(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have identified a new
protein required for the circadian response to light in fruit flies.
The discovery of this protein - named JET - brings investigators
one step closer to understanding the process by which the body’s
internal clock synchronizes to light. Understanding how light affects
circadian (24-hour) rhythms will likely open doors to future treatments
The body’s 24-hour clock controls a multitude of internal
functions such as periods of sleep and wakefulness, body temperature,
and metabolism. Although circadian function produces a stable rhythm
in the body, the biological clock will reset in response to light.
The human condition known as jet lag takes place during the period
when the body is attempting to resynchronize to the environmental
light changes brought on by travel, namely from one time zone to
A mutant fruit fly that possesses jetlag-like behaviors enabled
senior author Amita Sehgal, PhD, Professor of Neuroscience
at Penn and a Howard Hughes Medical Institute (HHMI) Investigator,
and colleagues to identify the gene and subsequent protein that
aids in the response of the internal biological clock to light.
The researchers report their findings in most recent issue of Science.
To test the circadian rhythm of fruit flies, Sehgal and others exposed
wild type (control) and mutant flies to several light and dark settings
- constant darkness, constant light, and equal periods of light
and darkness (a light-dark cycle). During exposure to constant light
for one week, the controls developed a disrupted sleep pattern after
a few days, while the mutants maintained a regular circadian rhythm.
The mutant and control flies displayed no behavioral differences
during their exposure to constant darkness and the light-dark cycle.
However, when the fruit flies were shifted from one light-dark cycle
to another, the mutant flies took two days longer to adjust their
sleep-wake cycle to the new light-dark schedule.
“The behavior of the mutant flies is similar to that displayed
in a person who has prolonged jetlag,” notes Sehgal. In search
of answers to the mutant’s defective circadian response to
light, Sehgal and colleagues looked to the molecular details of
the clock cells in the jetlag flies.
When a fruit fly is exposed to light, a photoreceptor called cryptochrome
(CRY) transduces the light signal and kicks off a series of reactions
within the clock cells of the brain. Under normal conditions, CRY
will respond to light by binding to a protein called timeless (TIM).
A second protein, a member of the F-box protein family, also binds
to TIM, signaling TIM for cellular destruction.
Genetic analysis revealed that the jetlag flies possess a mutation
in a gene that encodes a member of the F-box protein family. A closer
examination of the protein produced by the mutated sequence led
researchers to JET, a new protein within the F-box protein family.
“Since the degradation of TIM always happens in the presence
of light, the animal associates the absence of TIM with daytime
hours,” explains Sehgal. The mutated JET protein reduces the
light-dependent degradation of TIM and the circadian response to
Sehgal and others were able to reverse the behaviors in the jetlag
flies by genetically replacing the mutated gene sequence with the
normal sequence, which led to the production of the wild-type (control)
JET protein. When the jetlag flies acquired the normal JET protein,
regular TIM degradation took place and the fruit fly was better
able to adjust to shifts in the light-dark cycle.
Future studies in the Sehgal lab will focus on continuing to identify
other molecules required for the circadian response to light. “Some
of the molecules required for the circadian light response in flies
may be conserved in humans. Over time, we will have a better understanding
of how the human clock responds to light and may be able to design
drugs to treat jetlag,” concludes Sehgal.
Study co-authors are Kyunghee Koh and Xiangzhong Zheng, both from
Penn. These studies were funded by the National Institutes of Health
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