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Defining timeless
Non-circadian role for mouse gene
  
By
Edward R. Winstead


In 1998, scientists identified a human version and a mouse version of the fruit fly gene timeless. The timeless gene in flies is essential for a normal sleep-wake cycle; flies missing the gene have no biological clock. The mammalian versions of timeless were identified on the basis of their structural similarity to the Drosophila gene, but the functions have not been defined. Now, researchers report that mouse timeless is essential for embryonic development but does not appear to have an important role in biological time-keeping.


The mouse timeless gene has been reported to be active in the central clock mechanism in the mouse brain, but the reported data on gene function have been inconsistent. In Drosophila, timeless interacts with other genes and proteins as part of the clock's self-regulating feedback loops. See Feedback loops: How genomes mark time The role of timeless in the mouse has been harder to discern.

According to a paper in the August issue of Nature Neuroscience, researchers tried without success to detect evidence of circadian function such as oscillations in gene activity or responsiveness to light. "We knew that timeless wasn't doing in mice what it was doing in Drosophila," says Steven M. Reppert, of Harvard Medical School. The next step was to "knock out" the gene and look for clock-related effects in mice born without timeless. This proved impossible because embryos without the gene do not survive, indicating a developmental function for the gene. Mouse timeless does not appear to be the true mammalian version of clock-relevant fly timeless, the researchers concluded. "The gene still may have some clock function, but the evidence is building in the opposite direction," says Reppert.

What turned the corner for Reppert was the discovery of a second timeless gene in the fly. After the Drosophila genome sequence became available in March, a computer search of the fly data turned up a previously unidentified gene the researchers are calling timeout. Based on DNA structure, timeout is more closely related to mammalian versions of timeless than to fly timeless.


What happened to the mammalian timeout gene?

The fact that two structurally similar clock genes—timeout and timeless—exist in Drosophila raises the possibility that the same pair exists in mammals. "We know that there are two timeless genes in the fly and only one in mammals," says Reppert. "So what happened to that second mammalian gene?" His suspicion is that a clock-relevant mammalian timeless gene will turn up in human and mouse data in the future.

The research nicely makes the point that structurally similar genes may or may not be functionally similar, says Jay Dunlap, a chronobiologist at Dartmouth Medical School. "The hypothesized role of mouse timeless was based on gene sequence rather than function in the mouse," he says. "Except what was known from fly timeless, no in vivo function was associated with mouse timeless until Reppert knocked the gene out." Dunlap notes that timeless may still be involved in keeping time but proving so will be difficult since embryos without the gene die.

"If timeless is not involved in the mouse clock, this case provides the second example of real divergence between mammalian clocks and the Drosophila clock," says Dunlap. The first example was the protein cryptochrome, which plays a distinct role in the fly and mouse clocks. Although proteins may have different circadian roles in different species, the clocks themselves are fundamentally the same.


Evidence that clocks share common ancestor

For example, Dunlap and two colleagues recently published a paper describing the biochemical gears in the circadian clock of bread mold. As in the Drosophila and mouse clocks, the gears consist of interconnected feedback loops involving multiple genes and proteins. In each of the three species, the layout of the feedback loops is similar, and all the loops feature "cross-talk" between genes and proteins throughout the day. "That is," Dunlap explains, "instead of protein A acting on protein B and B acting on C within a loop, A acts on C in addition to acting on B."

That biological clocks in different species share the mechanism of feedback loops is not surprising to Dunlap. The surprise, he says, "is that all the feedback loops are laid out in the same way and use molecules of similar sequence. This is very strong evidence that the clocks share a common ancestor."

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Gotter, A.L. et al. A time-less function for mouse Timeless. Nat Neurosci 3, 755-756 (August 2000).
 
Lee, K., Loros, J.J. & Dunlap, J.C. Interconnected feedback loops in the Neurospora circadian system. Science 289, 107-110 (July 7, 2000).
 

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