Ignacio Provencio

Univrersity of Virginia · Department of Biology

Chronobiology investigations have revealed much about cellular and physiological clockworks but we are far from having a complete mechanistic understanding of the physiological and ecological implications. Here we present some unresolved questions in circadian biology research as posed by the editorial staff and guest contributors to the Journal of...

Circadian Biology intersects with diverse scientific domains, intricately woven into the fabric of organismal physiology and behavior. The rhythmic orchestration of life by the circadian clock serves as a focal point for researchers across disciplines. This retrospective examination delves into several of the scientific milestones that have fundame...

Glaucoma is a group of eye diseases afflicting more than 70 million people worldwide. It is characterized by damage to retinal ganglion cells (RGCs) that ultimately leads to the death of the cells and vision loss. The diversity of RGC types has been appreciated for decades, and studies, including ours, have shown that RGCs degenerate and die in a t...

Glaucoma is a group of eye diseases characterized by retinal ganglion cell (RGC) loss and optic nerve damage. Studies, including this study, support that RGCs degenerate and die in a type-specific manner following the disease insult. Here we specifically examined one RGC type, the intrinsically photosensitive retinal ganglion cell (ipRGC), and its...

Since the discovery of melanopsin as a retinal non-visual photopigment, opsins have been described in several organs and cells. This distribution is strikingly different from the classical localization of photopigments in light-exposed tissues such as the eyes and the skin. More than 10 years ago, a new paradigm in the field was created as opsins w...

Since the discovery of the non-image-forming visual system, tremendous research efforts have been dedicated to understanding its mechanisms and functional roles. Original functions associated with the melanopsin system include the photoentrainment of circadian sleep-wake cycles and the pupillary light reflex. Recent findings, however, suggest a muc...

Metabolic disorders have been established as major risk factors for ocular complications and poor vision. However, little is known about the inverse possibility that ocular disease may cause metabolic dysfunction. To test this hypothesis, we assessed the metabolic consequences of a robust dietary challenge in several mouse models suffering from ret...

Light is a potent stimulus for regulating circadian, hormonal, and behavioral systems. In addition, light therapy is effective for certain affective disorders, sleep problems, and circadian rhythm disruption. These biological and behavioral effects of light are influenced by a distinct photoreceptor in the eye, melanopsin-containing intrinsically p...

Daniel M Warthen,1,2 Ignacio Provencio11Department of Biology, University of Virginia, Charlottesville, VA, USA; 2Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USAAbstract: Light exerts many effects on behavior and physiology. These effects can be characterized as either image-forming or nonimage-formin...

Melanopsin (gene symbol: Opn4) is the G protein-coupled photopigment that confers photosensitivity upon intrinsically photosensitive retinal ganglion cells (ipRGCs). ipRGCs are the third class of retinal photoreceptor in mammals, complementing the two previously identified classes, the rods and cones. This novel class, however, differs from rods an...

The ability to learn, remember, and respond to emotional events is a powerful survival strategy. However, dysregulated behavioral and physiological responses to these memories are maladaptive. To fully understand learned fear and the pathologies that arise during response malfunction we must reveal the environmental variables that influence learned...

Our bodies adjust to the cycle of day and night thanks to specialized neurons in our eyes. Ongoing Study of these cells could lead to new treatments for winter depression and other conditions

In mammals, photoreception is restricted to the eye. By contrast, nonmammalian vertebrates possess photoreceptors in a wide array of extraocular tissues, including the pineal complex and brain (1). The identity of the deep brain photoreceptors has remained elusive. They continue to be the least studied of all nonvisual photoreceptor classes, althou...

Melanopsin is the photopigment of intrinsically photosensitive retinal ganglion cells (ipRGCs). Melanopsin immunoreactivity reveals two dendritic plexuses within the inner plexiform layer (IPL) and morphologically heterogeneous retinal ganglion cells. Using enhanced immunohistochemistry, we provide a fuller description of murine cell types expressi...

