Central and peripheral circadian clocks in mammals

Abstract

The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.

Figure 1

The molecular mechanism of the circadian clock in mammals. An autoregulatory transcriptional feedback loop involving the activators, CLOCK and BMAL1, and their target genes, Per1, Per2, Cry1 and Cry2, whose gene products form a negative feedback repressor complex, constitute the core circadian clock mechanism. In addition to this core transcriptional feedback loop, there are other feedback loops driven by CLOCK:BMAL1. One feedback loop involving Rev-erbα and Rorα that represses Bmal1 transcription leads to an antiphase oscillation in Bmal1 gene expression. CLOCK:BMAL1 also regulates many downstream target genes known as clock-controlled genes (Ccg). At a post-transcriptional level, the stability of the PER and CRY proteins is regulated by SCF (Skp1-Cullin-F-box protein) E3 ubiquitin ligase complexes involving β-TrCP and FBXL3, respectively. The kinases, casein kinase 1ε/δ (CK1ε/δ) and AMP kinase (AMPK) phosphorylate the PER and CRY proteins, respectively, to promote polyubiquitination by their respective E3 ubiquitin ligase complexes, which in turn tag the PER and CRY proteins for degradation by the 26S proteasome complex.

Figure 2

Network and autonomous properties of SCN neurons. Network properties of the SCN can compensate for genetic defects affecting rhythmicity at the cell autonomous level. A) Bioluminescence images of a Cry1^−/− SCN in organotypic slice culture. Note the stable, synchronized oscillations. Numbers indicate hours after start of imaging; 3V indicates the 3^rd ventricle. B) Bioluminescence images of dissociated individual Cry1^−/− SCN neurons showing cell-autonomous, largely arrhythmic patterns of high bioluminescence intensity. C and D) Heatmap representations of bioluminescence intensity of individual Cry1^−/− neurons in SCN slice (A) and dispersed culture (B). Values above and below the mean are shown in red and green, respectively, for 40 SCN neurons in each condition. E and F) Ten single SCN neuron rhythms from wild-type (E) and Cry1^−/− (F) mice. Imaging began immediately following a media change at day 0. Dissociated Cry1^−/− SCN neurons are largely arrhythmic, whereas dissociated wild-type cells are rhythmic. By contrast, in organotypic slice cultures, both wild-type and Cry1^−/− SCN cells are robustly rhythmic and tightly synchronized. Figure and legend adapted and reprinted from (Liu et al 2007a), with permission from Elsevier.

Figure 3

Pathways of peripheral clock entrainment. The master circadian pacemaker within the SCN relays temporal information to peripheral oscillators through autonomic innervation, body temperature, humoral signals (such as glucocorticoids), and feeding-related cues. Local signaling pathways can also affect peripheral oscillators independently from the SCN.