Genetic Interaction of Per1 and Dec1/2 in the Regulation of Circadian Locomotor Activity

In mammals, 24-h rhythms are controlled by a hierarchical system of endogenous clocks, with a circadian pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus that synchronizes peripheral oscillators throughout the body. The molecular clock machinery is regulated by interlocked transcriptional translational feedback loops (TTLs). The core TTL includes the transcriptional modulators PER (1-3) and CRY (1/2) that feed back on their own expression by interaction with CLOCK/BMAL1. An accessory loop involving the transcription factors DEC1 and DEC2 has been described that also impinges on CLOCK/BMAL1-mediated transactivation. In Drosophila, the DEC ortholog CWO shows synergistic activity to PER. This prompted the authors to analyze PER1-DEC interaction in the mammalian SCN. They generated Per1/Dec double and triple mutant mice to monitor activity rhythms under entrained and free-running conditions. Furthermore, they analyzed expression of the clock genes Per2, Rev-Erba, and Bmal1 in wild-type and Per1/Dec mutant SCN by in situ hybridization. The experiments reveal a critical role for Per1-Dec interaction in regulating activity phase under entrained conditions. In constant darkness, a synergistic function for Per1 and Dec1/2 in period regulation was found, correlating with disrupted clock gene mRNA levels in the SCN. Luciferase reporter gene assays indicate an activatory function of DECs on Bmal1 expression. Together, the results suggest a partially redundant and bidirectional regulatory function for the 2 Dec genes in the TTL and a conservation of Per-Dec (Cwo) synergism between vertebrate and invertebrate clocks.