To study the melanopsin system of the albino CD1 mouse retina during postnatal development. Pups were kept under different ambient conditions: light/dark (LD) cycles, constant light (LL), constant darkness (DD), LL followed by LD, and DD followed by LL. Using immunohistochemistry, melanopsin-expressing cells were classified as M1 or M2 according to...

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are a relatively recently discovered novel class of photoreceptor in the vertebrate retina. The photopigment melanopsin confers photosensitivity upon these cells. ipRGCs mediate nonvisual effects of light. The anatomy, physiology, and function of these cells are described herein.

Melanin granule (melanosome) dispersion within Xenopus laevis melanophores is evoked either by light or alpha-MSH. We have previously demonstrated that the initial biochemical steps of light and alpha-MSH signaling are distinct, since the increase in cAMP observed in response to alpha-MSH was not seen after light exposure. cAMP concentrations in re...

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Melanopsin, a non-visual photopigment, may play a role in aberrant responses to low winter light levels in Seasonal Affective Disorder (SAD). We hypothesize that functional sequence variation in the melanopsin gene could contribute to increasing the light needed for normal functioning during winter in SAD. Associations between alleles, genotypes, a...

Non-image related responses to light, such as the synchronization of circadian rhythms to the day/night cycle, are mediated by classical rod/cone photoreceptors and by a small subset of retinal ganglion cells that are intrinsically photosensitive, expressing the photopigment, melanopsin. This raises the possibility that the melanopsin cells may be...

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Light, including artificial light, has a range of effects on human physiology and behavior and can therefore alter human physiology when inappropriately timed. One example of potential light-induced disruption is the effect of light on circadian organization, including the production of several hormone rhythms. Changes in light-dark exposure (e.g.,...

Melanopsin is the photopigment that confers photosensitivity upon intrinsically photosensitive retinal ganglion cells (ipRGCs). This subset of retinal ganglion cells comprises less than 2% of all RGCs in the mammalian retina. The paucity of melanopsin-positive cells has made studies on melanopsin signaling difficult to pursue in ipRGCs. To address...

Intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin (OPN4), together with rods and cones, provide light information driving nonvisual light responses. We examined nonvisual photoreception in mice lacking RPE65, a protein that is required for regeneration of visual chromophore in rods and cones. Althou...

Intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate numerous nonvisual phenomena, including entrainment of the circadian clock to light-dark cycles, pupillary light responsiveness, and light-regulated hormone release. We have applied multielectrode array recording to characterize murine ipRGCs. We find that all ipRGC photosensitivi...

Within the past decade, several non-canonical opsins have been identified in mammals. These include RGR, peropsin, melanopsin, encephalopsin, and neuropsin. Although all are expressed in the eye, it is likely that they serve to mediate non-visual effects of light on physiology. Some of these opsins, however, may play an indirect role in vision by g...

Melanopsin1, 2, 3, 4, 5, 6, 7, 8 has been proposed to be the photopigment of the intrinsically photosensitive retinal ganglion cells (ipRGCs)7, 8, 9, 10, 11, 12, 13, 14, 15; these photoreceptors of the mammalian eye drive circadian and pupillary adjustments through direct projections to the brain5, 6, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18. Their act...

Melanopsin is the photopigment that confers light sensitivity on intrinsically photosensitive retinal ganglion cells. Mammalian intrinsically photosensitive retinal ganglion cells are involved in the photic synchronization of circadian rhythms to the day–night cycle. Here, we report molecular components of melanopsin signaling using the cultured Xe...

The avian retina and pineal gland contain autonomous circadian oscillators and photo-entrainment pathways, but the photopigment(s) that mediate entrainment have not been definitively identified. Melanopsin (Opn4) is a novel opsin involved in entrainment of circadian rhythms in mammals. Here, we report the cDNA cloning of chicken melanopsin and show...

