Mouse Gene Knockout Illuminates How Light Resets Clock

December 16, 2002 (Washington, DC) A key role in synchronizing daily rhythms to the day/night
cycle has been traced to a light-sensitive protein in the
eye, by knocking out the gene that codes for it. Mice
lacking a gene for the photopigment melanopsin show a
dramatic deficiency in their ability to regulate their
circadian rhythms by light. The discovery, by National
Institute of Mental Health (NIMH) grantees, helps unravel
the heretofore elusive mechanisms by which day/night cycles
regulate such rhythms in mammals. NIMH grantees Ignacio
Provencio, Ph.D., Uniformed Services University of the
Health Sciences (USUHS), and Steve Kay, Ph.D., The Scripps
Research Institute, and colleagues report on their findings
in the December 13 “Science”.*


In a similar knockout mouse study reported in the same
issue of “Science”, another research team, led by NIMH
grantee Norman Ruby, Ph.D., Stanford University, also found
melanopsin to be a “significant contributor” to circadian
function.**


Each day, a clock in the brain’s hypothalamus that governs
daily rhythms — sleeping/waking, body temperature, eating,
arousal. — is reset by light detected in the eyes. Yet,
how this works has been a mystery. Light can still reset
the clock even if the rods and cones, the photoreceptors in
the retina for vision, are removed, but not if the eyes are
removed. Hence, scientists have hypothesized that the eyes
must contain a system of photoreceptors for resetting the
clock that is separate from the system for sight.


Retinal ganglion cells, which contain melanopsin, have
emerged as a prime candidate only within the past year.
While most of these cells are wired to parts of the brain
involved in vision, about one or two percent of those in a
rodent’s retina project to other areas, including the
clock, located in an area of the hypothalamus called the
suprachiasmatic nucleus.


“Unlike the rods and cones, this light-detection system is
thought to respond to the level of illumination rather than
to images,” explained Provencio. “It may have an important
impact on general well being, since among other functions,
light levels and time of day can modulate mood, activity
levels, and even performance.”


Using mouse embryonic stem cells, Provencio, Kay and
colleagues altered the gene to create a strain of mice that
lacked a functioning gene for melanopsin. The mice
appeared healthy and showed normal activity rhythms as they
ran on wheels in constant darkness. This suggested that
melanopsin is not involved in the normal functioning of the
clock itself.


Then, the researchers exposed the melanopsin knockout mice
to 15 minutes of blue light at a time in their cycle when
normal mice show strong phase delays — alterations in the
time of onset of activity in response to light. The mice
lacking melanopsin showed significantly less phase delay
than normal control mice, likely because of reduced
sensitivity in signals from the retina to the clock. To
confirm this deficit in light input, the knockout mice were
exposed to constant white light, which normally would
trigger phase adjustments resulting in a longer internal
clock day than in constant darkness. The melanopsin-
deprived mice showed a shorter lengthening of their
internal clock day than the control mice.


“Light input to the clock was significantly reduced in the
melanopsin-deficient animals,” said Provencio. “The
sensitivity of their circadian system to light was reduced
by 50 to 80 percent.”


Although the study shows that melanopsin significantly
influences the resetting of the clock at three different
light intensities, exactly how this protein translates
light into a neural signal isn’t yet known.


The researchers propose that melanopsin is required for
normal setting of the brain’s clock by light, but that
other mechanisms for light input also play a role, since
the animals still show some phase shifting. As in plants
and flies, “independent photoreceptors with overlapping
roles may function to adapt the organism to the natural
changes in light quality and irradiance,” they suggest.


Also participating in the study were: Drs. Satchidananda
Panda, Trey Sato, John Hogenesch, Genomics Institute of the
Novartis Research Foundation; Drs. Ana Maria Castrucci,
Mark Rollag, USUHS; and Dr. Willem DeGrip, University of
Nijmegen.


Other funders of the Provencino/Kay study included the
American Cancer Society, the European Union, and the
Novartis Science Foundation. The Ruby study was also
supported by grants from the National Heart, Lung, and
Blood Institute (NHLBI), the National Institute on Drug
Abuse (NIDA), and Deltagen, Inc.


NIMH, NHLBI and NIDA are part of the National Institutes of
Health (NIH), the Federal Government’s primary agency for
biomedical and behavioral research. NIH is a component of
the U.S. Department of Health and Human Services.


* Panda S, Sato TK, Castrucci AM, Rollag MD, DeGrip WJ,
Hogenesch JB, Provencio I, and Kay SA. Melanopsin (Opn4)
Requirement for Normal Light-Induced Circadian Phase
Shifting, “Science” Dec 13 2002: 2213-2216.


** Ruby NF, Brennan TJ, Xie X, Cao V, Franken P, Heller HC,
and O’Hara BF. Role of Melanopsin in Circadian Responses to
Light, “Science” Dec 13 2002: 2211-2213.

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