Experimental Eye Research 81 (2005) 503–512 www.elsevier.com/locate/yexer

Review Mouse mutants as models for congenital disorders

Claudia Dalke*, Jochen Graw

GSF-National Research Center for Environment and Health, Institute of Developmental Genetics, D-85764 Neuherberg, Germany

Received 1 February 2005; accepted in revised form 1 June 2005 Available online 18 July 2005

Abstract

Animal models provide a valuable tool for investigating the genetic basis and the pathophysiology of human diseases, and to evaluate therapeutic treatments. To study congenital retinal disorders, mouse mutants have become the most important model organism. Here we review some mouse models, which are related to hereditary disorders (mostly congenital) including , Leber’s congenital amaurosis, macular disorders and optic atrophy. q 2005 Elsevier Ltd. All rights reserved.

Keywords: animal model; retina; mouse; ; retinal degeneration

1. Introduction Although mouse models are a good tool to investigate retinal disorders, one should keep in mind that the mouse Mice suffering from hereditary eye defects (and in retina is somehow different from a human retina, particular from retinal degenerations) have been collected particularly with respect to the number and distribution of since decades (Keeler, 1924). They allow the study of the photoreceptor cells. The mouse as a nocturnal animal molecular and histological development of retinal degener- has a retina dominated by rods; in contrast, cones are small ations and to characterize the genetic basis underlying in size and represent only 3–5% of the photoreceptors. Mice retinal dysfunction and degeneration. The recent progress of do not form cone-rich areas like the human fovea. Instead of genomic approaches has added increasing numbers of such three cone pigments present in the human retina, mice models. express only two distinct pigments with absorption maxima In recent years systematic phenotype-driven approaches near 350 and 510 nm (Lyubarsky et al., 1999). have been developed to screen for mice harboring In this review we discuss important mouse mutants for chemically induced , mainly by use of N-ethyl- retinal degenerations (for cross information on their mutated N-nitrosourea (ENU), which predominantly causes point and chromosomal localization see Table 1 and Fig. 1). mutations (Justice et al., 1999). Moreover, many transgenic Concerning the nomenclature of genes and mutations, we and knockout animal models were created to investigate the follow the mouse genetic nomenclature as outlined by the Jackson Laboratory (http://www.informatics.jax.org). role of specific genes on retinal function. Finally, the gene- trapping method was developed for the systematic generation of knockout mice (Skarnes et al., 2004). 1.1. Retinal disorders including degeneration of photoreceptor cells

Abbreviations BBS, Bardet-Biedl syndrome; ENU, N-ethyl-N-nitro- 1.1.1. Models for retinitis pigmentosa (RP) sourea; ERG, electroretinogram; LCA, Leber’s congenital amaurosis; RP, One of the first mouse mutants described in the field of retinitis pigmentosa; RPE, retinal pigment epithelium; STGD, Stargardt’s vision research was the rodless mouse (r; Keeler, 1924), macular dystrophy. * Corresponding author. Dr Claudia Dalke, GSF-National Research which carries a nonsense mutation in the Pde6b gene coding Center for Environment and Health, Institute of Developmental Genetics, for the b-subunit of phosphodiesterase. The gene mutation Ingolstaedter Landstr. 1, D-85764 Neuherberg, Germany. was later discovered in the retinal degeneration mouse E-mail address: [email protected] (C. Dalke). (actual gene symbol Pde6brd1, formerly referred to as rd1 or 0014-4835/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. rd; Pittler and Baehr, 1991). A viral insertion in intron 1 of rd1 doi:10.1016/j.exer.2005.06.004 the Pde6b allele (Bowes et al., 1993)codingfor 504 C. Dalke, J. Graw / Experimental Eye Research 81 (2005) 503–512

Table 1 Overview of mutations in the mouse, affecting the structure or function of the retina. For allelic series just a few examples are listed

Gene Symbol Chr. Defect alleles Mutation Reference (cM) Crb1 1 (73.0) Crb1rd8 1 bp deletion causing a frame shift and Mehalow et al., 2003 crumbs homolog 1 (Drosophila) premature stop codon Crb1tm1Wij Knockout, insertion of a hygromycin resistance van de Pavert cassette the region, exon 1 and part of et al., 2004 intron 1 Cnga3 1 cyto- Cnga3tm1Biel Knockout, the gene was disrupted by replace- Biel et al., 1999 cyclic nucleotide gated band B ment of exon 7 with a neomycin resistance channel alpha 3 cassette Vsx1 2 (83.9) Vsx1tm1Bhr Knockout, a neo cassette replacing the coding Ohtoshi et al., 2004 visual system 1 region for the entire homeodomain and CVC homolog (zebrafish) domain Vsx1tm1Mci Knockout, a genomic fragment, was replaced Chow et al., 2004 with a neomycin selection cassette inserted by homologous recombination Abca4 3 (61.8) Abca4tm1Ght Knockout, replacement of a 4 kb genomic Weng et al., 1999 ATP-binding cassette, fragment containing the promoter and first exon sub-family A (ABC1), member 4 with a neomycin cassette Rpe65 3 (87.6) Rpe65tm1Tmr Knockout, exons 1–3 of the gene were replaced Redmond et al., 1998 retinal pigment epithelium 65 with a PGK-neo cassette Rpe65rd12 (retinal Nonsense mutation, base substitution (C to T) in Pang et al., 2005 degeneration 12) codon 44 Pde6b 5 (57.0) Pde6brd1 (retinal Nonsense mutation, C-A transversion in codon Pittler and Baehr, rod phospodiesterase, beta degeneration 1) 347 (exon 7) 1991 subunit (r,rodless; rd, retinal degeneration) Pde6brd10 (retinal Missense mutation in exon 13 Chang et al., 2002 degeneration 10) Pde6b2J 2 Jackson Point mutation in exon 16 Pde6batrd2 atypical ENU induced Thaung et al., 2002 retinal degeneration 2 Mitf 6 (40.0) Mitfmi-sp microphthal- Insertion of an extra C residue in the poly- Steingrimsson microphthalmia-associated mia spotted pyrimidine tract located upstream of an 18 bp et al., 1994 alternative exon Mitfmi-vit vitiligo G to A transition at bp 793 that leads to an Steingrimsson aspartate to asparagine substitution et al., 1994 MitfMi-wh micro- T to A transversion at bp 764, which leads to an Steingrimsson phthalmia white isoleucine to asparagine substitution et al., 1994 Rho 6 (51.5) Rhotm1Jlem Knockout, a PGK-neo cassette was inserted into Lem et al., 1999 rhodopsin the first coding exon Rhotm1Phm Knockout, a neomycin cassette under the Humphries et al., control of a polymerase II promoter was 1997 inserted at codon 135 in exon 2 Crx 7 (8.5) Crxtm1Clc Knockout, the homeodomain coding region Furukawa et al., 1999 cone-rod homeobox containing exon 3 and a portion of exon 4 was containing gene replaced by a neomycin selection cassette Tub 7 (51.4) Tubtub-rd5 G to T transversion resulting in a larger Noben-Trauth tubby candidate gene transcript et al., 1996 Tubtm1Rok Knockout, a neomycin cassette replaced 16 kb Stubdal et al., 2000 of sequence spanning exons 1–8 Cln8 8 (6.0) Cln8mnd(motor neur- A single nucleotide insertion (267-268C, codon Ranta et al., 1999 ceroid-lipofuscinosis, neuronal 8 on degeneration) 90) predicts a frameshift and a truncated nr nervous 8 (8.0) nr spontaneous De Jager et al., 1998 Bbs2 8 synte- Bbs2tm1Vcs Knockout, exons 5–13 were replaced with a neo Nishimura et al., 2004 Bardet-Biedl syndrome 2 nic homolog (human) Mfrp 9 (25.5) Mfrprd6 4 bp deletion in the splice donor sequence of Kameya et al., 2002 membrane-type frizzled-related intron 4 - skipping of exon 4 (no frame shift) protein Bbs4 9 (33.0) Bbs4Gt1Nk A gene trap vector was inserted into intron 1, Kulaga et al., 2004 Bardet-Biedl syndrome 4 causing aberrant splicing homolog (human) Bbs4tm1Vcs Exons 6–11 were replaced with a neo cassette Mykytyn et al., 2004 (continued on next page) C. Dalke, J. Graw / Experimental Eye Research 81 (2005) 503–512 505

