Genetic Animal Models for Retinal Degeneration

SURVEY OF OPHTHALMOLOGY VOLUME 47 • NUMBER 4 • JULY–AUGUST 2002

CURRENT RESEARCH EDWARD COTLIER AND ROBERT WEINREB, EDITORS

Genetic Animal Models for Retinal Degeneration Sascha Fauser, MD, Janina Luberichs, MD, and Frank Schüttauf, MD Universitäts-Augenklinik, Tübingen, Germany Abstract. Inherited retinal degenerations are a common cause of blindness in Western countries. A mechanism for most retinal degenerations is still unknown; hence, a suitable treatment for most of these diseases has yet to be found. Before one can rationally design a treatment, it is necessary to understand the pathway from a gene mutation to the phenotype in patients. Animal models are crucial to understand this process and to develop a treatment. Some naturally occurring animal models are known. However, over the past few years, transgenic engineering has allowed the generation of a rapidly growing number of animal models. In this review, we give an overview of the broad variety of genetic animal models for retinal degeneration. (Surv Ophthalmol 47:357–367, 2002. © 2002 by Elsevier Science Inc. All rights reserved.) Key words. animal model • genetics • photoreceptor • pigment epithelium • retina degeneration • retinitis pigmentosa

Inherited retinal degenerations are a common cause of blindness in Western countries. Clinically and genetically, it is a very heterogeneous group of diseases. Recent advances in molecular genetics have led to the mapping of more than 130 loci and cloning of more than 70 genes (http://www.sph.uth.tmc. edu/RetNet/). The mechanism of most degenerations is unknown. Before one can rationally design a treatment, it is necessary to understand the pathway from a gene mutation to the phenotype in a patient. In this process, animal models are crucial for both the investigation of the mechanism and for the development of a treatment. Some naturally occurring animal models are known today. However, over the past few years, transgenic engineering has allowed the generation of a rapidly growing number of animal models. With the new technology, genes can be specifically disrupted or overexpressed, and single mutations can be introduced. This review summarizes cur-

rently available genetic animal models for retinal photoreceptor degeneration. Some models, generated to investigate important aspects of normal retinal physiology, are also included, as understanding the normal retinal function might provide additional data on human diseases. If the defective gene is known, we have grouped the animals according to the known or likely function of the gene.

Animal Models An important finding using animal models has been that photoreceptor cell death occurs by apoptosis in many different models with various underlying gene defects.24,109 Although this does not tell anything about the mechanism, it has important therapeutic implications as this final common pathway might be blocked. To date, efforts to block apoptosis in order to prevent retinal degeneration have been inefficient.27,61 However, a recent report showed that the 357

© 2002 by Elsevier Science Inc. All rights reserved.

0039-6257/02/$–see front matter PII S0039-6257(02)00314-4

358

Surv Ophthalmol 47 (4) July–August 2002

combination of two apoptosis-inhibitor genes in transgenic mice has a synergistic effect and can delay retinal degeneration in a genetic model.39 Animal models have been used to investigate potentially protective/therapeutic agents, such as Vitamin A,79 or to test somatic gene therapy strategies.2,12 They are also valuable to study environmental effects like diet or light on the degeneration process. Excessive light was found to accelerate retinal degeneration in various animal models.50,71 Rodents, mice in particular, are the most popular models as transgenic technology is far advanced and animal housing is inexpensive. Another advantage is the rapid progression of the disease process, which can be measured in weeks as opposed to years in humans. While many aspects of human disease can be investigated, the low cone:rod ratio and the lack of a macula make most rodent models less suitable for questions regarding cone disease. Additionally, besides a lot of similarities there are a number of important differences that require consideration when transferring knowledge from animal studies to humans. Recently, transgenic pigs were generated which have advantages due to a higher cone to rod ratio, a slower disease process resembling human disease, and the large size of the eye.

Genes PHOTOTRANSDUCTION Many genes that are mutated in retinal degenerations have been identified to play a role in the phototransduction cascade. In this cascade, light is converted into a neuronal signal in the outer segment of photoreceptors cells. After the absorption of light by rhodopsin, the G-protein transducin and a cGMP phosphodiesterase are activated. The hydrolysis of cGMP closes cGMP-gated channels, hyperpolarizes the cell, and leads to signaling. Phototransduction is terminated when rhodopsin is phosphorylated by rhodopsin kinase followed by the binding of arrestin. In many cases, rods and cones use different homologous proteins. Rod degeneration leads to a subsequent loss of cones, whereas a primary cone defect usually does not affect rods. Numerous models have been described which cover now many aspects of the phototransduction process (see Table 1). Although rhodopsin is part of this process, it is also an important structural component of the outer segment of the photoreceptor cell. The majority of mutations in this protein seem to affect folding and transport and thus impair the structural integrity of the outer segment.78,80,127–129 Depending on the kind of mutation, vitamin A supplementation was found to be beneficial for the survival of the cells.79

FAUSER ET AL

VISUAL CYCLE Other genes affect the visual cycle, a process in which the pigment epithelium supplies rods with the chromophore of rhodopsin, 11-cis retinal, and recycles the photo-activated product. Mutations in RPE65 cause a severe blindness from early childhood due to a disruption of the RPE-based metabolism of all-trans-retinyl esters to 11-cis-retinal. Animal studies showed that orally administered 9-cis-retinal bypassed the block.139 Within 48 hours there was formation of rhodopsin. Gene replacement therapy was also shown to overcome this deficit in dogs.2 STRUCTURE A third group of genes is involved in the structure of the outer segment. Peripherin/rds is a transmembrane glycoprotein expressed in both rod and cone photoreceptors. It is located at the rim of the disk membranes of the photoreceptor outer segments, presumably involved in folding and stacking of the disks. The rds (retinal degeneration slow, or rd2) mouse has a naturally occurring null mutation. The relative slow degeneration makes it an ideal model to study therapeutic intervention. Subretinal injection of recombinant adeno-associated virus encoding an rds gene resulted in the generation of outer segments and formation of new stacks of disks.12 It also resulted in the functional correction in these already differentiated cells. Another structural protein is Rom-1 that associates with rds as oligomers at the disc rims of photoreceptor outer segments. There is a digenic form of retinitis pigmentosa caused by a simultaneous nonsense mutation in Rom-1 and a missense mutation in rds.63 TRANSPORT A growing number of genes is implicated in the transport of proteins to the outer segment. The disks of the outer segments are continuously shedded and renewed. About 107 molecules of opsin are transported per cell and day to the outer segment.84 Therefore, a complex machinery must be utilized to enable such a tremendous task. RPGR, for example, seems to be necessary for the polarized protein distribution across the connecting cilium55 and kinesin II for transport of opsin and arrestin from the inner to the outer segment.90 PIGMENTATION Two mouse mutants exist with defects in the pigmentation of the RPE. The vitiligo mouse has a recessive mutation in the microphthalmia (mi) gene that regulates the transcription of the tyrosinase gene, the rate-limiting enzyme in melanin biosynthesis.122 The Ocular albinism 1 knockout mouse shows defects in the melanosomal biogenesis in the RPE.59

