Clockwork orange beats time for the body

A RIKEN-led team of researchers from Japan and the US has used an innovative combination of genome survey techniques in live Drosophila fruit flies to reveal a previously unknown master gene involved in setting circadian rhythms. It is the tenth of a series of genes which generate proteins that interact in complex interlocking feedback loops to measure day length.

This network of genes, which has been highly conserved during evolution, ensures that the rhythms of organisms—sleep and wakefulness, changes in body temperature, the secretion of hormones—are attuned to daily and seasonal cycles. In humans, such common problems as jet lag and lack of alertness of shift workers arise when the body’s circadian rhythms are not properly adjusted to the external environment. But permanent disruption of the body’s clock can lead to much more serious disorders, such as delayed sleep phase syndrome. It has also been implicated in mental illness. The work could well have relevance to treating these conditions.

In a recent issue of the journal Genes & Development (1), the research group—from RIKEN’s Center for Developmental Biology in Kobe, Kyushu University, Japan’s National Institute of Genetics and two universities in Texas—detailed how they found the new gene, clockwork orange (cwo).

With micro-array technology that shows which genes are switched on, the researchers initially followed the daily activity pattern of all genes in the genome of the head region of the fruit fly. Then, using RNA interference techniques, they blocked the activity of each of the nearly 130 genes which showed regular daily cycles of activity, and looked for dramatic disturbances of overall rhythmic behavior. This happened in only the few cases where they disrupted the core circadian genes which set the body’s clock. Of these, cwo was the gene that had the most pronounced impact.

Using a combination of micro-array technology and antibodies, the group then set out to discover the proteins and genes with which cwo interacts. The genes they found were all known to play a key role in the network which regulates the body’s internal clock.

“The work is still far from complete,” says Hiroki Ueda, the research team leader. “But I feel the discovery of cwo, which has a counterpart in the human genome, represents an important step in deciphering biological clocks. We next want to apply our techniques to the mouse, which is very near to humans compared with the fruit fly.”