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After hours Mutant Reveals a Role for FBXL3 in Determining Mammalian Circadian Period

Wheel-running mice have helped scientists to identify an altered body clock gene that can make a normal day up to three hours longer. The altered gene, named ‘after hours’ or Afh, is a variant of a gene called Fbxl3 which was previously unknown to play a role in keeping mammals internal body clocks running on time.

The discovery was a team effort involving scientists from the Medical Research Council Mammalian Genetics Unit, the MRC Laboratory for Molecular Biology and colleagues based at New York University. The results are published in Science.

By monitoring when and how often the mice chose to run on an exercise wheel the team spotted an alteration in some of the animals’ normal rhythms. Instead of following the typical 24-hour-pattern, some of the mice had body clocks that stretched to up to a 27-hour-day.

Closer study of the DNA from the mice then revealed that those on a 27-hour-cycle had the after hours version of the Fbxl3 gene, one of a large family of genes that control the breakdown of specific proteins within body cells.

Dr Patrick Nolan, of the MRC Mammalian Genetics Unit, who led the study said:

The internal body clocks of mice with the after hours gene run on a longer cycle than mice that have a normal copy of the gene, who like most of us live on a 24-hour-schedule.’’

Explaining the finding, he described how the gene might have an effect on the body clock:

the after hours version of the Fbxl3 gene appears to interfere with normal regulation of the body clock on a cellular level. In mice and humans, there are molecular feedback loops that run over a period of roughly 24 hours to keep the body clock on time. A feedback loop is a cyclical system that relies on the input and breakdown of molecules to keep it running. One of the key components of this loop is a protein called Cry. We found that mice that carried the after hours gene also had a delayed Cry protein breakdown rate, leading to a slowdown in the molecular feedback loops and a lengthening of the body clock cycle.’’

Many questions remain as to how molecular feedback loops govern daily biological cycles. Exactly how and when Fbxl3 targets Cry for breakdown is the scientists next target. Dr Nolan commented: ‘‘We need to do a lot more research before this discovery could be applied to the human body clock cycle in any way, what it has shown us is yet another gene involved in controlling circadian rhythms and this in itself is a useful starting point for further study.’’

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