Nonsense mutation Insertion KO W70A tg Y84G tg KO

PDE 

PDE  PDE  PDE  PDE  CNG3

Rhodopsin kinase

arrestin

GCAP1

GC1 PLC  4

Diptheria toxin Diptheria toxin RGS9-1

RGC E

Irish Setter dog (rcd1) Sloughi dog Mouse Mouse Mouse Mouse

Mouse

Mouse

Mouse

Chicken (rd1) Mouse

Mouse Mouse Mouse

Mouse

KO

Cone-specific expression tg Rod-specific-expression tg KO

Null mutation KO

KO

KO

KO

Null mutation

PDE 

KO K296E tg P347S tg T17M tg

Mutation

P23H tg V20G, P23H, P27L tg S334ter tg Q344ter tg P23H tg S334ter tg P357L tg KO Deletion

Rhodopsin Rhodopsin Rhodopsin Rhodopsin

Gene

Rhodopsin Rhodopsin Rhodopsin Rhodopsin Rhodopsin Rhodopsin Rhodopsin Rod transductin  PDE 

Mouse Mouse Mouse Mouse Rat Rat Pig Mouse Cardigan Welsh Corgi dog (rcd3) rd mouse

Phototransduction Mouse Mouse Mouse Mouse

Animal

TABLE 1

LCA, cone-rod dystrophy

LCA

Dominant cone dystrophy

Recessive RP, CSNB

Recessive CSNB

Recessive RP Recessive RP Recessive CSNB Recessive CSNB Achromatopsia

Recessive RP

Recessive RP

Dominant RP Dominant RP Dominant RP Dominant RP Dominant RP Dominant RP Dominant RP Dominant CSNB Recessive RP

Recessive RP Dominant RP Dominant RP Dominant RP

Human Disease

Genetic Animal Models for Retinal Degeneration

Inactive PDE Inactive PDE In rod ERG no a-wave Partially inactive PDE Slow degeneration of cones, no cone function No phosophorylation of excited rhodopsin Failure to switch off activated rhodopsin Ca dependent regulation of cGMP synthesis cGMP synthesis Mediates rod signaling downstream of initial phototransduction Ablation of cones Ablation of rods Less acceleration of hydrolysis of GTP, normal morphology Orphan guanylyl cyclase, cone dystrophy, rod function deficit in ERG

Fast degeneration, inactive PDE, common model Inactive PDE

All-cone ERG, mild degeneration

Vitamin A supplementation was beneficial

No outer segments in rods

Comment

150

(continued)

124, 151 92 25, 86

118, 119, 135, 136 60

93

29, 149

26

35 132 116 133 17

14, 41, 126

19, 73, 108

85, 103 97, 148 28 127 77, 89 47, 89 15, 81, 107, 134 20 106

57, 74 78 56, 80 79

Reference

GENETIC ANIMAL MODELS FOR RETINAL DEGENERATION

359

KO KO

RAR 2/RAR2 RGR

Peripherin/rds

Mouse Mouse

Structure rds mouse

Mutation

RPGR

Myosin VIIa

Mutation at splice site Kif3a

Mouse

Mouse (shaker)

Tubby mouse, rd5 Tub

CRX TLX

Pax 2 Norrie

Rep-1

Development Mouse Mouse

Mouse Mouse

Mouse

Mouse

KO

Tulp1

KO

Choroideremia

Renal-coloboma syndrome Norrie disease

LCA, dominant RP

Usher 1B

X-linked RP

Recesive RP

Dominant RP Recessive RP

Recessive/dominant RP

RPE atrophy Recessive RP

RPE atrophy

Recessive RP

LCA LCA Stargardt disease

Human Disease

Reduced expression of several genes Receptor regulates Pax2, degeneration of retina and optic nerve Pax2 involved in retinal development Malformation of ganglion cell layer and vasculature Lethal in male embryos

Conditional KO, molecular motor protein

Polarized transport of opsin to OS, rods and cones RPGR interacts with RPGRIP a structural component of the ciliary axoneme Retinal phenotype in humans much more severe, rhodopsin transport Phenotype identical to KO

Structural protein of outer segments

Digenic RP with ROM-1, structural protein of OS, gene replacement therapy

Block of 11-cis retinal synthesis Successful gene therapy Accumulation of lipofuscin fluorophore in RPE Not involved in visual pigment turnover Specific carrier for retinol in the blood Mediates activity of retinoic acid Formation of 11-is-retinal, no degeneration in mice

Comment

138 (continued)

42, 64, 104, 130 16, 113

43 152

90

65, 101, 102, 125

82

54

51, 58

62 31

32, 87, 131

48 30

110

83, 114

111 8, 140, 147 91

Reference

Surv Ophthalmol 47 (4) July–August 2002

Several mutations KO

KO KO

KO

BBS, Alstrom

Missense mutations

KO

P216L tg KO

Peripherin/rds Rom-1

Mouse Mouse Transport Mouse

Null mutation

KO

RBP

Mouse

KO

KO Deletion KO

IRBP

RPE65 RPE65 ABCR

Gene

Mouse

Visual cycle Mouse Briard-Beagle dog Mouse

Animal

Continued

TABLE 1

360 FAUSER ET AL

Mutation

KO KO

Pcd

Nr

ROR 

P27

Mouse

Mouse

Mouse

Mouse Unknown gene Mouse Mouse

Mouse

Nob mouse Apoptosis Mouse

Synaptic transmission Mouse

Mouse

Overexpression in Müller cells tg KO

Bcl-2

Recessive

?

rd3 rd4

rd6

Overexpression in rods tg -

BAG-1

Bax

chr. X

Nonsense mutation tg

KO

chr. 13

?