Retinal input to the hypothalamic suprachiasmatic nucleus (SCN) synchronizes the SCN circadian oscillator to the external day/night cycle. Retinal ganglion cells that innervate the SCN via the retinohypothalamic tract are intrinsically light sensitive and express melanopsin. In this study, we provide data indicating that not all SCN-projecting reti...

The circadian clock in the suprachiasmatic nucleus (SCN) receives direct retinal input via the retinohypothalamic tract (RHT), and the retinal ganglion cells contributing to this projection may be specialized with respect to direct regulation of the circadian clock. However, some ganglion cells forming the RHT bifurcate, sending axon collaterals to...

Although mice lacking rod and cone photoreceptors are blind, they retain many eye-mediated responses to light, possibly through photosensitive retinal ganglion cells. These cells express melanopsin, a photopigment that confers this photosensitivity. Mice lacking melanopsin still retain nonvisual photoreception, suggesting that rods and cones could...

An understanding of the retinal mechanisms in mammalian photoentrainment will greatly facilitate optimization of the wavelength, intensity, and duration of phototherapeutic treatments designed to phase shift endogenous biological rhythms. A small population of widely dispersed retinal ganglion cells projecting to the suprachiasmatic nucleus in the...

Melanopsin is a novel opsin synthesized in a small subset of retinal ganglion cells. Ganglion cells expressing melanopsin are capable of depolarizing in response to light in the absence of rod or cone input and are thus intrinsically light sensitive. Melanopsin ganglion cells convey information regarding general levels of environmental illumination...

Anatomical and physiological studies have suggested that the pineal gland of neonatal mammals has a photoreceptive capacity. Using the golden hamster (Mesocricetus auratus) as our model, we applied biochemical approaches to look for a functional photopigment within the pineal during early development. Immunocytochemistry and enzyme-linked immunosor...

The master circadian oscillator in the hypothalamic suprachiasmatic nucleus is entrained to the day/night cycle by retinal photoreceptors. Melanopsin (Opn4), an opsin-based photopigment, is a primary candidate for photoreceptor-mediated entrainment. To investigate the functional role of melanopsin in light resetting of the oscillator, we generated...

Mammalian free-running circadian rhythms are entrained to the external light/dark cycle by photic signaling to the suprachiasmatic nuclei via the retinohypothalamic tract (RHT). We investigated the circadian entrainment and clock properties of math5-/- mutant mice. math5 is a critical regulator of retinal ganglion cell development; math5-/- mice sh...

We report microspectrophotometric (MSP) data for the visual pigments and oil droplets of 17 species of Caribbean anoline lizard known to live in differing photic habitats and having distinctly different dewlap colors. The outgroup Polychrus marmoratus was also examined to gain insight into the ancestral condition. Except for Anolis carolinensis, wh...

We have discovered an expansive photoreceptive 'net' in the mouse inner retina, visualized by using an antiserum against melanopsin, a likely photopigment. This immunoreactivity is evident in a subset of retinal ganglion cells that morphologically resemble those that project to the suprachiasmatic nucleus (SCN), the site of the primary circadian pa...

The profound effects of the circadian clock on physiology and behavior are frequently ignored. Differences in the time of day during which drugs are administered can result in dramatic differences in efficacy and tolerance of side effects. Chronic fatigue and gastrointestinal irritability experienced by shift workers, and the general malaise of jet...

Canavan disease is caused by mutations in aspartoacylase, the enzyme that degrades N-acetylaspartate (NAA) into acetate and aspartate. Murine aspartoacylase (mASPA) was cloned using sequence information from mouse expressed sequence tags homologous to the human cDNA. The open reading frame was cloned into a thioredoxin fusion vector, overexpressed...

Melanopsin is expressed by scattered perikarya among the amacrine and ganglion cells of the primate retina. In amphibians, melanopsin is expressed in the retina, hypothalamus, iridial myocytes, and melanophores. Amphibian melanophore responses to light protect vital organs against ultraviolet irradiation and produce rapid color changes needed for c...

