Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin

Fu, Yingbin; Zhong, Haining; Wang, Min Hua H.; Luo, Dong; Liao, Hsi Wen; Maeda, Hidetaka; Hattar, Samer; Frishman, Laura J.; Yau, King Wai

doi:10.1073/pnas.0501866102

Cited by 133 publications

(118 citation statements)

References 40 publications

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“…Alternatively, loss of visual cycle enzymes might alter chromophore availability to the inner retina, without directly affecting the inner retinal photocycle itself. Such a mechanism is consistent with the observations of Fu et al (25) that pupillary sensitivity of gnat1 Ϫ/Ϫ ;cnga3 Ϫ/Ϫ ;rpe65 Ϫ/Ϫ could be increased after treatment with 9-cis-retinal. Thus, it becomes important to distinguish acute from chronic effects of visual cycle enzyme loss.…”

Section: Pharmacologic Inhibition Of Visual Retinoid Cycle Causes Lossupporting

confidence: 81%

“…1). Consistent with previous reports (23,25,31), mice with mutations in visual cycle enzymes showed PLRs substantially less sensitive than those of mice with outer retinal degeneration. Lrat Ϫ/Ϫ and rpe65 Ϫ/Ϫ mice showed half-maximal constriction of pupils at Ϸ8.9 ϫ 10 14 photons⅐cm Ϫ2 ⅐s Ϫ1 compared with half-maximal constriction at 6.3 ϫ 10 12 photons⅐cm Ϫ2 ⅐s Ϫ1 for rd͞rd and rdta, and 1.5 ϫ 10 11 photons⅐cm Ϫ2 ⅐s Ϫ1 for wild-type C57BL͞6 mice.…”

Section: Plrs Of Rpe65supporting

confidence: 80%

“…3). Consistent with the previous report of Fu et al (25), treatment of rpe65 Ϫ/Ϫ ; rdta mice with 9-cis-retinal resulted in a Ϸ0.7 log increase in PLR sensitivity, indicating that the inner retinas of these mice have chronic, reversible chromophore depletion. Interestingly, we saw a small but statistically significant increase in the PLR sensitivity of rd͞rd mice treated with 9-cis-retinal, suggesting that in the rd͞rd animal, melanopsin may not be saturated with chromophore.…”

Section: Pharmacologic Inhibition Of Visual Retinoid Cycle Causes Lossupporting

confidence: 80%

“…However, such a model predicts that the effects of outer retinal degeneration should be additive with those of rpe65 Ϫ/Ϫ and lrat Ϫ/Ϫ . Fu et al (25) reported that combining two mutations, rod transducin (gnat1) and cone nucleotide gated channel (cnga3), with rpe65 Ϫ/Ϫ resulted in mice that had significantly lower PLRs than gnat1 Ϫ/Ϫ ; cnga3 Ϫ/Ϫ mice alone; however, comparison of the gnat1 Ϫ/Ϫ ; cnga3 Ϫ/Ϫ ; rpe65 Ϫ/Ϫ mutant mice to rpe65 Ϫ/Ϫ was not reported. In the present experiments, we similarly found that compounding outer retinal degeneration mutations rdta and rd͞rd with rpe65 Ϫ/Ϫ and lrat Ϫ/Ϫ , respectively, resulted in mice with less sensitive PLRs than those with outer retinal degeneration mutations alone.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that the PLRs of mice lacking RPE65 or Lrat are Ϸ1,000-fold less sensitive than wild-type animals (23); furthermore, these animals show Ϸ100-fold lower pupillary response sensitivity than animals blind from outer retinal degeneration caused by the rodless-coneless (rdta;cl) and outer retinal degeneration (rd͞rd) mutations (4,24). Fu et al (25) compounded mutations causing loss of outer retinal function [rod transducin (gnat1) and cone nucleotide gated channel (cnga3)] with mutations in rpe65 and found less sensitive PLRs in the gnat1 Ϫ/Ϫ ;cnga3 Ϫ/Ϫ ;rpe65 Ϫ/Ϫ mice than in the gnat1 Ϫ/Ϫ ; cnga3 Ϫ/Ϫ mice.…”

mentioning

confidence: 99%

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Inner retinal photoreception independent of the visual retinoid cycle

