Mammalian circadian biology: elucidating genome-wide levels of temporal organization

Abstract

During the past decade, the molecular mechanisms underlying the mammalian circadian clock have been defined. A core set of circadian clock genes common to most cells throughout the body code for proteins that feed back to regulate not only their own expression, but also that of clock output genes and pathways throughout the genome. The circadian system represents a complex multioscillatory temporal network in which an ensemble of coupled neurons comprising the principal circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus is entrained to the daily light/dark cycle and subsequently transmits synchronizing signals to local circadian oscillators in peripheral tissues. Only recently has the importance of this system to the regulation of such fundamental biological processes as the cell cycle and metabolism become apparent. A convergence of data from microarray studies, quantitative trait locus analysis, and mutagenesis screens demonstrates the pervasiveness of circadian regulation in biological systems. The importance of maintaining the internal temporal homeostasis conferred by the circadian system is revealed by animal models in which mutations in genes coding for core components of the clock result in disease, including cancer and disturbances to the sleep/wake cycle.

Figure 1

(A) A representative wheel-running locomotor activity record from a wild-type mouse. The record is double-plotted so that 48 h are shown for each horizontal trace. Dark regions represent locomotor activity. For the first seven days the animal was housed in an LD 12:12 cycle, denoted by the bar above the record. The animal was transferred to DD conditions on day 8, as indicated by the horizontal line to the right of the record. After approximately 3 weeks of DD exposure, a light pulse was administered (arrow). A phase shift (delay) in locomotor activity is observed following the light pulse. (B) A phase response curve (PRC) to light. Rodents were first housed in DD conditions for several weeks. Light pulses were then administered to animals at different circadian times, every two hours, for one complete cycle. Phase advances and delays are plotted above and below the horizontal line, respectively. Light pulses cause phase delays during the early subjective night (CT 13–15) and phase advances during the late subjective night (CT 18–20).

Figure 2

A diagram of the mammalian core circadian clock as described in the text. Abbreviations: PER (P), CRY (Cr), BMAL1 (B), CLOCK (C), CKIε (CKI), REV-ERBα (Rα), light-responsive elements in the Per promoters (LRE). Phosphorylation is represented by gray diamonds.