Circadian Gene Expression in the Suprachiasmatic Nucleus 901 Circadian Gene Expression in the Suprachiasmatic Nucleus

Regulated expression of a core set of clock genes is the basis of circadian timekeeping in vertebrates, as in other organisms. Clock genes are defined as being necessary to generate normal circadian rhythms, near 24 h oscillations in biological processes. With the enlargement of the brain in vertebrates, control of circadian rhythms became centralized. In lower vertebrates, such as fishes, lizards, and some birds, the pineal gland, near the surface of the brain, is directly photosensitive and exerts significant circadian control. In mammals, the pineal is overlain by enlarged cerebral hemispheres and is no longer photoreceptive. The central circadian clock of mammals resides within the suprachiasmatic nucleus (SCN) of the hypothalamus. Clock genes are under study in the range of vertebrate taxa, but have been most fully studied in the mammalian SCN. Rhythmic expression of clock genes within the SCN is required for the production of circadian rhythms throughout the brain and body. Circadian clock genes also are expressed rhythmically in the cells of most tissues. Clock gene expression modulates myriad processes that oscillate daily at levels from behavior to tissue-specific cellular function. States of sleep and arousal, release of neuroendocrine hormones, autonomic control of organs, contractile strength of muscle, and production of liver enzymes all oscillate with circadian rhythmicity. Regulated clock gene expression within the SCN enables this central clock to act as the conductor to the orchestra of local body clocks. In concert, these circadian clock-driven oscillations enable the organism to anticipate predictable changes in the environment, to coordinate diverse internal processes, and to align itself adaptively with the major variable in its environment, the cycle of night and day. Circadian rhythms emerge from cell-autonomous processes, posttranslational modifications (PTMs) of clock proteins that regulate transcriptionaltranslational feedback loops of clock genes. These cellular processes together form a dynamic timekeeping mechanism with a near-24 h period. Interlocking positive and negative feedback loops wherein clock proteins alternately activate or repress transcription is the apparent basis of the circadian clocks in plants and diverse animals, including mammals. Key to the oscillatory process is the tight regulation of proteins encoded by clock genes; during their lives within the circadian cycle, clock proteins associate dynamically with other clock proteins to form macromolecular assemblies, move between different subcellular compartments, and undergo extensive changes in posttranslational state and stability. The regulated expression of clock genes and proteins underlies the three primary components of the circadian system as it functions within the organism: the central clock, which generates the circadian time base in the SCN; input pathways, by which light entrains the SCN clock to the day–night cycle; and output pathways from the SCN, which transmit timing information beyond the central clock.