Circadian rhythms in mice can be regulated by photoreceptors with cone-like characteristics

Provencio, Ignacio; Foster, Russell G.

doi:10.1016/0006-8993(95)00694-l

Cited by 173 publications

(109 citation statements)

References 22 publications

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“…Action spectra of rodent circadian responses more closely resemble the spectral absorbance profile of opsin-based photopigments rather than flavin-based cryptochromes (Takahashi et al, 1984;Provencio and Foster, 1995;Yoshimura and Ebihara, 1996). Melanopsin is one of four opsins expressed outside the photoreceptor layer in human and mouse retinas, the other three being retinal G-protein-coupled receptor (RGR), peropsin, and encephalopsin.…”

Section: Discussionmentioning

confidence: 99%

A Novel Human Opsin in the Inner Retina

et al. 2000

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Here we report the identification of a novel human opsin, melanopsin, that is expressed in cells of the mammalian inner retina. The human melanopsin gene consists of 10 exons and is mapped to chromosome 10q22. This chromosomal localization and gene structure differs significantly from that of other human opsins that typically have four to seven exons. A survey of 26 anatomical sites indicates that, in humans, melanopsin is expressed only in the eye. In situ hybridization histochemistry shows that melanopsin expression is restricted to cells within the ganglion and amacrine cell layers of the primate and murine retinas. Notably, expression is not observed in retinal photoreceptor cells, the opsin-containing cells of the outer retina that initiate vision. The unique inner retinal localization of melanopsin suggests that it is not involved in image formation but rather may mediate nonvisual photoreceptive tasks, such as the regulation of circadian rhythms and the acute suppression of pineal melatonin. The anatomical distribution of melanopsinpositive retinal cells is similar to the pattern of cells known to project from the retina to the suprachiasmatic nuclei of the hypothalamus, a primary circadian pacemaker.

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Section: Discussionmentioning

confidence: 99%

A Novel Human Opsin in the Inner Retina

et al. 2000

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“…When taken at face value, one might come to the conclusion that a Cry-like protein is responsible for light-dependent entrainment of the zebrafish circadian clock. However, until detailed action spectra analyses and functional experiments are done, the possibility still exists that novel opsins, similar to those predicted to be responsible for mammalian photoreception (30)(31)(32), are the primary circadian photopigments in zebrafish.…”

Section: Discussionmentioning

confidence: 99%

A cell-based system that recapitulates the dynamic light-dependent regulation of the vertebrate clock

Pando

Pinchak

Cermakian

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

159

142

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The primary hallmark of circadian clocks is their ability to entrain to environmental stimuli. The dominant, and therefore most physiologically important, entraining stimulus comes from environmental light cycles. Here we describe the establishment and characterization of a new cell line, designated Z3, which derives from zebrafish embryos and contains an independent, light-entrainable circadian oscillator. Using this system, we show distinct and differential light-dependent gene activation for several central clock components. In particular, activation of Per2 expression is shown to be strictly regulated and dependent on light. Furthermore, we demonstrate that Per1, Per2, and Per3 all have distinct responses to light-dark (LD) cycles and light-pulse treatments. We also show that Clock, Bmal1, and Bmal2 all oscillate under LD and dark-dark conditions with similar kinetics, but only Clock is significantly induced while initiating a light-induced circadian oscillation in Z3 cells that have never been exposed to a LD cycle. Finally, our results suggest that Per2 is responsible for establishing the phase of a circadian rhythm entraining to an alternate LD cycle. These findings not only underscore the complexity by which central clock genes are regulated, but also establishes the Z3 cells as an invaluable system for investigating the links between light-dependent gene activation and the signaling pathways responsible for vertebrate circadian rhythms.I n recent years, a new and exciting dimension has been added to our knowledge of the vertebrate circadian clock system. The classical view of the circadian system describes it as diverse physiological rhythms, which are regulated by a centralized clock structure (1, 2). Over the past few years, the idea that the clock consists exclusively of a few centralized structures has been challenged. Data coming from both vertebrate and invertebrate systems have demonstrated that the circadian timing system is dispersed throughout the animal (3-7), and that possibly every cell contains a functional circadian clock (8). In these studies, it has been revealed that a variety of tissues and cells contain functional autonomous clocks. These clocks are able to maintain an oscillation when placed in vitro and removed from any external cues or signals that originate from the classical clock structures and͞or the environment.The discovery of a number of genes involved in the generation and maintenance of circadian oscillations (9, 10) and the recent realization that the circadian system consists of a complex network of independent clocks, which are somehow synchronized to properly regulate all physiological rhythms (5,11,12), has necessitated the development of new tools and methodologies for deciphering the circadian system. An ideal tool is an in vitro cell-based system that displays robust circadian rhythms. Cultured cells may be used to fully understand the complex molecular mechanisms, signal coupling, and regulatory feedback loops that are responsible for the proper timing of a circa...

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“…However, in part because the same experiments on a different strain of rd mice gave a λ max between 500 nm and 515 nm (ref. 32) and interpreted to reflect the action spectrum of mouse middle-wavelength-sensitive (M)-cones, the significance of the first study was never settled. With the rd/rd cl mouse line described here in which the loss of rods and cones is essentially complete, however, the signal from residual cones is no longer an issue.…”

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Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice

Hattar

Lucas

Mrosovsky

et al. 2003

Nature

1,040

917

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In the mammalian retina, besides the conventional rod-cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment [1][2][3][4][5][6][7] . On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive 8 . Furthermore, pupil reflex 8 , light-induced phase delays of the circadian clock 9,10 and period lengthening of the circadian rhythm in constant light 9,10 are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype 11 , and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells 7 . We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions. © 2003 Nature Publishing GroupCorrespondence and requests for materials should be addressed to K.-W.Y. (kwyau@mail.jhmi.edu). Supplementary Information accompanies the paper on www.nature.com/nature. Competing interests statementThe authors declare that they have no competing financial interests. 8 . In independently produced melanopsin-knockout mice, others have found that the ability of light to phase-delay and lengthen the period of the circadian rhythm is also diminished 9,10 . For the pupil reflex, this photic response can be quantitatively accounted for by a functional complementarity between the rod-cone system and the melanopsin system, without the need to invoke any additional light-detection system 8 . Nonetheless, the proposal has persisted that cryptochromes-flavoproteins reported to have a direct light-detecting role in Drosophila 12,13 -may have the same function in mammals [14][15][16] despite earlier evidence to the contrary 17 . To settle this question, we first examined the action spectrum for phase-shifting the circadian rhythm in mice lacking rod and cone photoreceptors (rd/rd cl) 18 . Next, we generated triple-knockout mice lacking all confirmed photodetection systems-Opn4 −/− Gnat1 −/− Cnga3 −/− (melanopsin (also known as opsin 4), guanine nucleotide-binding protein α-transducin 1 (also known as rod transducin α-subunit, or Trα) and cyclic GMP-gated channel A-subunit 3, respectively)-and tested these animals for pupil reflex, circadian photo-entrainment and the masking response to light. NIH Public AccessIrradiance-response relations for the light-induced phase shifting of the circadian rhythm of l...

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Circadian rhythms in mice can be regulated by photoreceptors with cone-like characteristics

Cited by 173 publications

References 22 publications

A Novel Human Opsin in the Inner Retina

A Novel Human Opsin in the Inner Retina

A cell-based system that recapitulates the dynamic light-dependent regulation of the vertebrate clock

Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice

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