[Supertraining] Circadian Rhythms and Cryptochromes

R. A. Hettinga rah@shipwright.com
Tue, 31 Dec 2002 23:14:35 -0500

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Date: Tue, 31 Dec 2002 13:38:45 EST
Subject: [Supertraining] Circadian Rhythms and Cryptochromes
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Periodically we have had some discussions on our sleeping habits and
circadian rhythms.  The following studies examinethe role played by an
interesting group of multi-purpose photoreceptors, called the cryptochromes
(from "crypto" meaning hidden and "chroma" meaning brightness) in regulating
rhythms in living creatures as different as plants and mammals.

Annu Rev Biochem 2000;69:31-67

Cryptochrome: the second photoactive pigment in the eye and its role in
circadian photoreception.

Sancar A

Circadian rhythms are oscillations in the biochemical, physiological, and
behavioral functions of organisms that occur with a periodicity of
approximately 24 h. They are generated by a molecular clock that is
synchronized with the solar day by environmental photic input. The
cryptochromes are the mammalian circadian photoreceptors. They absorb light
and transmit the electromagnetic signal to the molecular clock using a pterin
and flavin adenine dinucleotide (FAD) as chromophore/cofactors, and are
evolutionarily conserved and structurally related to the DNA repair enzyme

Humans and mice have two cryptochrome genes, CRY1 and CRY2, that are
differentially expressed in the retina relative to the opsin-based visual
photoreceptors. CRY1 is highly expressed with circadian periodicity in the
mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN). Mutant mice
lacking either Cry1 or Cry2 have impaired light induction of the clock gene
mPer1 and have abnormally short or long intrinsic periods, respectively. The
double mutant has normal vision but is defective in mPer1 induction by light
and lacks molecular and behavioral rhythmicity in constant darkness.

Thus, cryptochromes are photoreceptors and central components of the
molecular clock. Genetic evidence also shows that cryptochromes are circadian
photoreceptors in Drosophila and Arabidopsis, raising the possibility that
they may be universal circadian photoreceptors. Research on cryptochromes may
provide new understanding of human diseases such as seasonal affective
disorder and delayed sleep phase syndrome.


Proc Natl Acad Sci U S A 1999 Oct 12;96(21):12114-9

Differential regulation of mammalian period genes and circadian rhythmicity
by cryptochromes 1 and 2.

Vitaterna MH, Selby CP, Todo T, Niwa H, Thompson C, Fruechte EM, Hitomi K,
Thresher RJ, Ishikawa T, Miyazaki J, Takahashi JS, Sancar A.

Cryptochromes regulate the circadian clock in animals and plants. Humans and
mice have two cryptochrome (Cry) genes.

A previous study showed that mice lacking the Cry2 gene had reduced
sensitivity to acute light induction of the circadian gene mPer1 in the
suprachiasmatic nucleus (SCN) and had an intrinsic period 1 hr longer than
normal. In this study, Cry1(-/-) and Cry1(-/-)Cry2(-/-) mice were generated
and their circadian clocks were analyzed at behavioral and molecular levels.
Behaviorally, the Cry1(-/-) mice had a circadian period 1 hr shorter than
wild type and the Cry1(-/-)Cry2(-/-) mice were arrhythmic in constant
darkness (DD). Biochemically, acute light induction of mPer1 mRNA in the SCN
was blunted in Cry1(-/-) and abolished in Cry1(-/-)Cry2(-/-) mice. In
contrast, the acute light induction of mPer2 in the SCN was intact in
Cry1(-/-) and Cry1(-/-)Cry2(-/-) animals. Importantly, in double mutants,
mPer1 expression was constitutively elevated and no rhythmicity was detected
in either 12-hr light/12-hr dark or DD, whereas mPer2 expression appeared
rhythmic in 12-hr light/12-hr dark, but nonrhythmic in DD with intermediate

These results demonstrate that Cry1 and Cry2 are required for the normal
expression of circadian behavioral rhythms, as well as circadian rhythms of
mPer1 and mPer2 in the SCN. The differential regulation of mPer1 and mPer2 by
light in Cry double mutants reveals a surprising complexity in the role of
cryptochromes in mammals.


Science 1999 Oct 22;286(5440):768-71

Light-independent role of CRY1 and CRY2 in the mammalian circadian clock.

Griffin EA Jr, Staknis D, Weitz CJ.

Cryptochrome (CRY), a photoreceptor for the circadian clock in Drosophila,
binds to the clock component TIM in a light-dependent fashion and blocks its
function. In mammals, genetic evidence suggests a role for CRYs within the
clock, distinct from hypothetical photoreceptor functions. Mammalian CRY1 and
CRY2 are here shown to act as light-independent inhibitors of CLOCK-BMAL1,
the activator driving Per1 transcription. CRY1 or CRY2 (or both) showed
light-independent interactions with CLOCK and BMAL1, as well as with PER1,
PER2, and TIM.

Thus, mammalian CRYs act as light-independent components of the circadian
clock and probably regulate Per1 transcriptional cycling by contacting both
the activator and its feedback inhibitors.


***This study uncovers some important differences between the roles played by
cryptochromes in plants and mammals.  Since life developed on earth it should
not be surprising that the same biochemical compound should be exploited to
fill related roles in all life forms and the response of living creatures to
light is one of the most basic of all environmental acts.

Plant Cell 2000 Dec;12(12):2499-2510

Cryptochromes are required for phytochrome signaling to the circadian clock
but not for rhythmicity.

Devlin PF, Kay SA.

The circadian clock is entrained to the daily cycle of day and night by light
signals at dawn and dusk. Plants make use of both the phytochrome  (phy) and
cryptochrome (cry) families of photoreceptors in gathering information about
the light environment for setting the clock.

We demonstrate  that the phytochromes phyA, phyB, phyD, and phyE act as
photoreceptors in red light input to the clock and that phyA and the
cryptochromes  cry1 and cry2 act as photoreceptors in blue light input. phyA
and phyB act additively in red light input to the clock, whereas cry1 and
cry2 act  redundantly in blue light input. In addition to the action of cry1
as a photoreceptor that mediates blue light input into the clock, we
demonstrate a  requirement of cry1 for phyA signaling to the clock in both
red and blue light.

Importantly, Arabidopsis cry1 cry2 double mutants still show robust
rhythmicity, indicating that cryptochromes do not form a part of the central
circadian oscillator in plants as they do in mammals.


Dr Mel C Siff
Denver, USA

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R. A. Hettinga <mailto: rah@ibuc.com>
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