The Circadian Clock in Mammals
The circadian clock in mammals resembles that in Drosophila in a number of ways with many of the participating genes being homologous. However, there are some differences:
- The transcription factors that turn on the light-induced promoters are dimers of the CLOCK protein and a protein designated BMAL1. These dimers turn on
- two Per genes;
- two Cry genes, the genes encoding cryptochrome
- hundreds of effector genes whose products control a wide variety of metabolic functions (e.g., cellular respiration, glycolysis,gluconeogenesis, lipid metabolism)
- The PER and CRY mRNAs are exported to the cytoplasm where they are translated.
- The PER and CRY proteins then enter the nucleus where
- they inhibit CLOCK-BMAL1 thus turning OFF transcription of Per and Cry, and are then
- degraded in proteasomes.
The blood levels of many hormones have strong circadian rhythms. Examples:
- hormones synthesized in the hypothalamus, e.g. vasopressin, or
- whose secretion is controlled by the hypothalamus such as
- insulin
- some 1–2% of the ganglion cells in their retina — instead of depending on signals arriving from rods and/or cones --
- detect light directly.
- These ganglion cells have an extensive network of dendrites that contain the pigment melanopsin.
- When exposed to light (diffuse light is fine), these ganglion cells become depolarized and send their signals back to the suprachiasmatic nucleus (SCN).
The clock mechanism is the same as the light/dark-driven clock in the SCN, but the machinery that sets the clock by food is located in a different part of the hypothalamus, the dorsomedial hypothalamic nuclei (DMH).
Mice with both copies of the Bmal1 gene knocked out, are unable to establish circadian rhythms to either light or food. However, injections of an adeno-associated virus vector (AAV) containing the Bmal1gene
- into the SCN restores the light clock but not the food-set clock
- into the DMH restores the food but not the light-set clock.