HRG4

Cyclin D1

?

Hugger Mnd

Mouse Mouse

Mouse Cell cycle Mouse

Overexpression in rods tg

Ataxin-7 ? ?

Recessive

KO

OAT

OAT?

KO

Recessive mutation

OA1

mi

Gene

Cat Brain Mouse

Mouse Metabolism Mouse

Vitiligo mouse (mivit)

Pigmentation

Animal

Flecked retina disorder

Recessive RP Dominant RP

CSNB

Cone-rod dystrophy

Batten disease

Spinocerebellar ataxia

Gyrate atrophy

Gyrate atrophy

Ocular albinism

RPE atrophy

Human Disease

Continued

TABLE 1

White subretinal dots

Homozygosity is lethal

Increased cell numbers in GCL and INL, ONL normal Synergistic effect of BAG-1 and Bcl-2

Primary Müller cell death

Depressed b-wave in ERG, late-onset degeneration No b-wave in ERG

Timing of cell cycle withdrawal, retinal dysplasia due to displacement of Müller glia Promotes progression through G1 phase, PR death in clusters producing holes

Polyglutaine expansion, severe retinal degeneration Ataxia and retinal degeneration Motor neuron and retinal degeneration Recessive cerebellar and retinal degeneration Recessive cerebellar and retinal degeneration Phenotype similar to vacillans mouse

Hyperornithinemia leads to chorioretinal degeneration Hyperornithinemia

Regulates transcription of tyrosinase (melanin synthesis) Melanosomal biogenesis in the RPE

Comment

53

23 115

39

(continued)

95, 144

38

105

66

45, 46

46, 76, 98

13

72, 112

18, 70

121 22, 94

153

137

142

59

100, 120, 123, 146

Reference

GENETIC ANIMAL MODELS FOR RETINAL DEGENERATION

361

Overexpression in rods tg

Nr2e3 Mertk

IFN-

Mouse (rd7) Rat (RCS)

Mouse

Inflammatory disorders

Enhanced S-cone syndrome Recessive RP

Overexpression in rods tg -

Rod-cone degeneration

Rod-cone dysplasia

Recessive RP

X-linked RP CSNB Rod-cone degeneration

Age-related retinal degeneration Rod-cone degeneration Rod-cone degeneration Rod-cone dysplasia Achromatopsia

Human Disease

Fibroblast factors are required for photoreceptor survival Expression causes proliferation and cell death Nuclear receptor superfamily Phagocytosis by RPE, common model Inflammation and PR loss

Abnormal cGMP metabolism, but rod PDE complex not mutated

No structural abnormalities Defect in outer segment renewal

Cone-less retina

Late onset

Late-onsest degeneration

Comment

44

10, 52 34, 96

11

21

143

1, 3, 4

154, 155 145 5, 6, 7

67, 68 33, 99, 141 33, 75 9, 33, 49

36, 37, 69

Reference

Surv Ophthalmol 47 (4) July–August 2002

Abbreviations: ABCR, ATP-binding cassette transporter; BBS, Bardet–Biedl syndrome; cd, cone degeneration; chr.; chromosome; CNG, cyclic nucleotide gated channel; CRX, cone-rod otx-like transcription factor; CSNB, congenital stationary night blindness; erd, early retinal degeneration; ERG, electroretinogram; FGFR, fibroblast growth factor receptor; GC, guanylate cyclase; GCAP, guanylate cyclase activating protein; HRG4, human retinal gene 4; IFN, interferon; IRBP, interphotoreceptor retinoid-binding protein; KO, knockout; LCA, Leber congenital amaurosis; Mertk, receptor tyrosine kinase Mer; Mi, microopthalmia; Mnd, motor neuron disease; Nob, no b-wave; Nr, nervous; OA, ocular albinism; OAT, ornithine aminotransferase; OS, outer segment; Pcd, Purkinje cell degeneration; PDE, phosphodiesterase; PLC, phospholipase C; PR, photoreceptor; prcd, progressive rod-cone degeneration; RAR, retinoic acid receptor; RBP, retinal-binding protein; RCS, Royal College of Surgeons; rd, retinal degeneration rds, retinal degeneration slow; rep-1, Rab escort protein1; RGC, retinal guanylyl cyclase; RGR, retinal G protein-coupled receptor; RGS, regulator of G-protein signaling; Rom-1, rod outer segment membrane protein 1; ROR, Retinoid-related orphan receptor; RP, retinitis pigmentosa; RPE, retinal pigment epithelium; RPGR, retinitis pigmentosa GTPase regulator; tg, transgenic; Tulp1, tubby-like protein.

Deletion Deletion

SV40

Dominant negative mutations Large tumor antigen

Recessive

rcd2

FGFR-1/2

Recessive

erd

Recessive

chr. X ? Recessive

? ? prcd

?

? Rececssive Dominant Recessive

?

Mutation

rdy rdy rdy cd

?

Gene

Mouse

Dog (Tibetan Terrier) Miscellaneous Mouse

Labrador retriever dog Abyssinian cat Abyssinian cat Dog (Alaskan Malamute) Dog (Siberian Husky) Appaloosa horse Dog (Minature Poodle) Dog (Norwegian Elkhound) Dog (Collie)

Unknown gene Fischer 344 rat

Animal

Continued

TABLE 1

362 FAUSER ET AL

363

GENETIC ANIMAL MODELS FOR RETINAL DEGENERATION

References

DEVELOPMENT Photoreceptor development is regulated by another group of genes. Knockout mice of the homeobox gene CRX were used to see the influence on expression of various photoreceptor-specific genes.43 As opposed to humans, a defect in the murine rep-1 gene underlying choroideremia is lethal in male embryos; in female embryos it is only lethal if the mutation is of maternal origin. In mice, the expression of the rep-1 gene is essential in murine extraembryonic membranes.138 OTHERS

1. 2. 3. 4.

5.

The Ornithine delta aminotransferase knockout mouse showed that the resulting hyperornithinemia can be treated with an arginine-restricted diet. The restoration of OAT activity is not necessary to prevent degeneration in the retina.142 The Royal College of Surgeons (RCS) rat is a naturally occurring model of retinal degeneration and has been known for many years. The underlying gene mutation was found in the receptor tyrosine kinase Mertk gene.34 The retinal pigment epithelium (RPE) fails to phagocytose shed outer segments. The RCS phenotype can be rescued by transplantation of normal RPE cells into the interphotoreceptor space.117,146 Several studies showed that administration of neurotrophic factors delays the progression of photoreceptor degeneration.40,88 Several mouse models exist that affect both brain and retina. These models provide information on diseases such as spinocerebellar ataxia31or Batten disease.22,94 Other models address other aspects of retinal physiology, for example, cell cycle, apoptosis, growth factors, or synaptic transmission.

