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Period circadian clock (Per) genes  Per1  and  Per2  have essential roles in circadian oscillation. In this study, we identified a new role of  Per1 - Per2  cooperation, and its mechanism, using our new experimental methods. Under constant light conditions, the period length of  Per1  and  Per2  knockout mice depended on the copy number ratio of  Per1:Per2 . We then established a light-emitting diode-based lighting system that can generate any pattern of light intensity. Under gradually changing light in the absence of phase shift with different periods, both  Per1  (−/−)  and  Per2  (−/−)  mice were entrained to a broader range of period length than wild-type mice. To analyse  Per1 - Per2  cooperative roles at the cell culture level, we established a  Per2  knockout-rescue system, which can detect period shortening in a familial advanced sleep phase syndrome (FASPS) mutant. Upon introduction of the  Per1  coding region in this system, we saw period shortening. In conclusion, short period-associated protein Per1 and long period-associated Per2 cooperated to rigidly confine the circadian period to “circa” 24-h. These results suggest that the rigid circadian rhythm maintained through the cooperation of Per1-Per2 could negatively impact modern society, in which the use of artificial lighting is ubiquitous, and result in circadian disorders, including delirium.

Rigid Cooperation of Per1 and Per2 proteins