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Gene Responsible for Rewinding Body's "Clock" Described - Research May Lead to Relief of Sleep Disorders and Jet Lag

La Jolla, CA. December 12, 2002 - A group of scientists at The Scripps Research Institute (TSRI) and the Genomics Institute of the Novartis Research Foundation (GNF) has demonstrated that the gene Opn4, which codes for the protein Melanopsin, is the elusive pigment gene that captures light and keeps your body tuned to a daily cycle - called a circadian rhythm.

"This is the key protein in the eye that sends signals to the clock," says TSRI Cell Biology Professor Steve Kay, Ph.D., who led the study.

In an article appearing in the journal Science, Kay and his colleagues describe experiments in which they observe laboratory models that lack the Opn4 gene. They were able to show that without this gene, the models were not able to keep their circadian rhythms entrained to a 24-hour day. If a circadian rhythm were a grandfather clock, Opn4 (Melanopsin) would be the key that winds it every day. Previously, it was not known which genes were responsible.

This research should help in the development of strategies for correcting sleep disorders, many of which are related to circadian rhythms. Furthermore, understanding the protein that resets the body's clock should help in research aimed at countering the most common circadian problems - the jet-lag one feels after overseas flights or fatigue when working night shifts.

Circadian Rhythms are Entrained by Light

Humans, mice, and many other plants and animals possess internal clocks that keep track of time and coordinate biological processes to the rhythm of day and night. Scientists have provided evidence of the existence of internal clock mechanisms by placing organisms in chambers isolated from day/night cycles. In spite of this, their rhythms recur approximately every 24 hours.

This so-called circadian rhythm is used by plants, for example, to gear up their photosynthetic machinery and raise their leaves just before dawn. They also use their clocks to measure day length and in that way anticipate changes in the seasons - a system that determines when they shed their leaves or produce seeds in the fall, or make flowers or fruit in the spring.

Humans also have circadian rhythms and entrain our internal clocks to the 24-hour day. Under normal conditions, we time our major activities with the light phase, we sleep during the dark phase, and even our vital signs follow this pattern. Our blood pressure fluctuates daily, rising and falling at predictable times of day or night.

"Even if you put the lights out on us, we would still [time] our activity to when our body expects light," says investigator John Hogenesch, Ph.D., another one of the paper's authors.

Evolution did not occur in an isolation chamber, however, and nature has programmed organisms to entrain each day their circadian rhythms to the 24-hour day, which allows them to anticipate and adapt to daily variations in the environment.

This "phase-shifting" is a necessary part of maintaining a constant schedule, and people who do not have the ability to perform this phase shifting are often stricken with sleeping disorders. In addition, phase shifting is relevant to the ability to adapt to a change in schedule such as during jet travel or shift work.

But until this latest study, the genes that are responsible for doing this phase-shifting were not known. Melanopsin was hypothesized to be this photoreceptor, but scientists lacked proof of it until now.

A Light Even the Blind Can See

In mammals, melanopsin is expressed in approximately 1000 cells per retina. "Most of these cells project directly to the master circadian oscillator in the brain," says Satchidananda Panda, Ph.D., a graduate of TSRI's Kellogg School of Science and Technology.

The master circadian oscillator is a small center in the brain's hypothalamus with about 10,000 neurons that sits above the optic chasm - the location where the optic nerves cross each other.

Previously, many scientists had speculated that the key protein would be rhodopsin, the light-capturing protein present in rods and cones of the eye that are responsible for vision.

However, certain people who were born blind because they lacked rods and cones could nevertheless maintain their circadian balance. This convinced many scientists that there must be some other form of photo-reception.

In the Science study the TSRI and GNF team knocked out the Opn4 gene in mice and showed that in its absence, the mice could not reset their clocks.

The article, "Melanopsin (Opn4) Requirement for Normal Light-Induced Circadian Phase Shifting" was authored by Satchidananda Panda, Trey K. Sato, Ana Maria Castrucci, Willem J. DeGrip, John B. Hogenesch, Ignacio Provencio, and Steve A. Kay and appears in the December 13, 2002 issue of the journal Science.

This work was supported by the Novartis Science Foundation, the National Institutes of Health, the National Institute of Mental Health, and an EU grant.

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These three figures show melanopsin-containing cells in the retina.