Alternative titles; symbols
HGNC Approved Gene Symbol: OPN4
Cytogenetic location: 10q23.2 Genomic coordinates (GRCh38): 10:86,654,547-86,666,460 (from NCBI)
Provencio et al. (2000) used a chicken melanopsin cDNA fragment to isolate a human OPN4 genomic clone. Using PCR and RACE, they obtained a full-length 2.3-kb OPN4 cDNA from retina. Provencio et al. (2000) used the human OPN4 sequence to isolate a mouse melanopsin cDNA, which shares 86% identity with the human OPN4 cDNA sequence within the predicted transmembrane and loop domains. However, the cytoplasmic and extracellular tails of the human and mouse OPN4 are significantly different in sequence and length.
Using RT-PCR to survey 26 human anatomic sites, Provencio et al. (2000) detected OPN4 expression only in the eye. With in situ hybridization histochemistry, Provencio et al. (2000) detected OPN4 expression restricted to a few cells within the ganglion and amacrine cell layers of the primate and murine retinas. Provencio et al. (2000) concluded that the unique inner retinal localization of melanopsin suggests that OPN4 may mediate nonvisual photoreceptive tasks, such as the regulation of circadian rhythms and the acute suppression of pineal melatonin.
Provencio et al. (2002) used an antibody against melanopsin to identify a subset of retinal ganglion cells that morphologically resemble those that project to the suprachiasmatic nucleus, the site of the primary circadian pacemaker. The results indicated that this bilayered photoreceptive net is anatomically distinct from the rod and cone photoreceptors of the outer retina, and suggest that it may mediate nonvisual photoreceptive tasks such as the regulation of circadian rhythms. Provencio et al. (2002) concluded that this photoreceptive system could explain why photoentrainment of circadian rhythms is abolished by bilateral enucleation, yet persists in mice that lack rods and cones.
By cloning rat melanopsin and generating specific antibodies, Hattar et al. (2002) demonstrated that melanopsin is present in cell bodies, dendrites, and proximal axonal segments of a subset of rat retinal ganglion cells. In mice heterozygous for tau-lacZ targeted to the melanopsin gene locus, beta-galactosidase-positive retinal ganglion cell axons projected to the suprachiasmatic nucleus and other brain nuclei involved in circadian photoentrainment or the pupillary light reflex. Rat retinal ganglion cells that exhibited intrinsic photosensitivity invariably expressed melanopsin. Hattar et al. (2002) concluded that melanopsin is most likely the visual pigment of phototransducing retinal ganglion cells that set the circadian clock and initiate other non-image-forming visual functions.
Berson et al. (2002) demonstrated that retinal ganglion cells innervating the suprachiasmatic nucleus are intrinsically photosensitive. Unlike other ganglion cells, they depolarized in response to light even when all synaptic input from rods and cones was blocked. The sensitivity, spectral tuning, and slow kinetics of this light response matched those of the photic entrainment mechanism, suggesting that these ganglion cells may be the primary photoreceptors for this system.
Panda et al. (2005) found that expression of melanopsin in Xenopus oocytes results in light-dependent activation of membrane currents through the G-alpha(q)/G-alpha(11) G protein pathway, with an action spectrum closely matching that of melanopsin-expressing intrinsically photosensitive retinal ganglion cells and of behavioral responses to light in mice lacking rods and cones. When coexpressed with arrestins (181031), melanopsin could use all-trans-retinaldehyde as a chromophore, which suggests that it may function as a bireactive opsin. Panda et al. (2005) also found that melanopsin could activate the cation channel TRPC3 (602345), a mammalian homolog of the Drosophila phototransduction channels trp and trpl. Panda et al. (2005) concluded that melanopsin signals more like an invertebrate opsin than like a classic vertebrate rod and cone opsin.
Melyan et al. (2005) showed that heterologous expression of human melanopsin in a mouse paraneuronal cell line is sufficient to render these cells photoreceptive. Under such conditions, melanopsin acts as a sensory photopigment, coupled to a native ion channel via a G-protein signaling cascade, to drive physiologic light detection. The melanopsin photoresponse relies on the presence of cis isoforms of retinaldehyde and is selectively sensitive to short-wavelength light. Melyan et al. (2005) also presented evidence to show that melanopsin functions as a bistable pigment in this system, having an intrinsic photoisomerase regeneration function that is chromatically shifted to longer wavelengths.
