Rod-Cone Dysplasia in Irish Setters: A Defect in Cyclic GMP Metabolism in Visual Cells

Aquirre, G; Farber, Debora B.; Lolley, Richard N.; Fletcher, Reid; Gj, Chader

doi:10.1126/science.210508

Cited by 191 publications

(58 citation statements)

References 8 publications

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“…24 A total of 19 eyes of 12 dogs were injected; 11 dogs (18 eyes) were normal, and one was affected with a PDE6B mutation causing primary, early rod degeneration (Table 1). 26,27 In 16 eyes, the vector was injected into the subretinal space with visible bleb formation (Figure 3). In the remaining three eyes the vector was injected underneath the retinal pigment epithelium (RPE); the rAAV was unable to target the cone photoreceptors following these sub-RPE injections as no GFP expression was detected in these eyes.…”

Section: Resultsmentioning

confidence: 99%

“…This disease is caused by a mutation in the PDE6B gene, and leads to abnormal development and early degeneration of rod photoreceptors before the canine retina is fully developed. 26,27 At 5 weeks, the function and structure of the cone photoreceptors is still normal. 26 Strong and specific GFP expression could be seen in all the L/M cones of the rcd1-affected retina 4 weeks after injection (Figure 4g).…”

Section: Human Red Cone Opsin Promotersmentioning

confidence: 99%

“…26,27 At 5 weeks, the function and structure of the cone photoreceptors is still normal. 26 Strong and specific GFP expression could be seen in all the L/M cones of the rcd1-affected retina 4 weeks after injection (Figure 4g). At the age examined, the length of the cone photoreceptor cells appeared shorter because of the severe loss of rods which causes the cone inner segments to shorten and broaden.…”

Section: Human Red Cone Opsin Promotersmentioning

confidence: 99%

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Targeting gene expression to cones with human cone opsin promoters in recombinant AAV

et al. 2008

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Specific cone-directed therapy is of high priority in the treatment of human hereditary retinal diseases. However, not much information exists about the specific targeting of photoreceptor subclasses. Three versions of the human red cone opsin promoter (PR0.5, 3LCR-PR0.5 and PR2.1), and the human blue cone opsin promoter HB569, were evaluated for their specificity and robustness in targeting green fluorescent protein (GFP) gene expression to subclasses of cones in the canine retina when used in recombinant adeno-associated viral vectors of serotype 5. The vectors were administered by subretinal injection. The promoter PR2.1 led to most effective and specific expression of GFP in the long-and medium-wavelength-absorbing cones (L/M cones) of normal and diseased retinas. The PR0.5 promoter was not effective. Adding three copies of the 35-bp LCR in front of PR0.5 lead to weak GFP expression in L/M cones. The HB569 promoter was not specific, and GFP was expressed in a few L/M cones, some rods and the retinal pigment epithelium. These results suggest that L/M cones, the predominant class of cone photoreceptors in the retinas of dogs and most mammalian species can be successfully targeted using the human red cone opsin promoter.

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Section: Resultsmentioning

confidence: 99%

Section: Human Red Cone Opsin Promotersmentioning

confidence: 99%

Section: Human Red Cone Opsin Promotersmentioning

confidence: 99%

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Targeting gene expression to cones with human cone opsin promoters in recombinant AAV

et al. 2008

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“…That activation of NO-cGMP signaling caused an increase in growth of cone cells, but a decrease in growth of rod cells is consistent with the reports on rd1 mouse retina that showed exuberant cone cell sprouting but a lack of rod cell growth (Blanks et al, 1974;Fei, 2002). In the rod-cone dysplasia 1 canine retina, cGMP concentration is also increased (Aquirre et al, 1978), but synaptic morphology has not yet been examined. For the diseased mouse retina, an increase of cGMP in rod cells is easily envisioned, because mutant rod PDE6 with defective ␤ subunits is assumed to be unable to hydrolyze cGMP.…”

Section: Discussionmentioning

confidence: 99%

The Nitric Oxide-cGMP Signaling Pathway Differentially Regulates Presynaptic Structural Plasticity in Cone and Rod Cells

