Study of DNA repair deficient mice

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We isolated two mouse homologues of photolyase gene (mCry1 and mCry2), which encode proteins in the family of blue-light receptors. To explore the biological function of mammalian Cry1 and Cry2, we have generated cry1 and cry2 mutant mice through gene targeting in embryonic stem cells. Since these mutant mice are completely healthy and showed no overt phenotype, we analyzed the possible role for CRY proteins in the biological clock by measuring the circadian wheel-running behavior of cry-knockout mice under normal light/dark (LD) cycles and in constant darkness (DD). Since CRY proteins are able to function as blue-light receptor, these protein may be involved in the light entrainment ability. We found that mice lacking the Cry1 or Cry2 protein display accelerated and delayed free-running (DD) periodicity of locomotor activity, respectively. These findings suggest that Cry1 and Cry2 antagonistically modulate the period length of the clock. Above results indicate, however, that a deficiency in either gene does not produce a detectable loss of light entrainment of locomotor activity. Since cry1 mouse still contain a functional Cry2 protein, we generated double-mutant animals. To our surprise, 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 rhytjmicity.