Conclusion In this review, more than 80 genetic animal models for retinal degeneration are briefly described. They are grouped into functional categories. The wellestablished methods for generating transgenic animals will produce many additional models in the following years. The main goal will be to understand the function of disease genes in the process of retinal degeneration. Toward this goal, animal models have already provided a wealth of data and will be very important in the future. The rapid progress gives hope that we can find a treatment within the coming years.

6. 7. 8. 9. 10.

11.

12. 13.

14. 15. 16. 17. 18. 19.

Method of Literature Search The Medline database was searched (years included 1966–2001) for relevant literature. Topics were retina, photoreceptor, and animal model as the primary search terms. Data was also retrieved by searching on the specific animal model, for example, using the “related articles” feature. Additionally, journals in ophthalmology, neuroscience, and genetics were also used.

20.

21.

Acland GM, Aguirre GD: Retinal degenerations in the dog: IV. Early retinal degeneration (erd) in Norwegian elkhounds. Exp Eye Res 44:491–521, 1987 Acland GM, Aguirre GD, Ray J, et al: Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28:92–5, 2001 Acland GM, Fletcher RT, Gentleman S, et al: Non-allelism of three genes (rcd1, rcd2 and erd) for early-onset hereditary retinal degeneration. Exp Eye Res 49:983–98, 1989 Acland GM, Ray K, Mellersh CS, et al: A novel retinal degeneration locus identified by linkage and comparative mapping of canine early retinal degeneration. Genomics 59:134–42, 1999 Acland GM, Ray K, Mellersh CS, et al: Linkage analysis and comparative mapping of canine progressive rod-cone degeneration (prcd) establishes potential locus homology with retinitis pigmentosa (RP17) in humans. Proc Natl Acad Sci USA 95:3048–53, 1998 Aguirre G, Alligood J, OBrien P, Buyukmihci N: Pathogenesis of progressive rod-cone degeneration in miniature poodles. Invest Ophthalmol Vis Sci 23:610–30, 1982 Aguirre GD, Acland GM: Variation in retinal degeneration phenotype inherited at the prcd locus. Exp Eye Res 46: 663–87, 1988 Aguirre GD, Baldwin V, Pearce-Kelling S: Congenital stationary night blindness in the dog: common mutation in the RPE65 gene indicates founder effect. Mol Vis 4: 23, 1998 Aguirre GD, Rubin LF: The electroretinogram in dogs with inherited cone degeneration. Invest Ophthalmol 14:840–7, 1975 Akhmedov NB, Piriev NI, Chang B, et al: A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse. Proc Natl Acad Sci USA 97:5551–6, 2000 al-Ubaidi MR, Hollyfield JG, Overbeek PA, Baehr W: Photoreceptor degeneration induced by the expression of simian virus 40 large tumor antigen in the retina of transgenic mice. Proc Natl Acad Sci USA 89:1194–8, 1992 Ali RR, Sarra GM, Stephens C, et al: Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nat Genet 25:306–10, 2000 Andre E, Conquet F, Steinmayr M, et al: Disruption of retinoid-related orphan receptor beta changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice. EMBO J 17:3867–77, 1998 Aquirre G, Farber D, Lolley R, et al: Rod-cone dysplasia in Irish setters: a defect in cyclic GMP metabolism in visual cells. Science 201:1133–4, 1978 Banin E, Cideciyan AV, Aleman TS, et al: Retinal rod photoreceptor-specific gene mutation perturbs cone pathway development. Neuron 23:549–57, 1999 Berger W, van de Pol D, Bachner D, et al: An animal model for Norrie disease (ND): gene targeting of the mouse ND gene. Hum Mol Genet 5:51–9, 1996 Biel M, Seeliger M, Pfeifer A: Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3. Proc Natl Acad Sci USA 96:7553–7, 1999 Blanks JC, Spee C: Retinal degeneration in the pcd/pcd mutant mouse: accumulation of spherules in the interphotoreceptor space. Exp Eye Res 54:637–44, 1992 Bowes C, Li T, Frankel WN, et al: Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase. Proc Natl Acad Sci USA 90: 2955–9, 1993 Calvert PD, Krasnoperova NV, Lyubarsky AL, et al: Phototransduction in transgenic mice after targeted deletion of the rod transducin alpha-subunit. Proc Natl Acad Sci USA 97:13913–8, 2000 Campochiaro PA, Chang M, Ohsato M, et al: Retinal degeneration in transgenic mice with photoreceptor-specific expression of a dominant-negative fibroblast growth factor receptor. J Neurosci 16:1679–88, 1996

364 22.

23. 24. 25. 26. 27.

28. 29.

30. 31. 32.

33.

34. 35.

36. 37. 38.

39. 40. 41. 42.

43.