Zhang¹,

Beuve²,

Townes‐Anderson³

2005

J. Neurosci.

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Although abundant structural plasticity in the form of axonal retraction, neurite extension, and formation of presynaptic varicosities is displayed by photoreceptors after retinal detachment and during genetic and age-related retinal degeneration, the mechanisms involved are mostly unknown. We demonstrated recently that Ca 2ϩ influx through cGMP-gated channels in cones and voltage-gated L-type channels in rods is required for neurite extension in vitro (Zhang and Townes-Anderson, 2002). Here, we report that the nitric oxide (NO)-cGMP signaling pathway is active in photoreceptors and that its manipulation differentially regulates the structural plasticity of cone and rod cells. The NO receptor soluble guanylyl cyclase (sGC) was detected immunocytochemically in both cone and rod cells. Stimulation of sGC increased cGMP production in retinal cultures. In cone cells, quantitative analysis showed that NO or cGMP stimulated neuritic sprouting; this stimulatory effect was dependent on both Ca 2ϩ influx through cGMP-gated channels and phosphorylation by protein kinase G (PKG). At the highest levels of cGMP, however, cone outgrowth was no longer increased. In rod photoreceptors, NO or cGMP consistently inhibited neuritic growth in a dose-dependent manner; this inhibitory effect required PKG. When NO-cGMP signaling was inhibited, changes in the neuritic development of cone and rod cells were also observed but in the opposite direction. These results expand the role of cGMP in axonal activity to adult neuritogenesis and suggest an explanation for the neurite sprouting observed in an autosomal recessive form of retinitis pigmentosa that is characterized by high cGMP levels in photoreceptor layers.

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“…Recent studies have brought advances in understanding the genetics of breed development 15 and the availability of ever higher resolution maps [16][17][18][19][20][21] . These have led to the mapping of disease loci for a variety of diseases including metabolic disorders 22,23 , blindness [24][25][26][27][28] , cancer 29,30 neurologic disorders 31,32 , hip dysplasia 33 epilepsy 34 , as well as several morphologic traits 35,36 . In addition, the advancement of a framework for how to study complex canine traits 37 has led to deepening of our knowledge about the organization of the canine genome 38,39 and how it relates to morphological variation between breeds.…”

Section: Introductionmentioning

confidence: 99%

Finding cardiovascular disease genes in the dog

Parker

Meurs

Ostrander

2006

Journal of Veterinary Cardiology

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Recent advances in canine genomics are changing the landscape of veterinary biology, and by default, veterinary medicine. No longer are clinicians locked into traditional methods of diagnoses and therapy. Rather major advances in canine genetics and genomics from the past five years are now changing the way the veterinarian of the 21 st century practices medicine.First, the availability of a dense genome map gives canine genetics a much needed foothold in comparative medicine, allowing advances made in human and mouse genetics to be applied to companion animals. Second, the recently released 7.5x whole genome sequence of the dog is facilitating the identification of hereditary disease genes. Finally, development of genetic tools for rapid screening of families and populations at risk for inherited disease means that the cost of identifying and testing for disease loci will significantly decrease in coming years.Out of these advances will come major changes in companion animal diagnostics and therapy. Clinicians will be able to offer their clients genetic testing and counseling for a myriad of disorders. Such advances are certain to generate healthier and more long lived dogs, improving quality of life for owner and pet alike. The clinician of the 21 st century, therefore, faces incredible opportunities as well as challenges in the management of genetic disease. In this review we summarize recent findings in canine genomics and discuss their application to the study of canine cardiac health.

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Rod-Cone Dysplasia in Irish Setters: A Defect in Cyclic GMP Metabolism in Visual Cells

Cited by 191 publications

References 8 publications

Targeting gene expression to cones with human cone opsin promoters in recombinant AAV

Targeting gene expression to cones with human cone opsin promoters in recombinant AAV

The Nitric Oxide-cGMP Signaling Pathway Differentially Regulates Presynaptic Structural Plasticity in Cone and Rod Cells

Finding cardiovascular disease genes in the dog

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