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First Circadian Clock Gene Identified and Cloned in MammalsScientists affiliated with the National Science Foundation's (NSF) Center for Biological Timing have identified and cloned a gene for the biological clock in a mouse, the first such gene to be identified at the molecular level in a mammal. The identification of the "Clock" gene was proven by restoring a functioning biological clock in a line of mutant mice which had lost normal circadian rhythms. The researchers accomplished this by inserting DNA for the gene into developing embryos, which not only grew to have normal biological clocks, but incorporated them into their own genetic material, passing them on to their descendants. "The identification of the 'Clock' gene is definitive," said Joseph Takahashi, professor of neurobiology and physiology at Northwestern University in Evanston, Illinois, and author of two articles appearing in the Friday, May 16, 1997 issue of the journal Cell. "This is the first time that the discovery of a mammalian gene regulating behavior has been accompanied by simultaneous proof that the gene has been located, by 'rescuing' the lost function of the gene," Takahashi said. The work is the result of the Clock Genome Project at the NSF Center for Biological Timing. The project uses "forward genetics" to discover the genes regulating circadian clocks in mice, fruit flies, and plants. "The cloning and characterization of the Clock gene in mice is an important step forward in our understanding of the mechanisms underlying biological clocks in mammals. The work should ultimately lead to insights into the regulation of human circadian behaviors, such as the rhythms in sleep and wakefulness," Gene Block, director of the NSF center said. All life forms, including humans, possess internal 24-hour clocks, known as "circadian" (from the Latin "circa," about, and "dian", a day) clocks, which regulate our daily activities such as sleep and waking. Difficulties in readjusting our clocks cause jet lag and shift work problems, as well as some types of sleep disorders. The circadian clock impacts almost every level of our bodily functions. A new understanding of the nature of the Clock gene may make it possible to target it with drugs that would help restore normal clock functioning. "This research provides direct evidence that clocks in mammals may be built with the same principles as those seen in fruit flies and fungi," Takahashi said. Fruit flies and fungi were until now the only organisms in which clock genes had been cloned and identified at the molecular level. Takahashi's approach used a novel strategy called "rescue" to help locate the Clock gene. The behavior of the mice was used to track down the responsible gene. The team inserted a number of different artificial chromosomes carrying normal DNA into the embryos of mutant mice, to see which might have an impact on the mouse's behavior. One of these proved to be able to restore the biological clock function in the mutated mice. This finding helped the team zero in on the precise location of the gene. Evidence of the Clock gene was found to be very high in two tissues known to be able to generate circadian signals, the eye and the suprachiasmatic nucleus (SCN) of the hypothalamus. Surprisingly, Clock was also found in other areas of the brain as well as the testis, ovary, liver, heart, lung and kidney. According to Takahashi, "This widespread expression of Clock leads to the speculation that Clock may regulate timing at many different levels in cells and tissues in the entire body."
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