Morphological and Physiological Consequences of the Selective Elimination of Rod Photoreceptors in Transgenic Mice

McCall, Maureen A.; Gregg, Ronald G.; Merriman, Kathryn E.; Goto, Yoshinobu; Peachey, Neal S.; Stanford, L. R.

doi:10.1006/exer.1996.0089

Cited by 64 publications

(40 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…rpe65 Ϫ/Ϫ , rdta (26), lrat Ϫ/Ϫ (23), and C3H͞HeJ (rd͞rd) mice were crossed to generate rpe65 Ϫ/Ϫ ; rdta and lrat Ϫ/Ϫ ; rd͞rd mice. Mice were genotyped by using established protocols from tailsnip DNA (22,23,26,48). Sibling mixed-strain mice were used for PLR measurements.…”

Section: Methodsmentioning

confidence: 99%

“…To test whether this relative insensitivity of lrat Ϫ/Ϫ and rpe65 Ϫ/Ϫ mice is due to a direct effect of these mutations on the inner retinal chromophore regeneration mechanism, we generated two compound mutations, combining outer retinal mutants rdta (in which diphtheria toxin is driven under a rod-specific promoter, resulting in early and severe outer retinal degeneration; ref. 26) and rd͞rd (a null mutation in Pde6b resulting in total loss of rod and near-total loss of cone function; refs. [27][28][29] with rpe65 Ϫ/Ϫ (22) and lrat Ϫ/Ϫ (23), respectively.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inner retinal photoreception independent of the visual retinoid cycle

Tu¹,

Owens²,

Anderson³

et al. 2006

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

View full text Add to dashboard Cite

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...

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Inner retinal photoreception independent of the visual retinoid cycle

Tu¹,

Owens²,

Anderson³

et al. 2006

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

View full text Add to dashboard Cite

show abstract

“…Retinas destined for organ culture experiments were isolated from 5-week-old C3H mice homozygous for the rd locus (C3H͞He, rd͞rd). This age was selected in view of earlier work (17,18) showing that, at this age, almost no rods are left whereas Ͼ50% of cones are still present. Retinas from rd mice aged 5 and 6 weeks also were isolated to estimate the cone cell loss during the sixth 1-week period in vivo.…”

Section: Methodsmentioning

confidence: 99%

“…In several models with selective elimination of rods, secondary loss of cones is observed (9)(10)(11). The cause of rod cell death in these animals, either transgenic or spontaneous mutants, cannot account for direct cone cell loss (9)(10)(11)(12)(13)(14)(15)(16)(17). Putative mechanisms of cone cell death include the liberation of endotoxins by degenerating rods, environmental alteration, or deprivation of rod-derived trophic factor(s).…”

mentioning

confidence: 99%

Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse

Mohand‐Saïd¹,

Deudon-Combe²,

Hicks³

et al. 1998

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

185

123

View full text Add to dashboard Cite

The role of cellular interactions in the mechanism of secondary cone photoreceptor degeneration in inherited retinal degenerations in which the mutation specifically affects rod photoreceptors was studied. We developed an organ culture model of whole retinas from 5-week-old mice carrying the retinal degeneration mutation, which at this age contain few remaining rods and numerous surviving cones cocultured with primary cultures of mixed cells from postnatal day 8 normal-sighted mice (C57BL͞6) retinas or retinal explants from normal (C57BL͞6) or dystrophic (C3H͞He) 5-week-old mice. After 7 days, the numbers of residual cone photoreceptors were quantified after specific peanut lectin or anti-arrestin antibody labeling by using an unbiased stereological approach. Examination of organ cultured retinas revealed significantly greater numbers of surviving cones (15-20%) if cultured in the presence of retinas containing normal rods as compared with controls or cocultures with rod-deprived retinas. These data indicate the existence of a diffusible trophic factor released from retinas containing rod cells and acting on retinas in which only cones are present. Because cones are responsible for high acuity and color vision, such data could have important implications not only for eventual therapeutic approaches to human retinal degenerations but also to define interactions between retinal photoreceptor types.Despite recent advances, our understanding of the mechanisms underlying visual malfunction and cell loss in retinitis pigmentosa (RP) has provided few clinically significant clues to improve retinal cell survival (1-3). RP forms a group of inherited photoreceptor dystrophies characterized largely by early features of rod photoreceptor impairment (1, 4). Most identified forms of RP are caused by defects in proteins restricted to rod photoreceptors (5-8). Yet, at various stages of the disease, a loss of the photopic function reflecting degeneration of cone photoreceptors is found consistently (1, 4). Of extreme importance for the patient, cone cell death and its functional consequences appear to be secondary events. No current data exist to account for cone cell death, but observations made on animal models of RP provide arguments for cone survival depending on the presence of rods. In several models with selective elimination of rods, secondary loss of cones is observed (9-11). The cause of rod cell death in these animals, either transgenic or spontaneous mutants, cannot account for direct cone cell loss (9-17). Putative mechanisms of cone cell death include the liberation of endotoxins by degenerating rods, environmental alteration, or deprivation of rod-derived trophic factor(s). Recent studies using chimeras of normal and transgenic mice carrying mutations in rods showed that photoreceptor cell death was diffuse rather than restricted to areas with mutations in rods, providing evidence for a role of cellular interactions between photoreceptors in survival and degeneration of these cells (18). Based on these dat...

show abstract

“…rd is a null mutation of the gene encoding the ␤-subunit of the rod-specific phosphodiesterase, which abolishes rod phototransduction and induces a gradual degeneration of rod cells (15). The rdta transgene also induces rod degeneration, but in this case, through targeted expression of diphtheria toxin (16). Both models experience substantial secondary effects on cone viability, but, importantly, ipRGCs seem to be largely unaffected.…”

mentioning

confidence: 99%

Chromophore regeneration: Melanopsin does its own thing

Lucas¹

2006

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

View full text Add to dashboard Cite

Morphological and Physiological Consequences of the Selective Elimination of Rod Photoreceptors in Transgenic Mice

Cited by 64 publications

References 0 publications

Inner retinal photoreception independent of the visual retinoid cycle

Inner retinal photoreception independent of the visual retinoid cycle

Normal retina releases a diffusible factor stimulating cone survival in the retinal degeneration mouse

Chromophore regeneration: Melanopsin does its own thing

Contact Info

Product

Resources

About