Surv Ophthalmol 47 (4) July–August 2002 Chang B, Bronson RT, Hawes NL, et al: Retinal degeneration in motor neuron degeneration: a mouse model of ceroid lipofuscinosis. Invest Ophthalmol Vis Sci 35:1071–6, 1994 Chang B, Heckenlively JR, Hawes NL, Roderick TH: New mouse primary retinal degeneration (rd-3). Genomics 16: 45–9, 1993 Chang GQ, Hao Y, Wong F: Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron 11:595–605, 1993 Chen CK, Burns ME, He W, et al: Slowed recovery of rod photoresponse in mice lacking the GTPase accelerating protein RGS9-1. Nature 403:557–60, 2000 Chen CK, Burns ME, Spencer M, et al: Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase. Proc Natl Acad Sci USA 96:3718–22, 1999 Chen J, Flannery JG, LaVail MM, et al: bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations. Proc Natl Acad Sci USA 93: 7042–7, 1996 Chen J, Makino CL, Peachey NS: Mechanisms of rhodopsin inactivation in vivo as revealed by a COOH-terminal truncation mutant. Science 267:374–7, 1995 Chen J, Simon MI, Matthes MT: Increased susceptibility to light damage in an arrestin knockout mouse model of Oguchi disease (stationary night blindness). Invest Ophthalmol Vis Sci 40:2978–82, 1999 Chen P, Hao W, Rife L: A photic visual cycle of rhodopsin regeneration is dependent on Rgr. Nat Genet 28:256–60, 2001 Clarke G, Goldberg AF, Vidgen D, et al: Rom-1 is required for rod photoreceptor viability and the regulation of disk morphogenesis. Nat Genet 25:67–73, 2000 Connell G, Bascom R, Molday L, et al: Photoreceptor peripherin is the normal product of the gene responsible for retinal degeneration in the rds mouse. Proc Natl Acad Sci USA 88:723–6, 1991 Curtis R, Barnett KC, Leon A: An early-onset retinal dystrophy with dominant inheritance in the Abyssinian cat. Clinical and pathological findings. Invest Ophthalmol Vis Sci 28:131–9, 1987 DCruz PM, Yasumura D, Weir J, et al: Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet 9:645–51, 2000 Dekomien G, Runte M, Godde R, Epplen JT: Generalized progressive retinal atrophy of Sloughi dogs is due to an 8bp insertion in exon 21 of the PDE6B gene. Cytogenet Cell Genet 90:261–7, 2000 DiLoreto D Jr, Cox C, Grover DA: The influences of age, retinal topography, and gender on retinal degeneration in the Fischer 344 rat. Brain Res 647:181–91, 1994 DiLoreto D Jr, Ison JR, Bowen GP: A functional analysis of the age-related degeneration in the Fischer 344 rat. Curr Eye Res 14:303–10, 1995 Dubois-Dauphin M, Poitry-Yamate C, de Bilbao F, et al: Early postnatal Muller cell death leads to retinal but not optic nerve degeneration in NSE-Hu-Bcl-2 transgenic mice. Neuroscience 95:9–21, 2000 Eversole-Cire P, Concepcion FA, Simon MI, et al: Synergistic effect of Bcl-2 and BAG-1 on the prevention of photo-receptor cell death. Invest Ophthalmol Vis Sci 41:1953–61, 2000 Faktorovich EG, Steinberg RH, Yasumura D, et al: Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor. Nature 347:83–6, 1990 Farber DB, Danciger JS, Aguirre G: The beta subunit of cyclic GMP phosphodiesterase mRNA is deficient in canine rod-cone dysplasia 1. Neuron 9:349–56, 1992 Favor J, Sandulache R, Neuhauser-Klaus A, et al: The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney. Proc Natl Acad Sci USA 93:13870–5, 1996 Furukawa T, Morrow EM, Li T, et al: Retinopathy and attenuated circadian entrainment in Crx-deficient mice. Nat Genet 23:466–70, 1999

FAUSER ET AL 44.

45. 46. 47.

48. 49.

50. 51.

52.

53. 54.

55.

56.

57. 58. 59. 60. 61. 62.

63.

64.

Geiger K, Howes E, Gallina M, et al: Transgenic mice expressing IFN-gamma in the retina develop inflammation of the eye and photoreceptor loss. Invest Ophthalmol Vis Sci 35:2667–81, 1994 Geng Y, Whoriskey W, Park MY, et al: Rescue of cyclin D1 deficiency by knockin cyclin E. Cell 97:767–77, 1999 Geng Y, Yu Q, Sicinska E: Deletion of the p27Kip1 gene restores normal development in cyclin D1-deficient mice. Proc Natl Acad Sci USA 98:194–9, 2001 Green ES, Menz MD, LaVail MM, Flannery JG: Characterization of rhodopsin mis-sorting and constitutive activation in a transgenic rat model of retinitis pigmentosa. Invest Ophthalmol Vis Sci 41:1546–53, 2000 Grondona JM, Kastner P, Gansmuller A, et al: Retinal dysplasia and degeneration in RARbeta2/RARgamma2 compound mutant mice. Development 122:2173–88, 1996 Gropp KE, Szel A, Huang JC, et al: Selective absence of cone outer segment beta 3-transducin immunoreactivity in hereditary cone degeneration (cd). Exp Eye Res 63:285– 96, 1996 Hafezi F, Marti A, Munz K, Reme CE: Light-induced apoptosis: differential timing in the retina and pigment epithelium. Exp Eye Res 64:963–70, 1997 51. Hagstrom SA, Duyao M, North MA, Li T: Retinal degeneration in tulp1-/- mice: vesicular accumulation in the interphotoreceptor matrix. Invest Ophthalmol Vis Sci 40:2795– 802, 1999 Haider NB, Naggert JK, Nishina PM: Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice. Hum Mol Genet 10:1619–26, 2001 Hawes NL, Chang B, Hageman GS, et al: Retinal degeneration 6 (rd6): a new mouse model for human retinitis punctata albescens. Invest Ophthalmol Vis Sci 41:3149–57, 2000 Hong DH, Pawlyk BS, Shang J, et al: A retinitis pigmentosa GTPase regulator (RPGR)-deficient mouse model for X-linked retinitis pigmentosa (RP3). Proc Natl Acad Sci USA 97:3649–54, 2000 Hong DH, Yue G, Adamian M, Li T: Retinitis pigmentosa GTPase regulator (RPGRr)-interacting protein is stably associated with the photoreceptor ciliary axoneme and anchors RPGR to the connecting cilium. J Biol Chem 276: 12091–9, 2001 Huang PC, Gaitan AE, Hao Y, et al: Cellular interactions implicated in the mechanism of photoreceptor degeneration in transgenic mice expressing a mutant rhodopsin gene. Proc Natl Acad Sci USA 90:8484–8, 1993 Humphries MM, Rancourt D, Farrar GJ, et al: Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nat Genet 15:216–9, 1997 Ikeda S, Shiva N, Ikeda A, et al: Retinal degeneration but not obesity is observed in null mutants of the tubby-like protein 1 gene. Hum Mol Genet 9:155–63, 2000 Incerti B, Cortese K, Pizzigoni A, et al: Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1. Hum Mol Genet 9:2781–8, 2000 Jiang H, Lyubarsky A, Dodd R, et al: Phospholipase C beta 4 is involved in modulating the visual response in mice. Proc Natl Acad Sci USA 93:14598–601, 1996 Joseph RM, Li T: Overexpression of Bcl-2 or Bcl-XL transgenes and photoreceptor degeneration. Invest Ophthalmol Vis Sci 37:2434–46, 1996 Kedzierski W, Lloyd M, Birch DG, et al: Generation and analysis of transgenic mice expressing P216L-substituted rds/peripherin in rod photoreceptors. Invest Ophthalmol Vis Sci 38:498–509, 1997 Kedzierski W, Nusinowitz S, Birch D, et al: Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa. Proc Natl Acad Sci USA 98:7718–23, 2001 Keller SA, Jones JM, Boyle A, et al: Kidney and retinal defects (Krd), a transgene-induced mutation with a deletion of mouse chromosome 19 that includes the Pax2 locus. Genomics 23:309–20, 1994

GENETIC ANIMAL MODELS FOR RETINAL DEGENERATION 65. 66.

