashi's laboratory to be on time. A few years ago, Takahashi and his colleagues randomly mutated genes in mice to disrupt their biological clock, the internal timepiece that creates daily cycles, or circadian rhythms, of activities such as sleeping, eating, and exploring.

Takahashi's group succeeded in creating mice whose clocks ticked in a cycle that ran significantly longer than the normal mouse's 23.7 hours. Indeed, some of these mice lost their circadian rhythms altogether (SN: 5/14/94, p. 319).

Now, the researchers have identified the gene at fault and named it clock. They report their finding in the May 16 Cell.

"It's the first molecular entry into the clock mechanism in mammals," says Takahashi of Northwestern University in Evanston, Ill.

While researchers had previously identified circadian rhythm genes in fruit flies and the bread mold Neurospora crassa, comparable mammalian genes had proved elusive. Investigators have long known that the primary mammalian pacemaker resides in brain regions called the suprachiasmatic nuclei (SCN). Last year, scientists also found that hamster retinas contain independent biological clocks (SN: 4/20/96, p. 245).

As expected, Takahashi's group observed that the clock gene is active in the mouse SCN and retina. More surprising, the gene is turned on elsewhere in the brain and in many tissues, including the heart, liver, and kidneys.

These findings don't challenge the SCN's dominant role in the circadian rhythms that govern sleeping and other behavioral functions, the scientists stress. In certain tissues, however, "there may be regional clocks that control specific functions," says Gene D. Block, director of the National Science Foundation Center for Biological Timing in Charlottesville, Va.

Another explanation may be that the protein encoded by clock can serve noncircadian roles in other tissues.

Definitive proof that Takahashi and his colleagues had found their quarry came from experiments that restored normal circadian rhythms in progeny of their genetically altered mice. By injecting snippets of DNA that included clock into eggs of the altered mice, the scientists produced offspring with normal rhythms, even some with shorter cycles.

The molecule encoded by clock can apparently bind DNA, suggesting that it's a transcription factor, a protein that can turn genes on and off, says Takahashi.

Investigators have not yet examined whether clock's protein acts directly to help establish a circadian rhythm. Instead, it could influence inputs to the mouse biological clock, such as perception of light, or disturb the signals sent out by the clock to the animal.

"We just don't know whether it's an essential gear of the clock," says Steven M. Reppert of Massachusetts General Hospital in Boston.

Another key issue centers on the presumed partner or partners of clock's protein. In the fruit fly, proteins called PER and TIM and at least one unidentified protein interact to generate the circadian rhythm. Scientists are curious as to whether mouse counterparts of PER and TIM bind to clock's protein and whether a fly version of that protein is the long-sought missing partner for PER and TIM.

The discovery of clock lends support to a proposal linking circadian rhythms and light sensitivity. In the May 2 Science, Jay C. Dunlap and his colleagues at Dartmouth Medical School in Hanover, N.H., report that proteins that help N. crassa respond to light also play a role in the organism's biological clock.

Moreover, the bread mold proteins have a structural feature, called a PAS domain, that also exists in clock's protein and in PER. Dunlap suggests that PAS is an element of many clock and photoresponse proteins, reflecting an evolutionary history in which the capacity to generate circadian rhythms arose from the ability of cells to sense the sun's daily light-dark cycles.