To determine whether melanopsin is a functional sensory photopigment, Qiu et al. (2005) transiently expressed it in HEK293 cells that stably expressed TRPC3 (602345) channels. Light triggered a membrane depolarization in these cells and increased intracellular calcium. The light response resembled that of intrinsically photosensitive retinal ganglion cells, with almost identical spectral sensitivity (lambda max equal approximate to 479 nm). The phototransduction pathway included Gq (600998) or a related G protein, phospholipase C (see 600810), and TRPC3 channels. Qiu et al. (2005) concluded that mammalian melanopsin is a functional sensory photopigment, that it is the photopigment of ganglion cell photoreceptors, and that these photoreceptors may use an invertebrate-like phototransduction cascade.
Dacey et al. (2005) described an anatomically distinct population of 'giant,' melanopsin-expressing ganglion cells in the primate retina that, in addition to being intrinsically photosensitive, are strongly activated by rods and cones, and display a rare, short-off, (long + medium)-on type of color-opponent receptive field. The intrinsic, rod, and (long + medium) cone-derived light responses combine in these giant cells to signal irradiance over the full dynamic range of human vision. In accordance with cone-based color opponency, the giant cells project to the lateral geniculate nucleus, the thalamic relay to primary visual cortex. Thus, Dacey et al. (2005) concluded that in the diurnal trichromatic primate, non-image-forming and conventional image-forming retinal pathways are merged, and the melanopsin-based signal might contribute to conscious visual perception.
Do et al. (2009) reported fundamental parameters governing the light responses and associated spike generation of intrinsically photosensitive retinal ganglion cells (ipRGCs), which use melanopsin as pigment. The membrane density of melanopsin is 10(4)-fold lower than that of rod and cone pigments, resulting in a very low photon catch and a phototransducing role only in relatively bright light. Nonetheless, each captured photon elicits a large and extraordinarily prolonged response, with a unique shape among known photoreceptors. Notably, like rods, these cells are capable of signaling single-photon absorption. A flash caused by a few hundred isomerized melanopsin molecules in a retina is sufficient for reaching threshold for the pupillary light reflex.
Xue et al. (2011) reported that an intrinsic component of the pupillary light reflex (PLR) is widespread in nocturnal and crepuscular mammals. In mouse, this intrinsic PLR requires the visual pigment melanopsin; it also requires PLC-beta-4 (600810), a vertebrate homolog of the Drosophila NorpA phospholipase C, which mediates rhabdomeric phototransduction. The Plcb4 -/- genotype, in addition to removing the intrinsic PLR, also essentially eliminates the intrinsic light response of the M1 subtype of melanopsin-expressing intrinsically photosensitive retinal ganglion cells (M1-ipRGCs), which are by far the most photosensitive ipRGC subtype and also have the largest response to light. Ablating in mouse the expression of both TRPC6 (603652) and TRPC7 (603749), members of the TRP channel superfamily, also essentially eliminated the M1-ipRGC light response, but the intrinsic PLR was not affected. Thus, Xue et al. (2011) concluded that melanopsin signaling exists in both iris and retina, involving a PLC-beta-4-mediated pathway that nonetheless diverges in the 2 locations.
In the mouse, Rao et al. (2013) identified a light response pathway that regulates both regression of embryonic hyaloid vasculature and formation of retinal vasculature. Rao et al. (2013) showed that in mice with mutations in the Opn4 gene, or that are dark-reared from late gestation, the hyaloid vessels are persistent at 8 days postpartum and the retinal vasculature overgrows. Rao et al. (2013) provided evidence that these vascular anomalies are explained by a light response pathway that suppresses retinal neuron number, limits hypoxia, and as a consequence holds local expression of VEGFA (192240) in check. Rao et al. (2013) also showed that the light response for this pathway occurs in late gestation at about embryonic day 16 and requires the photopigment in the fetus and not the mother. Measurements showed that visceral cavity photon flux is probably sufficient to activate melanopsin-expressing retinal ganglion cells in the mouse fetus. Rao et al. (2013) concluded that light, the stimulus for function of the mature eye, is also critical in preparing the eye for vision by regulating retinal neuron number and initiating a series of events that ultimately pattern the ocular blood vessels.
By comparing genomic sequence to cDNA sequence, Provencio et al. (2000) concluded that OPN4 is encoded by 10 exons distributed over 11.8 kb. Provencio et al. (2000) noted that the gene structure of OPN4 is unique among vertebrate opsins.
