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The clocks that rule us - circadian rhythms in mammals


The life and times of the first mammalian clock mutant

Dr. Martin Ralph, University of Toronto, Canada

The circadian period mutation called tau was discovered in 1985 in the golden hamster, but largely because the hamster has not been a major model for molecular genetics, it was not until 2000 that the gene itself was identified as casein kinase-1-_ (Lowrey et al., 2000). Nonetheless, at the time of its discovery, more than anything else, the mutation created a new interest in the mammalian circadian system, prompting some investigators to search for other clock genes and mutations in other mammals. The fate of the original male tau mutant is unknown. Shortly after producing three litters, it was stolen from the animal care facility in Oregon, and not seen again. Nonetheless, animals carrying the tau mutation have been maintained and continue to be valuable for research. While the hamster has not been the ideal species for genetics, it remains a model of circadian behavior and physiology. Tau mutants have been used in neural transplantation studies to demonstrate the importance of the suprachiasmatic nucleus in rhythm generation. The abnormal pattern of entrainment has been linked to impaired cardiovascular health and reduced longevity. Recent studies of patients with sleep disorders have identified related molecular mechanisms and phenotypes in human beings. Finally, the mutation is proving once again to be a useful tool for elucidating the functional organization of the mammalian circadian hierarchy.

Mice, melatonin and the circadian system

Dr. Horst-Werner Korf, J.W.-Goethe University, Frankfurt

Mice have become an interesting animal model to decipher the effects of melatonin on the mammalian circadian system which comprises
1) a circadian pacemaker located in the suprachiasmatic nuclei (SCN),
2) input pathways entraining the circadian rhythm to the environmental day/night rhythm, and
3) output pathways distributing signals from the SCN to the periphery.
Melatonin which is produced in the pineal gland with a high day/night amplitude is an important neuroendocrine messenger of both the output and the input pathways of the clock and has two major targets: the SCN and the hypophysial pars tuberalis (PT). In the SCN, melatonin interacts with PACAP, a neuropeptide of the retinohypothalamic tract: it suppresses the PACAP-induced phosphorylation of the transcription factor CREB (cyclic AMP response element binding protein) at serine 133 (von Gall et al. 1998). Moreover, melatonin modulates the light-induced excitation of the sympathetic nervous system via its action on the SCN (Mutoh et al. 2003). Despite these effects, melatonin is not required to maintain the rhythmic expression of clock genes, e.g., mPer1, in the SCN. By contrast, the rhythmic expression of mPer1 in the PT, a peripheral oscillator, depends on an intact melatonin signal transduction cascade which interacts with adenosine; apparently melatonin opens a temporally restricted gate for adenosine to induce cyclic AMP-sensitive genes by sensitizing adenylyl cyclase (von Gall et al. 2002). Very recent experiments with the PT of melatonin-producing wildtype and melatonin 1a receptor knockout (mel1a ko) mice have revealed that the expression of several other clock genes (mCry1, Clock and Bmal1) is also dramatically reduced in the mel1a ko mice. Surprisingly the expression of Cry2 and Per2 was not reduced in mel1a ko mice as compared to the wildtype mice (von Gall et al. 2005, Jilg et al. 2005). These results allow to draw the following conclusions:
1) Within the SCN, melatonin interacts with signals from the retinohypothalamic tract, but it is not required to maintain rhythmic clock gene expression.
2) Within the PT, melatonin is an important, but not the only regulator of rhythmic clock gene expression.
3) In both targets, melatonin does not elicit actions on its own, but interacts with other neuroactive substances, e.g. PACAP and adenosine.
4) The stress-reducing potency of melatonin needs to be explored in further studies.

Chronotypes in humans towards an effective phenotyping tool for a
model organism in the real world

Dr. Martha Merrow, Groningen University, The Netherlands

Birds do it, bees do it, even educated fleas do it.
When he wrote these words, Cole Porter was speaking of love, but he could just as well have been referring to the circadian clock. This biological timekeeper was discovered by the surprising persistence of daily rhythms in constant conditions, demonstrating that the oscillations represent an endogenous temporal program. Circa - 24 h rhythms - such as sleeping and waking, leaf movements, spore formation - have been observed in organisms from all phyla, suggesting that the circadian clock is a fundamental adaptation to daily cycles of light and darkness on earth.
The clock organises physiology and behaviour, such that various processes occur at predictable times. These times can vary between individuals, creating a distribution of chronotypes. In experimental models, chronotype has been linked to the circadian clock and its synchronization to the environment. We therefore propose using chro-notype to identify clock genes in humans. The Munich ChronoType Questionnaire (MCTQ) asks simple questions, such as sleeping and waking times, that allow an assignment of chronotype. Inspection of almost 40,000 MCTQ responses reveals that chronotype is modified during development. It is a heritable trait, albeit a complex one. First experiments are underway to determine if the MCTQ is a sufficient phenotyping tool to support genotyping.