Table 1 (continued)

Gene Symbol Chr. Defect alleles Mutation Reference (cM) Nr2e3 9 (33.5) Nr2e3rd7 Deletion of 380 bp (exon 4 and 5) - frame shift Akhmedov et al., nuclear receptor subfamily 2, resulting in a premature stop codon 2000 group E, member 3 (PNR- photoreceptor-specific nuclear receptor) Cln6 9 (35.0) Cln6nclf(neuronal cer- 1 bp insertion of a cysteine, located within a run Wheeler et al., 2002; ceroid-lipofuscinosis, neuronal 6 oid lipofuscinosis) of cysteines in exon 4, producing a frameshift at Gao et al., 2002 103, followed by a premature stop codon Elovl4 9 synte- Transgene, 5-bp deletion corresponding to the Karan et al., 2005 elongation of very long nic human mutation (delAACTT at 790–794) chain fatty acids (FEN1/Elo2, SUR4/Elo3, yeast)-like 4 Pde6g 11 (75.0) Pde6gtm1Goff Knockout, a neomycin selection cassette Tsang et al., 1996 phosphodiesterase 6G, replaced genomic sequences including the third cGMP-specific, rod, gamma exon Aipl1 aryl hydrocarbon receptor- 11 synte- Aipl1tm1Mad Knockout, a neo replaced exons 1 and 2 Dyer et al., 2004 interacting protein-like 1 nic Aipl1tm1Visu Knockout, exons 2–5 were replaced with a Ramamurthy et al., neomycin resistance gene 2004 Chx10 12 (38.0) Chx10or Truslove, 1962 C. elegans ceh-10 homeo domain containing homolog Chx10or-J Premature stop codon (Y176stop) Theiler et al., 1976 Agtpbp1 13 (37.5) Agtpbp1pcd Purkinje mutation is likely in a regulatory region of the Fernandez-Gonzalez ATP/GTP binding protein 1 (Pcd, cell degeneration gene et al., 2002 Purkinje cell degeneration; Nna1) Agtpbp1pcd-2J Pur- 7.8 kb insertion into intron 13 Fernandez-Gonzalez kinje cell degener- et al., 2002 ation-2 Jackson Agtpbp1pcd-3J Pur- deletion that creates splice junction between Fernandez-Gonzalez kinje cell degener- exons 5 and 9 that introduces a premature stop et al., 2002 ation-3 Jackson codon Nrl 14 (19.5) Nrltm1Asw Knockout, a PGK-neomycin resistance cassette Swain et al., 2001 neural retina leucine zipper gene replaced the entire coding region (exons 2 and 3) Rpgrip1 14 synte- Rpgrip1tm1Tili Knockout, the gene was disrupted by insertion Zhao et al., 2003 retinitis pigmentosa GTPase nic of a large cassette containing 3 duplicated exons regulator interacting protein and a neomycin resistance gene. Rds 17 (18.8) RdsPrph2-rd2 Insertion of w10kb, disrupting the coding Travis et al., 1989 retinal degeneration, slow sequence in exon 2 (Prph2-peripherin2; rd2) Rdstm1Nmc 1 bp deletion at codon 307 McNally et al., 2002 Ndph X (5.3) Ndphtm1Wbrg Knockout, the coding portion of exon 2 was Berger et al., 1996 Norrie disease homolog replaced with a neomycin cassette Rs1h X (70.0) Rs1htm1Bhfw Exon 3 was disrupted by insertion of a lacZ-neo Weber et al., 2002 retinoschisis 1 homolog (human) cassette via homologous recombination. Rs1htm1Sie Knockout, a neo replaced exon 1, including 9 bp Zeng et al., 2004 upstream of the ATG. Rpgr X synte- Rpgrtm1Tili Part of exon 4 through part of exon 6 was Hong et al., 2000 retinitis pigmentosa GTPase nic replaced with a promoter-less lacZ-neo cassette regulator via homologous recombination.

the b-subunit of Pde, allows the genotyping by PCR analysis became the most extensively studied model for human (Fig. 2a). Due to the early degeneration of the outer retina autosomal recessive retinitis pigmentosa (RP). Several and the complete loss of rods by 35 days (Fig. 2c), mice common mouse inbred strains, like C3H, SWR and FVB, homozygous for the Pde6brd1 allele completely lack an are homozygous carriers of the Pde6brd1 allele (Jax Notes, ERG response (Fig. 2b). Moreover, vessel attenuation and 2002). Recently, the presence of the Pde6brd1 allele also was pigment patches can be seen in the fundus. This mouse mutant reported in a colony of 129Sv mice (Dalke et al., 2004). 506 C. Dalke, J. Graw / Experimental Eye Research 81 (2005) 503–512

Rp1h

Cnga3

Raw Cln8 Crx nr tulp2 Ush1c Slc6a6 Mfrp Mitf Bbs4 Pde6b Rlbp1 Nr2e3 Bsg Cln6 Rwhs Rho Tub Crb1 Abca4 Rbp1 Rgs9 Pde6g Ush2a tulp3 rd3 Vsx1 Rpe65 Bbs2 Elovl4 Aipl1

12 3 45 67 8 9 10 11

Rpgr Ndph

Rbp3 Rvm tulp4 Pcdh21 Nrl Rpgrip1 Rds Chx10 Agtpbp1 rom1

Krd Rs1h

12 13 14 15 16 17 18 19 X Y

Fig. 1. Overview of genes involved in retinal disorders. Some mutations are mentioned in the text; for others additional information can be found in previously published reviews (Hafezi et al., 2000; Chang et al., 2002; Peachey and Ball, 2003) or in the MGI database (Mouse Genome Informatics, http://www. informatics.jax.org). Analysis of differentially expressed genes in the Pde6brd1 discovered, eight of them in ENU screens. All mutants show a mouse results in diverse patterns during rod and cone recessive inheritance, but in contrast to Pde6brd1, a slower degeneration, depending on the age (Hackam et al., 2004). onset of retinal degeneration was observed in three Pde6b So far, ten phenotypic alleles of the Pde6b gene were mutants (Thaung et al., 2002; Chang et al., 2002).

