March 30, 2000
Researchers Identify Unique Circadian Rhythm Photoreceptor
When an animal is exposed to constant, intense light, the internal
clock goes haywire, losing all sense of night and day. Fruit flies
exhibit the same reaction, and humans are predicted to respond
similarly. In the laboratories of Howard Hughes Medical Institute
investigator Michael
Rosbash and Jeffrey Hall at Brandeis University, however, there is
a strain of mutant flies that maintains a steady clock when barraged
with intense light.
The flies carry a crippled light-reactive pigment called a
cryptochrome. Experiments by Rosbash and his colleagues now indicate
that the fly cryptochrome dCRY is perhaps the only photoreceptor
molecule through which light regulates the fly's circadian rhythm, the
near-universal 24-hour biological clock that governs sleep and
wakefulness, rest and activity, body temperature, cardiac output, and
many other functions.
“A hallmark of every experimental organism from fruit flies to mice is that intense, constant light causes the normal circadian rhythm to go into arrhythmia, to essentially go whacko.”
Michael Rosbash
In an article published in the March 30, 2000 issue of the journal
Nature, Rosbash, Hall and Patrick Emery at Brandeis University,
and Ralf Stanewsky of the University of Regensburg in Germany, show
that mutant flies, called cryb flies, that have a
faulty cryptochrome gene dCRY exhibit an aberrant response to intense,
constant illumination.
"A hallmark of every experimental organism from fruit flies to mice
is that intense, constant light causes the normal circadian rhythm to
go into arrhythmia, to essentially go whacko," said Rosbash.
"However, we found that these cryb mutants did not
show such arrhythmia under constant light, as measured by their
activity. If there were circadian photoreceptors other than dCRY, then
constant light should have produced such arrhythmia.
"To find that these flies remain rhythmic under constant light
really starts to prove that dCRY is the major circadian rhythm
photoreceptor in this organism because there are no other
photoreceptors that can pick up the light signal and drive the clock
into a non-functioning arrhythmia," he said.
The cryb mutant flies still present a significant
mystery, Rosbash says, because they show the normal daily rhythmic
cycle of light-dark activity, even with the presumably crippled
photoreceptor molecules.
"One possibility is that there is still a bit of function left in
the mutant cryb cryptochrome," he said. "Another
possibility is that there remains another entrée route into the
circadian system, but not a true circadian route. It may be that light
entering the eyes tickles the internal biological clock with enough
information about the outside world to keep it in step with the
light-dark cycle."
Or, said Rosbash, the very appearance of a light signal may cause a
"startle response" in the flies that is sufficient to set their
internal biological clock to daytime.
The scientists' next efforts will be to identify fly mutants with
potential defects in the pathway that links dCRY to the proteins within
the central pacemaker. "By exploring other mutants that remain rhythmic
in constant light, we may be able to identify proteins that are linkers
between dCRY and the central clock mechanism.
"There is really very little evidence of how the dCRY protein
actually connects to the clockwork mechanism governed by the genes
period, timeless, clock and cycle," said
Rosbash. "Presumably, there is some kind of conformational change in
the dCRY protein— when it absorbs a photon of light— that
somehow affects the clock mechanism. But the system is almost a black
box at present."
According to Rosbash, applying findings about circadian
photosensitivity in fruit flies to mammals is currently problematic
because a mammalian circadian photoreceptor has not yet been
identified. Mammalian cryptochrome molecules appear to be involved in
the central clockwork mechanism, rather than in light-detection, he
said.
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