Sleeping With the Lights On: Discovery
of New Fruit Fly Protein
Illuminates Circadian Response to Light
(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 of jetlag.
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 another.
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
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 light.
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
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 and HHMI.
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