A C3H B6 SWR

550 bp 400 bp

B µV 100 C

50 OFL GCL 0 IPL –50 INL –100 RPE

ms 0 100 200 300

Fig. 2. C3H mice: well-known carrier strain of the Pde6brd1 allele. (A) PCR analysis for Pde6brd1 (modified according to Gimenez and Montoliu, 2001). Lanes 1–3 controls of a C3H, C57BL/6 and a SWR mouse, lanes 4–9 DNA of different mice to be tested for the Pde6brd1 allele. (B) A typical ERG response of a C3H mouse. (C). Histology of the retina of a C3H mouse. The arrow indicates the missing retinal layers, especially the photoreceptor cells. OFL, outer fiber layer; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; RPE, retinal pigment epithel C. Dalke, J. Graw / Experimental Eye Research 81 (2005) 503–512 507

The knockout of the g-subunit of Pde (Pde6gK/K) leads the spontaneous mutant (Crb1rd8) shows irregular white to rapid photoreceptor degeneration and reduced ERG spots from the age of 3 weeks, which are caused by retinal amplitudes. However, this disorder cannot be rescued by the folds and pseudorosettes. Shortened photoreceptor inner and expression of a transgene containing a mutant Pde6g gene outer segments are observed as early as 2 weeks after birth, (Tsang et al., 2002), although in humans no PDE6G suggesting a developmental defect. Interestingly, in Crb1rd8 mutations are known to be associated with retinal disorders. mutants, retinal dysplasia and spotting strongly varies with Mutations in the rhodopsin (RHO) gene account for genetic background (Mehalow et al., 2003). The recently approximately 15% of all inherited retinal degenerations in described CrbK/K knockout mice initially develop normal humans. Rho knockout mice do not develop rod outer retinas, but by 3 to 9 months the integrity of the outer segments and lose their photoreceptor cells within 3 months. limiting membrane is lost and giant half rosettes are formed At the age of 8 weeks, the visual function in Rho knockout (van de Pavert et al., 2004). mice is mediated by cones only. However, not only the loss- Defects in genes coding for retinitis pigmentosa GTPase of-function mutation lead to retinal degeneration, but also regulator (Rpgr) and RPGR-interacting protein (Rpgrip1) the additional activity of Rho. Transgenic mice expressing are known to be involved in the development of RP and different levels of were generated to analyze the LCA, respectively. Both gene products are localized in the consequences of opsin overexpression. Even an opsin photoreceptor connecting , the connection between expression level of 123% of normal leads to a reduction cell body and the light-sensing outer segment. Rpgrip1K/K of a-wave amplitudes in ERG to less than 30% of normal mice have grossly oversized outer segment disks and show a values, and ERG responses of the highest expressing line more severe disease than RpgrK/K mice (Zhao et al., 2003; (222% of normal opsin level) were indistinguishable from Hong et al., 2004). noise. The overexpression of normal opsin induces Mutations in the Rds gene (retinal degeneration slow) photoreceptor degeneration that is similar to that seen in coding for the photoreceptor-specific membrane glyco- many mouse models of RP (Tan et al., 2001). protein (peripherin) are associated with multiple retinal NRL, a basic neural retina motif-leucine zipper transcrip- diseases like macular dystrophy and autosomal dominant tion factor of the Maf subfamily, synergistically interacts RP. Peripherin is essential for outer segment disc with the homeodomain protein CRX to regulate rhodopsin morphogenesis. Mice homozygous for the spontaneous transcription. Missense mutations in the NRL gene cause RP mutation RdsPrph2-rd2 do not develop outer segments of rods in humans, a similar phenotype is observed in NrlK/K mice, and cones, and at the age of 12 months all photoreceptor exhibiting the complete loss of rod function and super- cells have disappeared. At first, the mutation was considered normal cone function, mediated by S-cones (short-wave- to be recessive, but progressive abnormalities were also length sensitive). Functional transformation of rods into observed in heterozygotes. Another Rds allele (Rdstm1Nmc) S-cones was demonstrated in the NrlK/K retina, suggesting with a targeted single base deletion at codon 307 is identical that Nrl acts as ‘molecular switch’ during to a human mutation associated with an autosomal dominant development (Mears et al., 2001). form of RP. The Rdstm1Nmc mutation leads to a more rapid A late onset of degeneration is development of the retinopathy than observed in the observed in mice with a mutant Nr2e3 gene, a member of naturally occurring null mutant, suggesting a dominant the nuclear receptor transcription factor family. After one negative phenotype in combination with haploinsufficiency year of relatively stable a- and b-wave ERG responses a (McNally et al., 2002). A positive correlation was observed progressive loss of their amplitudes follows. The retinal between Rds expression levels and the structural and fundus of one month old Nr2e3 mutant mice displays functional integrity of photoreceptor outer segments, about discrete white spots due to retinal waves, whorls and 60% of wild type Rds is nessecary for the functional rosettes in the outer nuclear layer. However, a higher integrity of the retina; whereas overexpression of Rds quantity of cone photoreceptors leads to the suggestion that caused no detectable adverse effects on rod or cone structure Nr2e3 mice could be a model for the human enhanced and function (Nour et al., 2004). S-cone syndrome (ESCS), but the obtained ERG results are quite different. Recent results demonstrate that Nr2e3 is 1.1.3. Mouse mutants as models for involved in regulating the expression of rod photoreceptor- Macular degeneration is a heterogeneous group of human specific genes (Cheng et al., 2004). disorders characterized by photoreceptor degeneration and atrophy of the retinal pigment epithelium in the central 1.1.2. Models for a combined phenotype of retinitis retina. An example of a congenital macular degeneration is pigmentosa and other photoreceptor degeneration diseases the Stargardt’s macular dystrophy (STGD). One gene found Two mouse models have been reported with mutation in to be mutated in patients suffering from STGD is the ABCA4 the Crb1 gene coding for the crumbs homolog 1. The human gene, coding for an ATP-binding cassette transporter, which patient mutations in the CRB1 gene lead to various forms of is expressed in the rim of rod outer segment disks. Mice hereditable retinal disorders like retinitis pigmentosa (RP) lacking both alleles of the Abca4 gene accumulate toxic and Leber’s congenital amaurosis (LCA). Similarly, lipofuscin pigments in ocular tissues, similar to affected 508 C. Dalke, J. Graw / Experimental Eye Research 81 (2005) 503–512 humans, and showed delayed dark adaptation. The major Rpe65K/K mice in which ERG responses were profoundly fluorophore of lipofuscin is the bis-, N-retinylidene- diminished to all but the brightest stimuli (Pang et al., 2005). N-retinylethanolamine (A2E), which was thought to Mutations in the AIPL1 gene, coding for aryl hydro- increase following light exposure. Nevertheless, increased carbon receptor-interacting protein-like 1, in humans lead to retinal illuminance was not correlated with higher A2E LCA. Several knockout mice were generated resulting in a levels in the mouse model (Radu et al., 2004). However, total loss of the protein. Therefore, similar phenotypes were Abca4 knockout mice develop progressive photoreceptor reported. Rapid retinal degeneration and lack of both rod degeneration and an enhanced delay in dark adaptation with and cone ERG responses were observed in Aipl1K/K mice. increasing age. However, no gross abnormalties of proliferation during A dominant form of human congenital STGD is caused retinal development were detected (Ramamurthy et al., by mutations in the ELOVL4 gene (elongation of very long 2004; Dyer et al., 2004). chain fatty acids-like 4). Transgenic mice expressing a Another model for LCA was recently created in which mutant form of human ELOVL4 show photoreceptor the cone-rod homeobox containing gene (Crx)was degeneration in the central retina in a pattern closely disrupted using homologous recombination. CrxK/K mice resembling that of human STGD and AMD (age-related display abnormal development of photoreceptors followed macular degeneration), therefore these mice provide a good by their degeneration (Pignatelli et al., 2004). Further, model for both disorders (Karan et al., 2005). CrxK/K outer segment morphogenesis was found to be A common form of macular degeneration in males is blocked in development, leading to a failure in the X-linked juvenile retinoschisis (RS) caused by mutations in production of the phototransduction apparatus. Highly the RS1 gene. For a corresponding mouse model Rs1h disorganized synapses of photoreceptors were observed in deficient mice were generated; Rs1h is the homolog to the the outer plexiform layer (Morrow et al., 2005). human RS1 gene. The pathologic changes in hemizygous mice are evenly distributed across the retina, contrasting 1.1.5. Other retinopathies with the macular-dominated features in human. However, For some genes an expression in the retina is known. similar functional anomalies were observed in man and