Using radiation hybrid panels, Provencio et al. (2000) mapped the OPN4 gene to chromosome 10q22.
Lucas et al. (2003) bred animals generated by Hattar et al. (2002) to homozygosity to generate mice in which the melanopsin gene is replaced by tau-LacZ coding sequence. While the retinal ganglion cells that would normally express melanopsin were still present in these animals they were no longer intrinsically photosensitive, although their number, morphology, and projections were unchanged. Opn4 -/- mice showed a pupillary light reflex indistinguishable from that of the wildtype at low irradiances, but at high irradiances the reflex was incomplete, a pattern that suggested that the melanopsin-associated system and the classical rod/cone system are complementary in function.
Ruby et al. (2002) generated melanopsin knockout mice. These mice entrained to a light/dark cycle, phase-shifted after a light pulse, and increased circadian period when light intensity increased. Induction of the immediate-early gene c-fos (164810) was observed after a nighttime light pulse in both wildtype and knockout mice. However, the magnitude of these behavioral responses in knockout mice was 40% lower than in wildtype mice. Although melanopsin is not essential for the circadian clock to receive photic input, it contributes significantly to the magnitude of photic responses.
Panda et al. (2002) independently generated melanopsin knockout mice. The mice entrained to a light/dark cycle and did not exhibit any overt defect in circadian activity rhythms under constant darkness. However, they displayed severely attenuated phase resetting in response to brief pulses of monochromatic light, highlighting the critical role of melanopsin in circadian photoentrainment in mammals.
Hattar et al. (2003) investigated whether photoreceptor systems besides rod-cone and melanopsin participate in pupillary reflex, light-induced phase delays of the circadian clock, and period lengthening of the circadian rhythm in constant light. Using mice lacking rods and cones, Hattar et al. (2003) measured the action spectrum for phase-shifting the circadian rhythm of locomotor behavior. This spectrum matched that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. Hattar et al. (2003) also generated triple-knockout mice (for Gnat, 139330, Cnga3, 600053, and Opn4) in which the rod-cone and melanopsin systems were both silenced. These animals had an intact retina but failed to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, Hattar et al. (2003) concluded that the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.
Panda et al. (2003) observed that mice with both outer retinal degeneration and a deficiency in melanopsin exhibited complete loss of photoentrainment of the circadian oscillator, pupillary light responses, photic suppression of arylalkylamine-N-acetyltransferase transcript, and acute suppression of locomotor activity by light. Panda et al. (2003) concluded that these observations indicated the importance of both nonvisual and classical visual photoreceptor systems for nonvisual photic responses in mammals.
To determine how melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) relay rod-cone light information for both image-forming and non-image-forming functions, Guler et al. (2008) genetically ablated ipRGCs in mice. The authors showed that animals lacking ipRGCs retained pattern vision but had deficits in both pupillary light reflex (PLR) and circadian photoentrainment that were more extensive than those observed in melanopsin knockouts. The defects in PLR and photoentrainment resembled those observed in animals that lack phototransduction in all 3 photoreceptor classes. Guler et al. (2008) concluded that light signals for irradiance detection are dissociated from pattern vision at the retinal ganglion cell level, and animals that cannot detect light for non-image-forming functions are still capable of image formation.
LeGates et al. (2012) demonstrated that aberrant light directly impairs mood and learning though melanopsin-expressing neurons. The aberrant light cycle, which is 3.5 hours light to 3.5 hours dark, also known as T7 lighting, neither changes the amount and architecture of sleep nor causes changes in the circadian timing system. Animals exposed to the aberrant light cycle maintained daily corticosterone rhythms, but the overall levels of corticosterone were increased. Despite normal circadian and sleep structures, these animals showed increased depression-like behaviors and impaired hippocampal long-term potentiation and learning. Administration of the antidepressant drugs fluoxetine or desipramine restored learning in mice exposed to the aberrant light cycle, suggesting that the mood deficit precedes the learning impairments. To determine the retinal circuits underlying this impairment of mood and learning, LeGates et al. (2012) examined the behavioral consequences of this light cycle in animals that lacked intrinsically photosensitive retinal ganglion cells, which express melanopsin. In these animals, the aberrant light cycle did not impair mood and learning, despite the presence of the conventional retinal ganglion cells and the ability of these animals to detect light for image formation. LeGates et al. (2012) concluded that these findings demonstrated the ability of light to influence cognitive and mood functions directly through intrinsically photosensitive retinal ganglion cells.
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