Body clock gene works in the opposite way

A collaboration between mathematicians and scientists working on circadian rhythms has led to a controversial finding that the widely researched tau mutation speeds up rather than inhibits the underlying gene activity.

Discovery of the tau mutation in hamsters, affecting the gene casein kinase 1 epsilon (CK1), was the first breakthrough in understanding how the internal body clock of mammals is controlled genetically. Biological clocks with a period of around 24 hours exist in most organisms and time a variety of functions including sleep-wake cycles, release of various hormones and body temperature. 'The key to developing treatments for problems like depression and insomnia - disorders influenced by circadian rhythm - is being able to predict how the body's internal clock can be controlled', said David Virshup, the biological co-author of the paper. 'If the working model is wrong, drugs will have the opposite effect', he added. The work is reported in the Proceedings of the National Academy of Sciences.

Until now, conventional scientific wisdom has accepted that the tau mutation leads to a loss of activity in the CK1 gene, resulting in hamsters on a free running cycle experiencing a day shorter than 24 hours. But Dr Daniel Forger, a mathematician at the University of Michigan, designed a computer simulation of the biological clock which predicted that the opposite actually happened and that the tau mutation increased CK1 activity.

Scientists at the Huntsman Cancer Institute at the University of Utah also had reason to doubt the accepted view as they had been working with a drug that inhibits CK1 in cultured rat cells. Again contrary to their expectation, the cells had a longer day, not the shorter one as predicted. After forming a collaboration the team then came up with a simple experiment based on Forger's model which found that an associated protein, PER, disappeared more quickly when CK1 activity increased in tau mutated cells leading to the shorter day length. Virshup's team are now working to develop a mouse model in order to test ways to regulate circadian rhythms based on their findings.