However, if no human mutation is described, frequently a mouse, suggesting that both conditions are a disease of the corresponding mouse model is generated by gene targeting entire retina, which affects the organization of the retinal approaches. cell layers as well as structural properties of the retinal The Chx10 homeobox gene (C. elegans ceh-10 homeo synapse (Weber et al., 2002). domain containing homolog) is expressed in neural progenitor cells during retinal development. The absence 1.1.4. Models for Leber’s congenital amaurosis (LCA) of Chx10 in spontaneously occurring mutant mice causes LCA describes a group of autosomal recessive blinding mutant ocular retardation and microphthalmia. In Chx10or- retinal dystrophies in early childhood. Beside Crb1, Rpgr and J/or-J mutants rod and cone outer segments are not correctly Rpgrip1 (described above), the conductive gene for this formed (Rutherford et al., 2004), additionally retinal cells disorder is RPE65 gene (retinal pigment epithelium 65). transdifferentiate into pigmented cells (Rowan et al., 2004). Corresponding knockout mice (Rpe65K/K) show disorga- This deflection of the neuroretina towards an RPE-like nized outer segment discs of their rod photoreceptors. identity is caused by the ectopic expression of Mitf in Residual ERG responses of Rpe65K/K mice were attributed Chx10or-J/or-J mice, which is repressed by Chx10 in wild-type to rods, enabled to mimic cone function by responding under mice. The antagonistic interaction between Chx10 and Mitf normally cone-isolating lighting conditions (Seeliger et al., in regulating retinal cell identity was confirmed, using Chx10 2001). Studies with Rpe65K/K mice clearly showed that and Mitf transgenic and mutant mice (Horsford et al., 2005). activation of sensory transduction by unliganded opsin The Vsx1, visual system homeobox 1 gene, is expressed induce light-independent retinal degeneration in LCA; the in differentiating and mature cone bipolar cells in mice. accumulation of retinal is not causative (Woodruff Vsx1 deficient mice showed altered ERG responses, et al., 2003). To quantify the impairment of the transient demonstrating defects in their cone visual pathway, whereas pupillary light reflex due to severe retinal dysfunction and the rod visual pathway was unaffected. A disturbed degeneration in a murine model and in human patients with differentiation of cone bipolar cells was assumed in these LCA, pupillometry was used (Aleman et al., 2004). mice (Chow et al., 2004; Ohtoshi et al., 2004). Additionally, a new, spontaneous Rpe65 mutant mouse Retinal degeneration frequently is associated with (Rpe65rd12) was detected. Homozygous Rpe65rd12 mice alterations in the fundus, reflecting structural aberrations of exhibit small punctuate white spots in the fundus at the age of the retinal cell layers. In spontaneous Mfrp mutant mice, 5 months. The first signs of retinal degeneration were seen at which represent a model for human retinitis punctata the age of 3 weeks, when occasional small lipid-like droplets albescens, the appearance of white spots in the retinal were detected in the retinal pigment epithelium (RPE). At the fundus, at the age of 8–10 weeks, corresponds to large cells, age of 3 months voids were detected in the outer nuclear juxtaposed to the retinal pigment epithelium and a layer. The ERG phenotype is similar to that reported in progressive photoreceptor cell loss. Beginning even at C. Dalke, J. Graw / Experimental Eye Research 81 (2005) 503–512 509 the age of one month, ERG responses show a slow and cardiac malformations, learning disabilities, and progressive retinal dysfunction of both rods and cones; hypogenitalism have been also reported in the affected ERG is extinguished at the age of 16 months (Hawes et al., patients. Two knockout mouse models, lacking expression 2000). Mfrp, coding for a membrane-type frizzeled-related of Bbs2 or Bbs4, respectively, display major components of protein, was found to be expressed specifically in the retinal the human phenotype including retinal degeneration and pigment epithelium and ciliary epithelium of the eye other defects associated with cilia dysfunction. Retinal (Kameya et al., 2002). degeneration in Bbs2K/K mice starts, after normal retinal Cnga3 (cyclic nucleotide gated channel alpha 3) knock- development, by apoptotic death of photoreceptors, the out mice lack any cone-mediated photoresponse, but have a primary ciliated cells of the retina. Molecularly, photo- completely intact rod pathway (Biel et al., 1999). To assess receptor cell death is preceded by mislocalization of the structural changes in the retina caused by functional rhodopsin, indicating a defect in transport (Mykytyn et al., block of rods and cones, double knockout mice were bred 2004; Nishimura et al., 2004). K/K K/K with Cnga3 and Rho mice. Retinal layers of these Another model for BBS, the Tubby mouse (Tub; double knockouts showed normal structural organization Noben-Trauth et al., 1996), exhibit retinal disorders and until the age of 4 weeks, but photoreceptors are almost progressive hearing loss, combined with obesity. The early completely lost at 3 months (Claes et al., 2004). onset of photoreceptor cell loss leads to reduced ERG amplitudes, which extinguish by 6 months of age. Mutations 1.2. Combined retinal and neuronal degeneration in other members of the Tub gene family, the tubby-like phenotype (Tulp1,2, 3, 4), are also involved in retinal degeneration, but with distinct phenotypes (Ikeda et al., In some human diseases and the corresponding mouse 2000). models a combined phenotype of retinal and neuronal Multiple phenotypes are associated also with mutations degenerations is observed. in the Mitf gene, a microphthalmia associated transcription Retinal degeneration combined with the loss of cerebel- factor. Common to the allelic series of up to now 26 lar Purkinje cells is observed in both, nervous (nr) and different mutations are defects in neural-crest-derived Agtpbp1 mutant mice. The recessive nervous (nr) mutation melanocytes, resulting in reduction or loss of pigmentation is associated with hyperactivity at the age of 3 weeks, retinal in the eye, inner ear, skin and coat. In addition to the reduced disorganization of the outer segment membranes and eye size, early-onset deafness and osteoporosis are thinning of the inner nuclear and plexiform layers. In observed. The allelic nature of some phenotypes was Agtpbp1 (ATP/GTP binding protein 1) mutant retinae, the confirmed by complementation tests of certain Mitf alleles, outer nuclear layer and the mitral neurons of the olfactory e.g. MitfMi-wh/Mitfmi animals dispay normal eye size while bulb were degenerated. The extensive loss of photoreceptor homozygous littermates exhibit severe (MitfMi-wh/MitfMi-wh) cells starts around weaning and proceeds slowly for about or intermediate (Mitfmi/Mitfmi)microphthalmia(Stein- one year. Two additional spontaneous Agtpbp1 alleles 2J 3J grimsson et al., 2003). Mice homozygous for the vitiligo (pcd and pcd ) were detected, but no major differences in mi-vit the retinal degeneration phenotype were reported (Fernan- mutation (Mitf ) show gradual depigmentation and dezKGonzalez et al., 2002). progressive loss of photoreceptor cells. The outer plex- Two spontaneous mouse mutants for neuronal ceroid iforme layer is significantly thinner at the age of 4 months, lipofuscinosis, Cln6 and Cln8, are associated with progress- and by 8 months, photoreceptor cell nuclei have diminished ive retinal degeneration, ataxia and neurodegeneration. to 2 or 3 rows (Smith, 1995). Mutations in the human orthologues have been shown to A syndrome including congenital blindness, sensori- underlie neurological syndromes including retinal disorders, neural deafness and mental retardation is displayed in the seizures and mental retardation. Homozygous mice of both X-linked Norrie disease. Hemizygous Ndph (Norrie disease lines die, at around 9 months of age. Progressive homolog) knockout mice develop retrolental structures in photoreceptor cell loss starts early in life and by 6 to 9 the vitreous body and an overall disorganization of the months the entire retina is atrophied (Bronson et al., 1998). retinal ganglion cell layer, with focal absence of the outer In Cln8 mice, oxidation and apoptotic processes are plexiform layer. These ocular findings are consistent with involved in the retinopathy (Guarneri et al., 2004). Both observations in human patients (Berger et al., 1996). Mice genes, Cln6 und Cln8, are active in similar biochemical deficient in norrin, the gene product of Ndph, additionally pathways; therefore, it is not surprising that mutation in both show a distinct failure in retinal angionesis, and completely genes lead to very similar phenotypes. lack the deep capillay layers of the retina. Ohlmann et al. (2005) showed that the transgenic expression of ectopic 1.3. Retinal degeneration as part of a multisyndromic defect norrin restores the formation of a normal retinal vasular network in Ndph (y/-) mutant mice, suggesting that The Bardet-Biedl syndrome (BBS) is characterized by pharmacologic modulation of norrin might be used for RP as a major defect, but obesity, polydactyly, renal treatment of Norrie disease. 510 C. Dalke, J. Graw / Experimental Eye Research 81 (2005) 503–512