Tu¹,

Owens²,

Anderson³

et al. 2006

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

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Mice lacking the visual cycle enzymes RPE65 or lecithin-retinol acyl transferase (Lrat) have pupillary light responses (PLR) that are less sensitive than those of mice with outer retinal degeneration (rd͞rd or rdta). Inner retinal photoresponses are mediated by melanopsinexpressing, intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting that the melanopsin-dependent photocycle utilizes RPE65 and Lrat. To test this hypothesis, we generated rpe65 ؊/؊ ; rdta and lrat ؊/؊ ; rd͞rd mutant mice. Unexpectedly, both rpe65 ؊/؊ ; rdta and lrat ؊/؊ ; rd͞rd mice demonstrate paradoxically increased PLR photosensitivity compared with mice mutant in visual cycle enzymes alone. Acute pharmacologic inhibition of the visual cycle of melanopsin-deficient mice with all-trans-retinylamine results in a near-total loss of PLR sensitivity, whereas treatment of rd͞rd mice has no effect, demonstrating that the inner retina does not require the visual cycle. Treatment of rpe65 ؊/؊ ; rdta with 9-cis-retinal partially restores PLR sensitivity. Photic sensitivity in P8 rpe65 ؊/؊ and lrat ؊/؊ ipRGCs is intact as measured by ex vivo multielectrode array recording. These results demonstrate that the melanopsin-dependent ipRGC photocycle is independent of the visual retinoid cycle.melanopsin ͉ pupillary light response ͉ retinal degeneration ͉ retinal ganglion cell ͉ visual photocycle M ice blind from outer retinal degeneration retain the ability to entrain their circadian rhythms to external light-dark cycles, have active pupillary light responses (PLRs), and exhibit photically induced melatonin suppression (1-4). These responses depend on the opsin family member melanopsin (5), which is expressed exclusively in a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) (6-8). Mice with nonfunctional or degenerated rods and cones that also lack melanopsin show no photically influenced behavior or physiology (9, 10), and intrinsic photosensitivity of retinal ganglion cells is lost in the absence of melanopsin (9,11,12). Melanopsin forms a functional photopigment when heterologously expressed in COS cells (13), Xenopus oocytes (14), Neuro-2A cells (15), or HEK-293 cells (16). Melanopsin is thus necessary for ipRGC photoreception, and is sufficient to confer photosensitivity on intrinsically insensitive cell types. Taken together, these results strongly suggest that melanopsin is the photopigment of inner retinal photoreception.All opsin photopigments use a retinoid chromophore that undergoes isomerization upon absorption of an appropriate wavelength photon. In rod photoreceptors, 11-cis-retinal chromophore is photoisomerized to all-trans-retinal which dissociates from the opsin protein (17). This all-trans-retinal photoproduct is recycled to the active (11-cis) form by enzymatic conversion in the adjacent retinal pigment epithelium (RPE) (18). The chromophore used by melanopsin in situ is not presently known. ipRGCs are physically distant from the enzymatic chromophore regeneration machinery of the RPE. It is present...

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Section: Pharmacologic Inhibition Of Visual Retinoid Cycle Causes Lossupporting

confidence: 81%

Section: Plrs Of Rpe65supporting

confidence: 80%

Section: Pharmacologic Inhibition Of Visual Retinoid Cycle Causes Lossupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Inner retinal photoreception independent of the visual retinoid cycle

Tu¹,

Owens²,

Anderson³

et al. 2006

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

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Central projections of melanopsin‐expressing retinal ganglion cells in the mouse

Hattar

Kumar

Park

et al. 2006

J of Comparative Neurology

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858

1,093

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A rare type of ganglion cell in mammalian retina is directly photosensitive. These novel retinal photoreceptors express the photopigment melanopsin. They send axons directly to the suprachiasmatic nucleus (SCN), intergeniculate leaflet (IGL), and olivary pretectal nucleus (OPN), thereby contributing to photic synchronization of circadian rhythms and the pupillary light reflex. Here, we sought to characterize more fully the projections of these cells to the brain. By targeting tau-lacZ to the melanopsin gene locus in mice, ganglion cells that would normally express melanopsin were induced to express, instead, the marker enzyme beta-galactosidase. Their axons were visualized by X-gal histochemistry or anti-beta-galactosidase immunofluorescence. Established targets were confirmed, including the SCN, IGL, OPN, ventral division of the lateral geniculate nucleus (LGv), and preoptic area, but the overall projections were more widespread than previously recognized. Targets included the lateral nucleus, peri-supraoptic nucleus, and subparaventricular zone of the hypothalamus, medial amygdala, margin of the lateral habenula, posterior limitans nucleus, superior colliculus, and periaqueductal gray. There were also weak projections to the margins of the dorsal lateral geniculate nucleus. Co-staining with the cholera toxin B subunit to label all retinal afferents showed that melanopsin ganglion cells provide most of the retinal input to the SCN, IGL, and lateral habenula and much of that to the OPN, but that other ganglion cells do contribute at least some retinal input to these targets. Staining patterns after monocular enucleation revealed that the projections of these cells are overwhelmingly crossed except for the projection to the SCN, which is bilaterally symmetrical.

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Morphology and mosaics of melanopsin‐expressing retinal ganglion cell types in mice

Berson

Castrucci

Provencio

2010

J of Comparative Neurology

191

281

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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 expressing melanopsin, their contribution to the plexuses of melanopsin dendrites, and mosaics formed by each type. M1 cells, corresponding to the originally described ganglion-cell photoreceptors, occupy the ganglion cell or inner nuclear layers. Their large, sparsely branched arbors (mean diameter 275 µm) monostratify at the outer limit of the OFF sublayer. M2 cells also have large, monostratified dendritic arbors (mean diameter 310 µm), but ramify in the inner third of the IPL, within the ON sublayer. There are approximately 900 M1 cells and 800 M2 cells per retina; each type comprises roughly 1–2% of all ganglion cells. The cell bodies of M1 cells are slightly smaller than those of M2 cells (mean diameters: 13 µm for M1, 15 µm for M2). Dendritic field overlap is extensive within each type (coverage factors ~3.8 for M1 and 2.5 for M2 cells). Rare bistratified cells deploy terminal dendrites within both melanopsin-immunoreactive plexuses. Because these are too sparsely distributed to permit complete retinal tiling, they lack a key feature of true ganglion cell types and may be anomalous hybrids of the M1 and M2 types. Finally, we observed weak melanopsin immunoreactivity in other ganglion cells, mostly with large somata, that may constitute one or more additional types of melanopsin-expressing cells.

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Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin

Cited by 133 publications

References 40 publications

Inner retinal photoreception independent of the visual retinoid cycle

Inner retinal photoreception independent of the visual retinoid cycle

Central projections of melanopsin‐expressing retinal ganglion cells in the mouse

Morphology and mosaics of melanopsin‐expressing retinal ganglion cell types in mice

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