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
  • 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.
In due course these actions allow CLOCK and BMAL1 to once again stimulate transcription of Per and Cry. Thus this negative feedback loop causes the levels of BMAL1 and PER/CRY to oscillate in opposite phases (as CLOCK and PER/TIM do in Drosophila — see the figure above).Many tissues in mammals, e.g., liver, skeletal muscle, and the beta cells of the pancreas have endogenous clocks. But all of these are under the control of a "master clock", the suprachiasmatic nucleus (SCN) — clusters of neurons in the hypothalamus.

The blood levels of many hormones have strong circadian rhythms. Examples:

Setting the ClockBy lightMice who are totally blind (lacking both rods and cones) have no trouble keeping their circadian clock on time.They are able to do this because

  • 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).
By foodIn mice, the SCN clock, set by light/dark cycles, is the master clock as long as food is available all the time (the normal situation in the laboratory). However, if food is offered for only a 4-hour period when the mice would normally be asleep, they shift several circadian activities so that, for example, once a day they begin running about just before they expect food to be given to them. This rhythm continues even if the mice are kept in constant darkness.

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.