Abstract
BackgroundOur recent studies demonstrate that the murine homolog of the human tumor suppressor promyelocytic leukemia (PML) regulates circadian behavior of mice. To further gather insight into PML’s contribution to circadian behavior, we generated two strains of mice deficient in one of the two period (Per) genes and the PML gene, with Per1−/−/Pml−/− and Per2−/−/Pml−/− genotypes.ResultsHere we report the circadian behavior of these mice based on wheel-running behavioral analysis. In a free-running environment, the Per1−/−/Pml−/− mice maintained circadian rhythm but displayed a significantly shorter period of 22.2 h. In addition, these mice displayed significantly enhanced phase response to a light pulse given at zeitgeber time (ZT) 14 and 22. The Per2−/−/Pml−/− mice lose persistent rhythm when in a free-running environment, as also the case for Per2−/− mice. A transient post-light pulse rhythm seen in the arrhythmic Per2−/− mice was less apparent in Per2−/−/Pml−/− mice. Both the Per1−/−/Pml−/− and Per2−/−/Pml−/− mice displayed a more advanced phase angle of entrainment activity during light–dark cycles than the single gene deficient mice.ConclusionsBeyond merely regulating PER1 and PER2, the current behavioral studies suggest PML has additional roles in mouse circadian behavior.
Highlights
Our recent studies demonstrate that the murine homolog of the human tumor suppressor promyelocytic leukemia (PML) regulates circadian behavior of mice
Wheel-running circadian behavior of Per1−/−/Pml−/− mice Male wild type, Pml−/−, Per1−/− and Per1−/−/Pml−/− mice were analyzed for their circadian behavior by monitoring their wheel-running activity in a light: h dark (LD) cycle followed by a free-running period of 12 h dark/12 h dark (DD) cycles
The Per1−/−/Pml−/− mice displayed a significant level of activity prior to light off at ZT12 during the LD cycle (Figure 1A, see Figure 2)
Summary
Our recent studies demonstrate that the murine homolog of the human tumor suppressor promyelocytic leukemia (PML) regulates circadian behavior of mice. To further gather insight into PML’s contribution to circadian behavior, we generated two strains of mice deficient in one of the two period (Per) genes and the PML gene, with Per1−/−/Pml−/− and Per2−/−/Pml−/− genotypes. The protein, Promyelocytic leukemia (PML) has been implicated in many important biological processes, including the DNA damage response, cell division control and chromosome instability [1,2]. A reciprocal chromosomal translocation t(15;17), which fuses the PML and the retinoic acid receptor alpha (RARα) genes is the underlying cause of over 95% of acute promyelocytic leukemia (APL) cases [1]. Our studies show that Pml−/− mice have abnormal phase shift responses to a light pulse and have circadian periods that display reduced precision and stability. The period length instability had features that were somewhat similar to the behavioral phenotype
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