2. Conclusions and perspectives Angeletti, B., Lo¨ster, J., Auricchio, A., Gekeler, F., Shinoda, K., Ballabio, A., Graw, J., Marigo, V., 2003. An in vivo doxycycline-controlled At present, 158 genes are known to be involved in the expression system for functional studies of the retina. Invest. Ophthalmol. Vis. Sci. 44, 755–760. formation of retinal diseases in humans (RetNet, http:// Berger, W., van de Pol, D., Bachner, D., Oerlemans, F., Winkens, H., www.sph.uth.tmc.edu/Retnet), but mouse models are avail- Hameister, H., Wieringa, B., Hendriks, W., Ropers, H.H., Ploos van able for only a few of them. Therefore, more mouse models Amstel, J.K., Bergman, A.J., van Beurden, E.A., Roijers, J.F., Peelen, are needed to cover the diversity of the clinical situations. T., van den Berg, I.E., Poll-The, B.T., Kvittingen, E.A., Berger, R., Studies can be improved using knockout and transgene 1996. An animal model for Norrie disease (ND): gene targeting of the mouse ND gene. Hum. Mol. Genet. 5, 51–59. techniques. Moreover screening efforts in ENU mutagenesis Biel, M., Seeliger, M., Pfeifer, A., Kohler, K., Gerstner, A., Ludwig, A., should be intensified because the phenotyping in these Jaissle, G., Fauser, S., Zrenner, E., Hofmann, F., 1999. Selective loss of screens is done according to clinical features. A system for cone function in mice lacking the cyclic nucleotide-gated channel inducible photoreceptor-specific in trans- CNG3. Proc. Natl Acad. Sci. USA 96, 7553–7557. genic mice was developed to control gene expression at Bowes, C., Li, T., Frankel, W.N., Danciger, M., Coffin, J.M., Applebury, M. L., Farber, D.B., 1993. Localization of a retroviral element within the rd temporal and spatial level to check for a reversal point gene coding for the beta subunit of cGMP phosphodiesterase. Proc. Natl (Chang et al., 2000; Angeletti et al., 2003). A rapid method Acad. Sci. USA 90, 2955–2959. for functional studies is the transfection of RNA inter- Bronson, R.T., Donahue, L.R., Johnson, K.R., Tanner, A., Lane, P.W., ference vectors into retinal cells leading to similar Faust, J.R., 1998. Neuronal ceroid lipofuscinosis (nclf), a new disorder phenotypes known from corresponding knockout mice of the mouse linked to 9. Am. J. Med. Genet. 77, 289–297. Chang, M.A., Horner, J.W., Conklin, B.R., DePinho, R.A., Bok, D., Zack, (Matsuda and Cepko, 2004), but the medical relevance D.J., 2000. Tetracycline-inducible system for photoreceptor-specific seems to be unclear. gene expression. Invest. Ophthalmol. Vis. Sci. 41, 4281–4287. One of the major challenges is to develop new therapies Chang, B., Hawes, N.L., Hurd, R.E., Davisson, M.T., Nusinowitz, S., for retinal disorders. The benefit of mouse models was Heckenlively, J.R., 2002. Retinal degeneration mutants in the mouse. shown recently as treatment with bone marrow-derived Vision Res. 42, 517–525. Cheng, H., Khanna, H., Oh, E.C., Hicks, D., Mitton, K.P., Swaroop, A., hematopoietic stem cells prevents cone loss in rd1 and rd10 2004. Photoreceptor-specific nuclear receptor NR2E3 functions as a mice (Smith, 2004). Moreover, some other successful transcriptional activator in rod photoreceptors. Hum. Mol. Genet. 13, approaches in retinal gene therapies were reported. In a 1563–1575. model of LCA the vision of blind Rpe65K/K mice was Chow, R.L., Volgyi, B., Szilard, R.K., Ng, D., McKerlie, C., Bloomfield, S. restored (Jacobson et al., 2005), and in rs1h deficient mice, a A., Birch, D.G., McInnes, R.R., 2004. Control of late off-center cone bipolar cell differentiation and visual signaling by the homeobox gene model for retinoschisis, significant improvement in the Vsx1. Proc. Natl Acad. Sci. USA 101, 1754–1759. ERGs, retinal morphology and preservation of photo- Claes, E., Seeliger, M., Michalakis, S., Biel, M., Humphries, P., receptors was demonstrated after subretinal injection of an Haverkamp, S., 2004. Morphological characterization of the retina of K K K K adeno-associated virus construct containing human RS1 the CNGA3 / Rho / mutant mouse lacking functional cones and gene (Weber et al., 2005). Mouse models are one of the few rods. Invest. Ophthalmol. Vis. Sci. 45, 2039–2048. Dalke, C., Lo¨ster, J., Fuchs, H., Gailus-Durner, V., Soewarto, D., Favor, J., test systems to develop new therapies for human patients. Neuhauser-Klaus, A., Pretsch, W., Gekeler, F., Shinoda, K., Zrenner, E., Meitinger, T., Hrabe de Angelis, M., Graw, J., 2004. Electro- retinography as a screening method for mutations causing retinal dysfunction in mice. Invest. Ophthalmol. Vis. Sci. 45, 601–609. Acknowledgements De Jager, P.L., Harvey, D., Polydorides, A.D., Zuo, J., Heintz, N., 1998. A high-resolution genetic map of the nervous on mouse The work was supported at least in part by the German chromosome 8. Genomics 48, 346–353. National Genome Research Network (NGFN; 01GR0430). Dyer, M.A., Donovan, S.L., Zhang, J., Gray, J., Ortiz, A., Tenney, R., The authors thank Jack Favor for critical comments on the Kong, J., Allikmets, R., Sohocki, M.M., 2004. Retinal degeneration in Aipl1-deficient mice: a new genetic model of Leber congenital manuscript. amaurosis. Brain Res. Mol. Brain Res. 132, 208–220. Fernandez-Gonzalez, A., La Spada, A.R., Treadaway, J., Higdon, J.C., Harris, B.S., Sidman, R.L., Morgan, J.I., Zuo, J., 2002. Purkinje cell degeneration (pcd) phenotypes caused by mutations in the axotomy- References induced gene, Nna1. Science 295, 1904–1906. Furukawa, T., Morrow, E.M., Li, T., Davis, F.C., Cepko, C.L., 1999. Akhmedov, N.B., Piriev, N.I., Chang, B., Rapoport, A.L., Hawes, N.L., Retinopathy and attenuated circadian entrainment in Crx-deficient Nishina, P.M., Nusinowitz, S., Heckenlively, J.R., Roderick, T.H., mice. Nat. Genet. 23, 466–470. Kozak, C.A., Danciger, M., Davisson, M.T., Farber, D.B., 2000. A Gao, H., Boustany, R.M., Espinola, J.A., Cotman, S.L., Srinidhi, L., deletion in a photoreceptor-specific nuclear receptor mRNA causes Antonellis, K.A., Gillis, T., Qin, X., Liu, S., Donahue, L.R., Bronson, R. retinal degeneration in the rd7 mouse. Proc. Natl Acad. Sci. USA 97, T., Faust, J.R., Stout, D., Haines, J.L., Lerner, T.J., MacDonald, M.E., 5551–5556. 2002. Mutations in a novel CLN6-encoded transmembrane protein Aleman, T.S., Jacobson, S.G., Chico, J.D., Scott, M.L., Cheung, A.Y., cause variant neuronal ceroid lipofuscinosis in man and mouse. Am. J. Windsor, E.A., Furushima, M., Redmond, T.M., Bennett, J., Hum. Genet. 70, 324–335. Palczewski, K., Cideciyan, A.V., 2004. Impairment of the transient Gimenez, E., Montoliu, L., 2001. A simple polymerase chain reaction assay pupillary light reflex in Rpe65K/K mice and humans with leber for genotyping the retinal degeneration mutation (Pdeb(rd1)) in FVB/N- congenital amaurosis. Invest. Ophthalmol. Vis. Sci. 45, 1259–1271. derived transgenic mice. Lab. Anim. 35, 153–156. C. Dalke, J. Graw / Experimental Eye Research 81 (2005) 503–512 511