67. 68. 69. 70. 71.

72.

73.

74. 75. 76. 77.

78.

79.

80.

81. 82.

83.

84. 85.

86.

Kleyn PW, Fan W, Kovats SG, et al: Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family. Cell 85:281–90, 1996 Kobayashi A, Higashide T, Hamasaki D, et al: HRG4 (UNC119) mutation found in cone-rod dystrophy causes retinal degeneration in a transgenic model. Invest Ophthalmol Vis Sci 41:3268–77, 2000 Kommonen B, Karhunen U: A late receptor dystrophy in the Labrador retriever. Vision Res 30:207–13, 1990 Kommonen B, Penn JS, Kylma T, et al: Early morphometry of a retinal dystrophy in Labrador retrievers. Acta Ophthalmol (Copenh) 72:203–10, 1994 Lai YL, Jacoby RO, Jonas AM: Age-related and light-associated retinal changes in Fischer rats. Invest Ophthalmol Vis Sci 17:634–8, 1978 LaVail MM, Blanks JC, Mullen RJ: Retinal degeneration in the pcd cerebellar mutant mouse. I. Light microscopic and autoradiographic analysis. J Comp Neurol 212:217–30, 1982 LaVail MM, Gorrin GM, Yasumura D, Matthes MT: Increased susceptibility to constant light in nr and pcd mice with inherited retinal degenerations. Invest Ophthalmol Vis Sci 40:1020–4, 1999 LaVail MM, White MP, Gorrin GM, et al: Retinal degeneration in the nervous mutant mouse. I. Light microscopic cytopathology and changes in the interphotoreceptor matrix. J Comp Neurol 333:168–81, 1993 Lem J, Flannery JG, Li T, et al: Retinal degeneration is rescued in transgenic rd mice by expression of the cGMP phosphodiesterase beta subunit. Proc Natl Acad Sci USA 89:4422–6, 1992 Lem J, Krasnoperova NV, Calvert PD, et al: Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proc Natl Acad Sci USA 96:736–41, 1999 Leon A, Hussain AA, Curtis R: Autosomal dominant rodcone dysplasia in the Rdy cat. 2. Electrophysiological findings. Exp Eye Res 53:489–502, 1991 Levine EM, Close J, Fero M, et al: p27(Kip1) regulates cell cycle withdrawal of late multipotent progenitor cells in the mammalian retina. Dev Biol 219:299–314, 2000 Lewin AS, Drenser KA, Hauswirth WW, et al: Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa. Nat Med 4:967–71, 1998 Li T, Franson WK, Gordon JW, et al: Constitutive activation of phototransduction by K296E opsin is not a cause of photoreceptor degeneration. Proc Natl Acad Sci USA 92:3551–5, 1995 Li T, Sandberg MA, Pawlyk BS: Effect of vitamin A supplementation on rhodopsin mutants threonine-17 —  methionine and proline-347 — serine in transgenic mice and in cell cultures. Proc Natl Acad Sci USA 95:11933–8, 1998 Li T, Snyder WK, Olsson JE, Dryja TP: Transgenic mice carrying the dominant rhodopsin mutation P347S: evidence for defective vectorial transport of rhodopsin to the outer segments. Proc Natl Acad Sci USA 93:14176–81, 1996 Li ZY, Wong F, Chang JH, et al: Rhodopsin transgenic pigs as a model for human retinitis pigmentosa. Invest Ophthalmol Vis Sci 39:808–19, 1998 Libby RT, Steel KP: Electroretinographic anomalies in mice with mutations in Myo7a, the gene involved in human Usher syndrome type 1B. Invest Ophthalmol Vis Sci 42: 770–8, 2001 Liou GI, Fei Y, Peachey NS, et al: Early onset photoreceptor abnormalities induced by targeted disruption of the interphotoreceptor retinoid-binding protein gene. J Neurosci 18:4511–20, 1998 Liu X, Udovichenko IP, Brown SD, et al: Myosin VIIa participates in opsin transport through the photoreceptor cilium. J Neurosci 19:6267–74, 1999 Liu X, Wu TH, Stowe S, et al: Defective phototransductive disk membrane morphogenesis in transgenic mice expressing opsin with a mutated N-terminal domain. J Cell Sci 110: 2589–97, 1997 Lyubarsky AL, Naarendorp F, Zhang X, et al: RGS9-1 is re-

87.

88.

89. 90. 91.

92.

93. 94. 95.

96. 97.

98.

99.

100. 101. 102. 103.

104. 105. 106.

107.

