Molecular components of the Mammalian circadian clock

Abstract

Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus. Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases. Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature. At the level of individual tissues, thousands of genes are brought to unique phases through the actions of a local transcription/translation-based feedback oscillator and systemic cues. In this molecular clock, the proteins CLOCK and BMAL1 cause the transcription of genes which ultimately feedback and inhibit CLOCK and BMAL1 transcriptional activity. Finally, there are also other molecular circadian oscillators which can act independently of the transcription-based clock in all species which have been tested.

Figure 1

Schematic of the molecular clock of mammals. CLOCK:BMAL1 heterodimers (green and blue ovals) bind DNA of clock target genes at E-boxes or E′-boxes and initiate the transcription of their RNA. The resulting PER and CRY proteins (red and yellow ovals) dimerize in the cytoplasm and translocate to the nucleus where they inhibit CLOCK:BMAL1 proteins from initiating further transcription.

Figure 2

Timing of circadian events in nocturnal rodents. A) Mouse core body temperature as measured by radio telemetry. B) Spontaneous firing rhythms from a cultured rat SCN as adapted from (175). C) Molecular clock events are plotted schematically without axes for clarity. Yellow sine wave represents the phase of PER2 protein abundance in the mouse SCN. Orange wave represents the phase of mPer2 mRNA abundance in the mouse SCN and the blue wave represents the phase of Bmal1 mRNA abundance. Chromatin information relates to the promoter regions of the Per genes and Dbp as reported by (31,32). Sin3A-HDAC phase from (36).