Guarneri, R., Russo, D., Cascio, C., D’Agostino, S., Galizzi, G., Bigini, P., Lem, J., Krasnoperova, N.V., Calvert, P.D., Kosaras, B., Cameron, D.A., Mennini, T., Guarneri, P., 2004. Retinal oxidation, and age- Nicolo, M., Makino, C.L., Sidman, R.L., 1999. Morphological, and sex-differences in the mnd mutant mouse, a model of neuronal physiological, and biochemical changes in rhodopsin knockout mice. ceroid lipofuscinosis. Brain Res. 1014, 209–220. Proc. Natl Acad. Sci. USA 96, 736–741. Hackam, A.S., Strom, R., Liu, D., Qian, J., Wang, C., Otteson, D., Lyubarsky, A.L., Falsini, B., Pennesi, M.E., Valentini, P., Pugh Jr.., E.N., Gunatilaka, T., Farkas, R.H., Chowers, I., Kageyama, M., Leveillard, 1999. UV- and midwave-sensitive cone-driven retinal responses of the T., Sahel, J.A., Campochiaro, P.A., Parmigiani, G., Zack, D.J., 2004. mouse: a possible phenotype for coexpression of cone photopigments. Identification of gene expression changes associated with the J. Neurosci. 19, 442–455. progression of retinal degeneration in the rd1 mouse. Invest. Matsuda, T., Cepko, C.L., 2004. Electroporation and RNA interference in Ophthalmol. Vis. Sci. 45, 2929–2942. the rodent retina in vivo and in vitro. Proc. Natl Acad. Sci. USA 101, Hafezi, F., Grimm, C., Simmen, B.C., Wenzel, A., Reme, C.E., 2000. 16–22. Molecular ophthalmology: an update on animal models for retinal McNally, N., Kenna, P.F., Rancourt, D., Ahmed, T., Stitt, A., Colledge, W. degenerations and dystrophies. Br. J. Ophthalmol. 84, 922–927. H., Lloyd, D.G., Palfi, A., O’Neill, B., Humphries, M.M., Humphries, Hawes, N.L., Chang, B., Hageman, G.S., Nusinowitz, S., Nishina, P.M., P., Farrar, G.J., 2002. Murine model of autosomal dominant retinitis Schneider, B.S., Smith, R.S., Roderick, T.H., Davisson, M.T., pigmentosa generated by targeted deletion at codon 307 of the rds- Heckenlively, J.R., 2000. Retinal degeneration 6 (rd6): a new mouse peripherin gene. Hum. Mol. Genet. 11, 1005–1016. model for human retinitis punctata albescens. Invest. Ophthalmol. Vis. Mears, A.J., Kondo, M., Swain, P.K., Takada, Y., Bush, R.A., Saunders, T. Sci. 41, 3149–3157. L., Sieving, P.A., Swaroop, A., 2001. Nrl is required for rod Hong, D.H., Pawlyk, B.S., Shang, J., Sandberg, M.A., Berson, E.L., Li, T., photoreceptor development. Nat. Genet. 29, 447–452. 2000. A retinitis pigmentosa GTPase regulator (RPGR)-deficient mouse Mehalow, A.K., Kameya, S., Smith, R.S., Hawes, N.L., Denegre, J.M., model for X-linked retinitis pigmentosa (RP3). Proc. Natl Acad. Sci. Young, J.A., Bechtold, L., Haider, N.B., Tepass, U., Heckenlively, J.R., USA 97, 3649–3654. Chang, B., Naggert, J.K., Nishina, P.M., 2003. CRB1 is essential Hong, D.H., Pawlyk, B.S., Adamian, M., Li, T., 2004. Dominant, gain-of- for external limiting membrane integrity and photoreceptor function mutant produced by truncation of RPGR. Invest. Ophthalmol. morphogenesis in the mammalian retina. Hum. Mol. Genet. 12, Vis. Sci. 45, 36–41. 2179–2189. Horsford, D.J., Nguyen, M.T., Sellar, G.C., Kothary, R., Arnheiter, H., Morrow, E.M., Furukawa, T., Raviola, E., Cepko, C.L., 2005. Synaptogen- McInnes, R.R., 2005. Chx10 repression of Mitf is required for the esis and outer segment formation are perturbed in the neural retina of maintenance of mammalian neuroretinal identity. Development 132, Crx mutant mice. BMC Neurosci. 6, 5. 177–187. Mykytyn, K., Mullins, R.F., Andrews, M., Chiang, A.P., Swiderski, R.E., Humphries, M.M., Rancourt, D., Farrar, G.J., Kenna, P., Hazel, M., Bush, Yang, B., Braun, T., Casavant, T., Stone, E.M., Sheffield, V.C., 2004. R.A., Sieving, P.A., Sheils, D.M., McNally, N., Creighton, P., Erven, Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in A., Boros, A., Gulya, K., Capecchi, M.R., Humphries, P., 1997. flagella formation but not global cilia assembly. Proc. Natl Acad. Sci. Retinopathy induced in mice by targeted disruption of the rhodopsin USA 101, 8664–8669. gene. Nat. Genet. 