365 quired for normal inactivation of mouse cone phototransduction. Mol Vis 7:71–8, 2001 Ma J, Norton JC, Allen AC, et al: Retinal degeneration slow (rds) in mouse results from simple insertion of a t haplotypespecific element into protein-coding exon II. Genomics 28: 212–9, 1995 Machida S, Chaudhry P, Shinohara T, et al: Lens Epithelium-Derived Growth Factor Promotes Photoreceptor Survival in Light-Damaged and RCS Rats. Invest Ophthalmol Vis Sci 42:1087–1095, 2001 Machida S, Kondo M, Jamison JA, et al: P23H rhodopsin transgenic rat: correlation of retinal function with histopathology. Invest Ophthalmol Vis Sci 41:3200–9, 2000 Marszalek JR, Liu X, Roberts EA, et al: Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors. Cell 102:175–87, 2000 Mata NL, Weng J, Travis GH: Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci USA 97:7154–9, 2000 McCall MA, Gregg RG, Merriman K, et al: Morphological and physiological consequences of the selective elimination of rod photoreceptors in transgenic mice. Exp Eye Res 63:35–50, 1996 Mendez A, Burns ME, Sokal I: Role of guanylate cyclase-activating proteins (GCAPs) in setting the flash sensitivity of rod photoreceptors. Proc Natl Acad Sci USA 98:9948–53, 2001 Messer A, Plummer J, MacMillen MC, Frankel WN: Genetics of primary and timing effects in the mnd mouse. Am J Med Genet 57:361–4, 1995 Mosinger Ogilvie J, Deckwerth TL, Knudson CM, Korsmeyer SJ: Suppression of developmental retinal cell death but not of photoreceptor degeneration in Bax-deficient mice. Invest Ophthalmol Vis Sci 39:1713–20, 1998 Mullen RJ, LaVail MM: Inherited retinal dystrophy: primary defect in pigment epithelium determined with experimental rat chimeras. Science 192:799–801, 1976 Naash MI, Hollyfield JG, al-Ubaidi MR, Baehr W: Simulation of human autosomal dominant retinitis pigmentosa in transgenic mice expressing a mutated murine opsin gene. Proc Natl Acad Sci USA 90:5499–503, 1993 Nakayama K, Ishida N, Shirane M, et al: Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85: 707–20, 1996 Narfstrom K, Ehinger B, Bruun A: Immunohistochemical studies of cone photoreceptors and cells of the inner retina in feline rod-cone degeneration. Vet Ophthalmol 4:141–5, 2001 Nir I, Ransom N, Smith SB: Ultrastructural features of retinal dystrophy in mutant vitiligo mice. Exp Eye Res 61:363– 77, 1995 Noben-Trauth K, Naggert JK, North MA, Nishina PM: A candidate gene for the mouse mutation tubby. Nature 380: 534–8, 1996 Ohlemiller KK, Hughes RM, Mosinger Ogilvie J, et al: Cochlear and retinal degeneration in the tubby mouse. Neuroreport 6:845–9, 1995 Olsson JE, Gordon JW, Pawlyk BS, et al: Transgenic mice with a rhodopsin mutation (Pro23His): a mouse model of autosomal dominant retinitis pigmentosa. Neuron 9:815–30, 1992 Otteson DC, Shelden E, Jones JM, et al: Pax2 expression and retinal morphogenesis in the normal and Krd mouse. Dev Biol 193:209–24, 1998 Pardue MT, McCall MA, LaVail MM, et al: A naturally occurring mouse model of X-linked congenital stationary night blindness. Invest Ophthalmol Vis Sci 39:2443–9, 1998 Petersen-Jones SM, Entz DD, Sargan DR: cGMP phosphodiesterase-alpha mutation causes progressive retinal atrophy in the Cardigan Welsh corgi dog. Invest Ophthalmol Vis Sci 40: 1637–44, 1999 Petters RM, Alexander CA, Wells KD, et al: Genetically engineered large animal model for studying cone photoreceptor

366

Surv Ophthalmol 47 (4) July–August 2002

survival and degeneration in retinitis pigmentosa. Nat Biotechnol 15:965–70, 1997 108. Pittler SJ, Baehr W: Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse. Proc Natl Acad Sci USA 88:8322– 6, 1991 109. Portera-Cailliau C, Sung CH, Nathans J, Adler R: Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proc Natl Acad Sci USA 91:974–8, 1994 110. Quadro L, Blaner WS, Salchow DJ, et al: Impaired retinal function and vitamin A availability in mice lacking retinolbinding protein. EMBO J 18:4633–44, 1999 111. Redmond TM, Yu S, Lee E, et al: Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Genet 20:344–51, 1998 112. Ren JC, Stubbs EB Jr, Matthes MT, et al: Retinal degeneration in the nervous mutant mouse. IV. Inner retinal changes. Exp Eye Res 72:243–52, 2001 113. Richter M, Gottanka J, May CA, et al: Retinal vasculature changes in Norrie disease mice. Invest Ophthalmol Vis Sci 39:2450–7, 1998 114. Ripps H, Peachey NS, Xu X, et al: The rhodopsin cycle is preserved in IRBP knockout mice despite abnormalities in retinal structure and function. Vis Neurosci 17:97–105, 2000 115. Roderick TH, Chang B, Hawes NL, Heckenlively JR: A new dominant retinal degeneration (Rd4) associated with a chromosomal inversion in the mouse. Genomics 42:393–6, 1997 116. Salchow DJ, Gouras P, Doi K, et al: A point mutation (W70A) in the rod PDE-gamma gene desensitizing and delaying murine rod photoreceptors. Invest Ophthalmol Vis Sci 40:3262–7, 1999 117. Seaton AD, Turner JE: RPE transplants stabilize retinal vasculature and prevent neovascularization in the RCS rat. Invest Ophthalmol Vis Sci 33:83–91, 1992 118. Semple-Rowland SL, Cheng KM: rd and rc chickens carry the same GC1 null allele (GUCY1*). Exp Eye Res 69:579–81, 1999 119. Semple-Rowland SL, Lee NR, Van Hooser JP, et al: A null mutation in the photoreceptor guanylate cyclase gene causes the retinal degeneration chicken phenotype. Proc Natl Acad Sci USA 95:1271–6, 1998 120. Sidman RL, Kosaras B, Tang M: Pigment epithelial and retinal phenotypes in the vitiligo mivit, mutant mouse. Invest Ophthalmol Vis Sci 37:1097–115, 1996 121. Sidman RL, Tang M, Kosaras B, et al: Mapping and retinal phenotype of the hugger mutation in the mouse. Mamm Genome 8:399–402, 1997 122. Smith SB: C57BL/6J-vit/vit mouse model of retinal degeneration: light microscopic analysis and evaluation of rhodopsin levels. Exp Eye Res 55:903–10, 1992 123. Smith SB, Hamasaki DI: Electroretinographic study of the C57BL/6-mivit/mivit mouse model of retinal degeneration. Invest Ophthalmol Vis Sci 35:3119–23, 1994 124. Soucy E, Wang Y, Nirenberg S, et al: A novel signaling pathway from rod photoreceptors to ganglion cells in mammalian retina. Neuron 21:481–93, 1998 125. Stubdal H, Lynch CA, Moriarty A, et al: Targeted deletion of the tub mouse obesity gene reveals that tubby is a lossof-function mutation. Mol Cell Biol 20:878–82, 2000 126. Suber ML, Pittler SJ, Qin N, et al: Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene. Proc Natl Acad Sci USA 90:3968–72, 1993 127. Sung CH, Makino C, Baylor D, Nathans J: A rhodopsin gene mutation responsible for autosomal dominant retinitis pigmentosa results in a protein that is defective in localization to the photoreceptor outer segment. J Neurosci 14:5818–33, 1994 128. Sung CH, Tai AW: Rhodopsin trafficking and its role in retinal dystrophies. Int Rev Cytol 195:215–67, 2000 129. Tai AW, Chuang JZ, Bode C, et al: Rhodopsins carboxy-terminal cytoplasmic tail acts as a membrane receptor for cytoplasmic dynein by binding to the dynein light chain Tctex-1. Cell 97:877–87, 1999 130. Torres M, Gomez-Pardo E, Gruss P: Pax2 contributes to in-