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 exo...

Many of the complex environmental demands, and hence selection pressures, imposed upon an organism are associated with periodic events like the day:night cycle, the seasons or the tides. An organism could simply change behaviour in response to these changing conditions but responses, by their very nature, are subject to delays. In many cases change...

The availability of naturally occurring and transgenic retinal mutants has made the mouse an attractive experimental model to address questions regarding photoentrainment of circadian rhythms. However, very little is known about the retinal cells and the retinal projections to the nuclei of the murine circadian timing system. Furthermore, the effec...

We have identified an opsin, melanopsin, in photosensitive dermal melanophores of Xenopus laevis. Its deduced amino acid sequence shares greatest homology with cephalopod opsins. The predicted secondary structure of melanopsin indicates the presence of a long cytoplasmic tail with multiple putative phosphorylation sites, suggesting that this opsin’...

In this report we have characterized the photopigments mediating circadian phase shifts in retinal degenerate (rd) mice. In aged rd/rd mice, which lack detectable opsin, high performance liquid chromatography (HPLC) was used to quantify the photopigment chromophore 11-cis-retinaldehyde. This chromophore was photoisomerized in whole eyes, suggesting...

In the retinal degeneration (rd) mouse the absence of rod cells and the progressive loss of cones does not result in a decrease in circadian phase shifting responses to light. By contrast, rd/rd mice are unable to perform simple visual tasks. In addition, rodless transgenic mice, and mice homozygous for the retinal degeneration slow (rds) mutation,...

The progression of photoreceptor degeneration in retinally degenerate (rd) mice commences early in postnatal development resulting in the complete loss of rods by 60-70 days of age followed by the more protracted loss of cones. We have previously shown that rd mice 80 days of age are capable of phase shifting their circadian locomotor rhythms in re...

Since the beginning of this century evidence has accumulated which demonstrates that nonmammalian vertebrates possess photoreceptors situated deep within the brain. These photoreceptors have been implicated in several different areas of physiology, but in all species examined, they play a critical role in the regulation of circadian and reproductiv...

Fully terrestrial vertebrates were previously thought to exclusively employ vitamin A1 to generate visual pigments. However, recent studies on the visual system of the lizard Anolis carolinensis have shown that its visual pigments are vitamin A2-based. This unexpected result prompted an investigation of the pineal photopigments in this species [13]...

Our recent studies have examined circadian photoreception in mice with hereditary retinal disorders (rd/rd and rds/rds). Despite the loss of visual function in these mice, circadian responses to light remain unaffected. Using c-fos expression within the suprachiasmatic nuclei (SCN) as a marker of neural activation of the circadian entrainment pathw...

Since the beginning of this century evidence has accumulated which demonstrates that non-mammalian vertebrates possess photoreceptors situated deep within the brain. While many attempts have been made to localize these sensory cells, studies have either failed or been inconclusive. In this report we have used several experimental approaches to loca...

As part of a broad study of the ocular and extraocular photoreceptors of reptiles, we have used high performance liquid chromatography (HPLC) to identify the retinoids present in whole eye extracts of the arboreal lizard Anolis carolinensis and the non-arboreal ruin lizard Podarcis sicula. Unexpectedly, only vitamin A2-derived chromophore was detec...

We have examined the effects of light on circadian locomotor rhythms in retinally degenerate mice (C57BL/6J mice homozygous for the rd allele: rd/rd). The sensitivity of circadian photoreception in these mice was determined by varying the irradiance of a 15 min light pulse (515 nm) given at circadian time 16 and meauring the magnitude of the phase...

In seasonally breeding mammals, seasonal alterations in day length are perceived via the pineal hormone melatonin. When exposed to short day lengths, hamsters and other long-day breeders undergo gonadal regression. With chronic exposure (greater than 20 weeks) to short days, however, the animals become photorefractory, or insensitive to the inhibit...