15, 216–219. Nishimura, D.Y., Fath, M., Mullins, R.F., Searby, C., Andrews, M., Davis, Ikeda, S., Shiva, N., Ikeda, A., Smith, R.S., Nusinowitz, S., Yan, G., Lin, T. R., Andorf, J.L., Mykytyn, K., Swiderski, R.E., Yang, B., Carmi, R., R., Chu, S., Heckenlively, J.R., North, M.A., Naggert, J.K., Nishina, P. Stone, E.M., Sheffield, V.C., 2004. Bbs2-null mice have neurosensory M., Duyao, M.P., 2000. Retinal degeneration but not obesity is observed deficits, a defect in social dominance, and retinopathy associated with in null mutants of the tubby-like protein 1 gene. Hum. Mol. Genet. 9, mislocalization of rhodopsin. Proc. Natl Acad. Sci. USA 101, 16588– 155–163. 16593. Jacobson, S.G., Aleman, T.S., Cideciyan, A.V., Sumaroka, A., Schwartz, S. Noben-Trauth, K., Naggert, J.K., North, M.A., Nishina, P.M., 1996. A B., Windsor, E.A., Traboulsi, E.I., Heon, E., Pittler, S.J., Milam, A.H., Maguire, A.M., Palczewski, K., Stone, E.M., Bennett, J., 2005. candidate gene for the mouse mutation tubby. Nature 380, 534–538. Identifying photoreceptors in blind eyes caused by RPE65 mutations: Nour, M., Ding, X.Q., Stricker, H., Fliesler, S.J., Naash, M.I., 2004. Prerequisite for human success. Proc. Natl Acad. Sci. USA Modulating expression of peripherin/rds in transgenic mice: critical 102, 6177–6182. levels and the effect of overexpression. Invest. Ophthalmol. Vis. Sci. 45, Jax Notes, 2002. Genetic background effects: can your mice see? Jax Notes 2514–2521. 485, 2. http://jaxmice.jax.org/library/notes/485.pdf. Ohlmann, A., Scholz, M., Goldwich, A., Chauhan, B.K., Hudl, K., Justice, M.J., Noveroske, J.K., Weber, J.S., Zheng, B., Bradley, A., 1999. Ohlmann, A.V., Zrenner, E., Berger, W., Cvekl, A., Seeliger, M.W., Mouse ENU mutagenesis. Hum. Mol. Genet. 8, 1955–1963. Tamm, E.R., 2005. Ectopic norrin induces growth of ocular capillaries Kameya, S., Hawes, N.L., Chang, B., Heckenlively, J.R., Naggert, J.K., and restores normal retinal angiogenesis in Norrie disease mutant mice. Nishina, P.M., 2002. Mfrp, a gene encoding a frizzled related protein, is J. Neurosci. 25, 1701–1710. mutated in the mouse retinal degeneration 6. Hum. Mol. Genet. 11, Ohtoshi, A., Wang, S.W., Maeda, H., Saszik, S.M., Frishman, L.J., Klein, 1879–1886. W.H., Behringer, R.R., 2004. Regulation of retinal cone bipolar cell Karan, G., Lillo, C., Yang, Z., Cameron, D.J., Locke, K.G., Zhao, Y., differentiation and photopic vision by the CVC homeobox gene Vsx1. Thirumalaichary, S., Li, C., Birch, D.G., Vollmer-Snarr, H.R., Curr. Biol. 14, 530–536. Williams, D.S., Zhang, K., 2005. Lipofuscin accumulation, abnormal Pang, J.J., Chang, B., Hawes, N.L., Hurd, R.E., Davisson, M.T., Li, J., electrophysiology, and photoreceptor degeneration in mutant ELOVL4 Noorwez, S.M., Malhotra, R., McDowell, J.H., Kaushal, S., Hauswirth, transgenic mice: a model for macular degeneration. Proc. Natl Acad. W.W., Nusinowitz, S., Thompson, D.A., Heckenlively, J.R., 2005. Sci. USA 102, 4164–4169. Retinal degeneration 12 (rd12): a new, spontaneously arising mouse Keeler, C.E., 1924. The inheritance of a retinal abnormality in white mice. model for human Leber congenital amaurosis (LCA). Mol. Vis. 11, Proc. Natl Acad. Sci. USA 10, 329–333. 152–162. Kulaga, H.M., Leitch, C.C., Eichers, E.R., Badano, J.L., Lesemann, A., Peachey, N.S., Ball, S.L., 2003. Electrophysiological analysis of visual Hoskins, B.E., Lupski, J.R., Beales, P.L., Reed, R.R., Katsanis, N., function in mutant mice. Doc. Ophthalmol. 107, 13–36. 2004. Loss of BBS proteins causes anosmia in humans and defects in Pignatelli, V., Cepko, C.L., Strettoi, E., 2004. Inner retinal abnormalities in olfactory cilia structure and function in the mouse. Nat. Genet. 36, a mouse model of Leber’s congenital amaurosis. J. Comp. Neurol. 469, 994–998. 351–359. 512 C. Dalke, J. Graw / Experimental Eye Research 81 (2005) 503–512

