In a long-standing collaborative effort, groups at MRC Harwell, the LMB, and the University of Oxford have discovered a new genetic mechanism in the circadian body clock that could have important implications for research in mental health and psychiatric disease. Biological clocks run in all our cells, controlling the timing of a number of crucial daily body functions such as core body temperature, hormone production and brain wave activity. These daily rhythms of metabolism and behaviour are known as circadian rhythms and adapt us to the 24 hour world, controlling our patterns of eating and sleeping.
Patrick Nolan’s group at the MRC Mammalian Genetics Unit at Harwell and Michael Hastings’ group in the LMB’s Neurobiology Division used cutting-edge genetic techniques to create mice with abnormally fast body clocks and found that these ‘short circuit’ mice had mutations in the zinc finger homeobox 3 (Zfhx3) gene. To find how this could cause the body clock acceleration, Marco Brancaccio in Michael’s group developed a new bioluminescent assay to look at how Zfhx3 affected gene expression in brain slices and showed how this activity was affected by mutations in Zfhx3.
The Zfhx3 gene is highly active in the suprachiasmatic nucleus (SCN), the main body clock in a part of the brain called the hypothalamus. This latest research showed that it controls transcription and gene expression of neuropeptides and their receptors in the SCN. All SCN cells have a molecular clock and can drive their own internal rhythm, but these results show that Zfhx3, by controlling neuropeptide signalling, can link individual clock cells together, harmonising their timing. This reveals a whole new level of clock cell organisation and a new genetic pathway for controlling the body clock.
Disorders of body clock regulation can cause profound problems, from jet lag and sleep disorders to poor health and early death of shift workers. A number of behavioural and psychiatric disorders such as schizophrenia and bipolar disease are also characterised by a lack of synchrony in the timing of brain networks. Understanding the mechanisms that control the body clock in health and sickness is crucial in learning more about these diseases. This fundamental research reveals how the Zfhx3 genetic pathway is linked to daily circadian behaviour, acting as a bridge between the internal timing mechanism of individual clock cells, synchronising the entire clock circuit in order to send time cues to the whole organism.
This research was funded by the MRC, the 6th Framework Project EUCLOCK, the European Research Council, and the Wellcome Trust.
Paper in Cell
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