FAUSER ET AL ner ear patterning and optic nerve trajectory. Development 122:3381–91, 1996 131. Travis GH, Groshan KR, Lloyd M, Bok D: Complete rescue of photoreceptor dysplasia and degeneration in transgenic retinal degeneration slow (rds) mice. Neuron 9:113–9, 1992 132. Tsang SH, Gouras P, Yamashita CK, et al: Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase. Science 272:1026–9, 1996 133. Tsang SH, Yamashita CK, Doi K, et al: In vivo studies of the gamma subunit of retinal cGMP-phophodiesterase with a substitution of tyrosine-84. Biochem J 353:467–74, 2001 134. Tso MO, Li WW, Zhang C, et al: A pathologic study of degeneration of the rod and cone populations of the rhodopsin Pro347Leu transgenic pigs. Trans Am Ophthalmol Soc 95:467–79; discussion 479–83, 1997 135. Ulshafer RJ, Allen C, Dawson WW, Wolf ED: Hereditary retinal degeneration in the Rhode Island Red chicken. I. Histology and ERG. Exp Eye Res 39:125–35, 1984 136. Ulshafer RJ, Allen CB: Hereditary retinal degeneration in the Rhode Island Red chicken: ultrastructural analysis. Exp Eye Res 40:865–77, 1985 137. Valle DL, Boison AP, Jezyk P, Aguirre G: Gyrate atrophy of the choroid and retina in a cat. Invest Ophthalmol Vis Sci 20:251–5, 1981 138. van den Hurk JA, Hendriks W, van de Pol DJ, et al: Mouse choroideremia gene mutation causes photoreceptor cell degeneration and is not transmitted through the female germline. Hum Mol Genet 6:851–8, 1997 139. Van Hooser JP, Aleman TS, He YG, et al: Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness. Proc Natl Acad Sci USA 97: 8623–8, 2000 140. Veske A, Nilsson SE, Narfstrom K, Gal A: Retinal dystrophy of Swedish briard/briard-beagle dogs is due to a 4-bp deletion in RPE65. Genomics 57:57–61, 1999 141. Voaden MJ, Curtis R, Barnett KC, et al: Dominant rod-cone dysplasia in the Abyssinian cat. Prog Clin Biol Res 247:369– 80, 1987 142. Wang T, Lawler AM, Steel G, et al: Mice lacking ornithine-deltaaminotransferase have paradoxical neonatal hypoornithinaemia and retinal degeneration. Nat Genet 11:185–90, 1995 143. Wang W, Acland GM, Ray K, Aguirre GD: Evaluation of cGMPphosphodiesterase (PDE) subunits for causal association with rod-cone dysplasia 2 (rcd2), a canine model of abnormal retinal cGMP metabolism. Exp Eye Res 69:445–53, 1999 144. White FA, Keller-Peck CR, Knudson CM: Widespread elimination of naturally occurring neuronal death in Bax-deficient mice. J Neurosci 18:1428–39, 1998 145. Witzel DA, Smith EL, Wilson RD, Aguirre GD: Congenital stationary night blindness: an animal model. Invest Ophthalmol Vis Sci 17:788–95, 1978 146. Woch G, Aramant RB, Seiler MJ, et al: Retinal transplants restore visually evoked responses in rats with photoreceptor degeneration. Invest Ophthalmol Vis Sci 42:1669–76, 2001 147. Wrigstad A, Narfstrom K, Nilsson SE: Slowly progressive changes of the retina and retinal pigment epithelium in Briard dogs with hereditary retinal dystrophy. A morphological study. Doc Ophthalmol 87:337–54, 1994 148. Wu TH, Ting TD, Okajima TI, et al: Opsin localization and rhodopsin photochemistry in a transgenic mouse model of retinitis pigmentosa. Neuroscience 87:709–17, 1998 149. Xu J, Dodd RL, Makino CL, et al: Prolonged photoresponses in transgenic mouse rods lacking arrestin. Nature 389:505–9, 1997 150. Yang RB, Robinson SW, Xiong WH, et al: Disruption of a retinal guanylyl cyclase gene leads to cone-specific dystrophy and paradoxical rod behavior. J Neurosci 19:5889–97, 1999 151. Ying S, Jansen HT, Lehman MN, et al: Retinal degeneration in cone photoreceptor cell-ablated transgenic mice. Mol Vis 6:101–8, 2000 152. Yu RT, Chiang MY, Tanabe T, et al: The orphan nuclear receptor Tlx regulates Pax2 and is essential for vision. Proc Natl Acad Sci USA 97:2621–5, 2000 153. Yvert G, Lindenberg KS, Picaud S, et al: Expanded polyglutamines induce neurodegeneration and trans-neuronal

GENETIC ANIMAL MODELS FOR RETINAL DEGENERATION

154. 155.

alterations in cerebellum and retina of SCA7 transgenic mice. Hum Mol Genet 9:2491–506, 2000 Zeiss CJ, Acland GM, Aguirre GD: Retinal pathology of canine X-linked progressive retinal atrophy, the locus homologue of RP3. Invest Ophthalmol Vis Sci 40:3292–304, 1999 Zhang Q, Acland GM, Zangerl B, et al: Fine mapping of canine XLPRA establishes homology of the human and canine RP3 intervals. Invest Ophthalmol Vis Sci 42:2466–71, 2001

367

The authors were supported by a grant from the Federal Ministry of Education and Research (Fö. 01KS9602) and the Interdisciplinary Center of Clinical Research Tübingen (IZKF). The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: Sascha Fauser, MD, Universitäts-Augenklinik, Röntgenweg 11, 72076 Tübingen, Germany; fax +49 7071 2987072; E-mail: [email protected]