Pittler, S.J., Baehr, W., 1991. Identification of a nonsense mutation in the Tan, E., Wang, Q., Quiambao, A.B., Xu, X., Qtaishat, N.M., Peachey, N.S., rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd Lem, J., Fliesler, S.J., Pepperberg, D.R., Naash, M.I., Al-Ubaidi, M.R., mouse. Proc. Natl Acad. Sci. USA 88, 8322–8326. 2001. The relationship between opsin overexpression and photoreceptor Radu, R.A., Mata, N.L., Bagla, A., Travis, G.H., 2004. Light exposure degeneration. Invest. Ophthalmol. Vis. Sci. 42, 589–600. stimulates formation of A2E oxiranes in a mouse model of Stargardt’s Thaung, C., West, K., Clark, B.J., McKie, L., Morgan, J.E., Arnold, K., macular degeneration. Proc. Natl Acad. Sci. USA 101, 5928–5933. Nolan, P.M., Peters, J., Hunter, A.J., Brown, S.D., Jackson, I.J., Cross, Ramamurthy, V., Niemi, G.A., Reh, T.A., Hurley, J.B., 2004. Leber S.H., 2002. Novel ENU-induced eye mutations in the mouse: models congenital amaurosis linked to AIPL1: a mouse model reveals for human eye disease. Hum. Mol. Genet. 11, 755–767. destabilization of cGMP phosphodiesterase. Proc. Natl Acad. Sci. Theiler, K., Varnum, D.S., Nadeau, J.H., Stevens, L.C., Cagianut, B., 1976. USA 101, 13897–13902. A new allele of ocular retardation: early development and morphogen- Ranta, S., Zhang, Y., Ross, B., Lonka, L., Takkunen, E., Messer, A., Sharp, etic cell death. Anat. Embryol. 150, 85–97. J., Wheeler, R., Kusumi, K., Mole, S., Liu, W., Soares, M.B., Bonaldo, Travis, G.H., Brennan, M.B., Danielson, P.E., Kozak, C.A., Sutcliffe, J.G., M.F., Hirvasniemi, A., de la Chapelle, A., Gilliam, T.C., Lehesjoki, A. 1989. Identification of a photoreceptor-specific mRNA encoded by the E., 1999. The neuronal ceroid lipofuscinoses in human EPMR and mnd gene responsible for retinal degeneration slow (rds). Nature 338, 70–73. mutant mice are associated with mutations in CLN8. Nat. Genet. 23, Truslove, G.M., 1962. A gene causing ocular retardation in the mouse. J. 233–236. Embryol. Exp. Morphol. 10, 652–660. Redmond, T.M., Yu, S., Lee, E., Bok, D., Hamasaki, D., Chen, N., Goletz, Tsang, S.H., Gouras, P., Yamashita, C.K., Kjeldbye, H., Fisher, J., Farber, P., Ma, J.X., Crouch, R.K., Pfeifer, K., 1998. Rpe65 is necessary for D.B., Goff, S.P., 1996. Retinal degeneration in mice lacking the gamma production of 11-cis-vitamin A in the retinal visual cycle. Nat. Genet. subunit of the rod cGMP phosphodiesterase. Science 272, 1026–1029. 20, 344–351. Tsang, S.H., Yamashita, C.K., Lee, W.H., Lin, C.S., Goff, S.P., Gouras, P., Rowan, S., Chen, C.M., Young, T.L., Fisher, D.E., Cepko, C.L., 2004. Farber, D.B., 2002. The positive role of the carboxyl terminus of the Transdifferentiation of the retina into pigmented cells in ocular gamma subunit of retinal cGMP-phosphodiesterase in maintaining retardation mice defines a new function of the homeodomain gene phosphodiesterase activity in vivo. Vision Res. 42, 439–445. Chx10. Development 131, 5139–51352. van de Pavert, S.A., Kantardzhieva, A., Malysheva, A., Meuleman, J., Rutherford, A.D., Dhomen, N., Smith, H.K., Sowden, J.C., 2004. Delayed Versteeg, I., Levelt, C., Klooster, J., Geiger, S., Seeliger, M.W., expression of the Crx gene and photoreceptor development in the Rashbass, P., Le Bivic, A., Wijnholds, J., 2004. Crumbs homologue 1 is Chx10-deficient retina. Invest. Ophthalmol. Vis. Sci. 45, 375–384. required for maintenance of photoreceptor cell polarization and Seeliger, M.W., Grimm, C., Stahlberg, F., Friedburg, C., Jaissle, G., adhesion during light exposure. J. Cell Sci. 117, 4169–4177. Zrenner, E., Guo, H., Reme, C.E., Humphries, P., Hofmann, F., Biel, Weber, B.H., Schrewe, H., Molday, L.L., Gehrig, A., White, K.L., Seeliger, M., Fariss, R.N., Redmond, T.M., Wenzel, A., 2001. New views on M.W., Jaissle, G.B., Friedburg, C., Tamm, E., Molday, R.S., 2002. RPE65 deficiency: the rod system is the source of vision in a mouse Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, model of Leber congenital amaurosis. Nat. Genet. 29, 70–74. suggests a role of retinoschisin in retinal cell layer organization and Skarnes, W.C., von Melchner, H., Wurst, W., Hicks, G., Nord, A.S., Cox, synaptic structure. Proc. Natl Acad. Sci. USA 99, 6222–6227. T., Young, S.G., Ruiz, P., Soriano, P., Tessier-Lavigne, M., Conklin, B. Weber, B.H., Janssen, A., Schrewe, H., Seeliger, M., Molday, R.S., Min, S.- R., Stanford, W.L., Rossant, J., 2004. A public gene trap resource for H., Hauswirth, W.W., 2005. Rescue of photoreceptor degeneration in a mouse functional genomics. Nat. Genet. 36, 543–544. Smith, S.B., 1995. Evidence of a difference in photoreceptor cell loss in the genetic mouse model for X-linked juvenile retinoschisis, 16th GfH peripheral versus posterior regions of the vitiligo (C57BL/6J-mi(vit) meeting, Halle, Germany, Medizinische Genetik 1, 39. /mi(vit)) mouse retina. Exp. Eye Res. 60, 333–336. Weng, J., Mata, N.L., Azarian, S.M., Tzekov, R.T., Birch, D.G., Travis, G. Smith, L.E., 2004. Bone marrow-derived stem cells preserve cone vision in H., 1999. Insights into the function of Rim protein in photoreceptors and retinitis pigmentosa. J. Clin. Invest. 114, 755–757. etiology of Stargardt’s disease from the phenotype in abcr knockout Steingrimsson, E., Moore, K.J., Lamoreux, M.L., Ferre-D’Amare, A.R., mice. Cell 98, 13–23. Burley, S.K., Zimring, D.C., Skow, L.C., Hodgkinson, C.A., Arnheiter, Wheeler, R.B., Sharp, J.D., Schultz, R.A., Joslin, J.M., Williams, R.E., H., Copeland, N.G., Jenkins, N.A., 1994. Molecular basis of mouse Mole, S.E., 2002. The gene mutated in variant late-infantile neuronal microphthalmia (mi) mutations helps explain their developmental and ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel phenotypic consequences. Nat. Genet. 8, 256–263. predicted transmembrane protein. Am. J. Hum. Genet. 70, 537–542. Steingrimsson, E., Arnheiter, H., Hallsson, J.H., Lamoreux, M.L., Cope- Woodruff, M.L., Wang, Z., Chung, H.Y., Redmond, T.M., Fain, G.L., Lem, land, N.G., Jenkins, N.A., 2003. Interallelic complementation at the J., 2003. Spontaneous activity of opsin apoprotein is a cause of Leber mouse Mitf locus. Genetics 163, 267–276. congenital amaurosis. Nat. Genet. 35, 158–164. Stubdal, H., Lynch, C.A., Moriarty, A., Fang, Q., Chickering, T., Deeds, J. Zeng, Y., Takada, Y., Kjellstrom, S., Hiriyanna, K., Tanikawa, A., D., Fairchild-Huntress, V., Charlat, O., Dunmore, J.H., Kleyn, P., Wawrousek, E., Smaoui, N., Caruso, R., Bush, R.A., Sieving, P.A., Huszar, D., Kapeller, R., 2000. Targeted deletion of the tub mouse 2004. RS-1 gene delivery to an adult Rs1h knockout mouse model obesity gene reveals that tubby is a loss-of-function mutation. Mol. Cell restores ERG b-wave with reversal of the electronegative waveform of Biol. 20, 878–882. X-linked retinoschisis. Invest. Ophthalmol. Vis. Sci. 45, 3279–3285. Swain, P.K., Hicks, D., Mears, A.J., Apel, I.J., Smith, J.E., John, S.K., Zhao, Y., Hong, D.H., Pawlyk, B., Yue, G., Adamian, M., Grynberg, M., Hendrickson, A., Milam, A.H., Swaroop, A., 2001. Multiple Godzik, A., Li, T., 2003. The retinitis pigmentosa GTPase regulator phosphorylated isoforms of NRL are expressed in rod photoreceptors. (RPGR)- interacting protein: subserving RPGR function and participat- J. Biol. Chem. 276, 36824–36830. ing in disk morphogenesis. Proc. Natl Acad. Sci. USA 100, 3965–3970.