Biology Reference
In-Depth Information
Cryptochrome (Cry1/Cry2) genes, which in turn provide the negative feedback sig-
nal that shuts down the Clock/Bmal drive to complete the circadian cycle
[4,5]
. Per
and Cry messenger RNAs peak in the SCN in mid- to late circadian day, regardless
of whether an animal is nocturnal or diurnal. Other clock genes provide additional
negative and positive transcriptional/translational feedback loops to form the rest of
the core clockwork, which has been characterized in rodents by a transgenic gene-
deletion methodology. Clock-gene expression oscillates because of the delay in the
feedback loops, regulated in part by phosphorylation of the clock proteins that con-
trol their stability, nuclear reentry, and transcription complex formation
[3,4,6]
.
Clock genes are expressed in a tissue-specific fashion, often with unknown func-
tion. Although a substantial number of genes are rhythmic (about 10% in the SCN
or peripheral tissues), the rhythmic genes tend to be different in the different tis-
sues. For example, in comparisons between heart and liver, or between the SCN and
liver, only a 10% coincidence was seen
[5,7,8]
. The phase of the peripheral clock
oscillations is delayed by 3-9 hours as compared to that of SCN cells, suggesting
that the peripheral tissues are receiving timing cues from the master SCN oscillator.
Furthermore, oscillations in isolated peripheral tissues dampen rapidly, unlike the
persistent rhythms in isolated SCN neurons
[5,7-9]
.
Sorting of the cycling transcripts into functional groups has revealed that the
major classes of clock-regulated genes are implicated in processes specific to the
tissue in which they are found. For example, many cycling transcripts in the liver
are involved in nutrient or xenobiotic metabolism. It is also of interest that many of
the regulated transcripts correspond to rate-limiting steps in their respective path-
ways, indicating that control is selective and very efficient. Indeed, about 10% of the
genome is under the control of the circadian clock
[10]
.
As noted, the trillions of cellular clocks in primates are synchronized by a few
thousand neurons located in the SCN. It is remarkable that such a small group of
neurons displays the properties of a central clock. Indeed, these “neuronal oligar-
chies,” like the human ones, control trillions of cells in the body by (a) taking con-
trol of the major communication channels (the endocrine and autonomic nervous
systems), and (b) concentrating the relevant information in a private way (e.g., light
information arriving via the retino-hypothalamic tract). Thus, it is not surprising that
anatomical studies have shown that the SCN projects to at least three different neu-
ronal targets: endocrine neurons, autonomic neurons of the paraventricular nucleus
(PVN) of the hypothalamus, and other hypothalamic structures that transmit the cir-
cadian signal to other brain regions
[2]
. The SCN projections are generally indirect,
via the sub-PVN zone
[11]
. Through autonomic nervous system projections involv-
ing the superior cervical ganglia, the SCN controls the release of a major internal
synchronizer, the pineal substance
melatonin
[12]
.
Although circadian rhythms are anchored genetically, they are synchronized by
and maintain certain phase relationships to external factors
[13]
. These rhythms will
persist with a period different from 24 hours when external time cues are suppressed
or removed, such as in complete social isolation or in constant light or darkness.
Research in both animals and humans has shown that only a few such environmental
cues are effective entraining agents for the circadian oscillator (“Zeitgebers”).
