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Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms

Abstract

Many biochemical, physiological and behavioural processes show circadian rhythms which are generated by an internal time-keeping mechanism referred to as the biological clock. According to rapidly developing models, the core oscillator driving this clockis composed of an autoregulatory transcription–(post) translation-based feedback loop involving a set of ‘clock’ genes1,6. Molecular clocks do not oscillate with an exact 24-hour rhythmicity but are entrained to solar day/night rhythms by light. The mammalian proteins Cry1 and Cry2, which are members of the family of plant blue-light receptors (cryptochromes) and photolyases, have been proposed as candidate light receptors for photoentrainment of the biological clock7,8,9,10. Here we show that mice lacking the Cry1 or Cry2 protein display accelerated and delayed free-running periodicity of locomotor activity, respectively. Strikingly, in the absence of both proteins, an instantaneous and complete loss of free-running rhythmicity is observed. This suggests that, in addition to a possible photoreceptor and antagonistic clock-adjusting function, both proteins are essential for the maintenance of circadian rhythmicity.

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Figure 1: Targeted disruption of the cry genes and generation of Cry-deficient mice.
Figure 2: Circadian phenotype of cry mutant mice.
Figure 3: Circadian phenotype of cry1 double-mutant mice under changing light conditions.

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Acknowledgements

We thank J. Miyazaki for help with construction of targeting vectors, and Y.Tsukahara and S. Okano for discussions on circadian rhythms. M. Kuit is acknowledged for photographic work. This work was supported in part by grants from the Dutch Cancer Society, the Association for International Cancer Research, Human Frontier Science, The Louis Jeantet Foundation and the Ministry of Education, Science, Sports and Culture of Japan, and by a Spinoza premium of the Dutch Scientific Organization NWO.

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Horst, G., Muijtjens, M., Kobayashi, K. et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398, 627–630 (1999). https://doi.org/10.1038/19323

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