Abstract
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.
Highlights
Period circadian clock (Per) genes Per[1] and Per[2] have essential roles in circadian oscillation
We hypothesized that the free-running periods of Per1(−/−) and Per2::Luciferase KI/KI (Per2)(−/−) under conditions of constant dark are similar because suprachiasmatic nucleus (SCN) coupling maintains the circadian free-running period
We found that the period length of each genotype depended on the ratio of Per[1] copy number to that of Per[2]
Summary
Period circadian clock (Per) genes Per[1] and Per[2] have essential roles in circadian oscillation. The SCN is important because SCN neurons have an intercellular coupling (synchronization) mechanism that makes the circadian oscillation robust and self-sustainable and maintains period length of approximately 24 h in all cells in the organ more precisely than clocks in individual cells[12]. Period circadian clock (Per) genes Per[1] and Per[2] are main components of the circadian clock feedback loop and have three important roles. They are essential for circadian oscillation, as demonstrated by the fact that Per1/Per[2] double-knockout mice become arrhythmic[13]. We found a new role, and its mechanism, of Per1-Per[2] cooperation using new methods we established
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