Retinol Dehydrogenase (RDH12) Protects Photoreceptors from Light-induced Degeneration in Mice

Abstract

RDH12 has been suggested to be one of the retinol dehydrogenases (RDH) involved in the vitamin A recycling system (visual cycle) in the eye. Loss of function mutations in the RDH12 gene were recently reported to be associated with autosomal recessive childhood-onset severe retinal dystrophy. Here we show that RDH12 localizes to the photoreceptor inner segments and that deletion of this gene in mice slows the kinetics of all-trans-retinal reduction, delaying dark adaptation. However, accelerated 11-cis-retinal production and increased susceptibility to light-induced photoreceptor apoptosis were also observed in Rdh12-/- mice, suggesting that RDH12 plays a unique, nonredundant role in the photoreceptor inner segments to regulate the flow of retinoids in the eye. Thus, severe visual impairments of individuals with null mutations in RDH12 may likely be caused by light damage1. RDH12 has been suggested to be one of the retinol dehydrogenases (RDH) involved in the vitamin A recycling system (visual cycle) in the eye. Loss of function mutations in the RDH12 gene were recently reported to be associated with autosomal recessive childhood-onset severe retinal dystrophy. Here we show that RDH12 localizes to the photoreceptor inner segments and that deletion of this gene in mice slows the kinetics of all-trans-retinal reduction, delaying dark adaptation. However, accelerated 11-cis-retinal production and increased susceptibility to light-induced photoreceptor apoptosis were also observed in Rdh12-/- mice, suggesting that RDH12 plays a unique, nonredundant role in the photoreceptor inner segments to regulate the flow of retinoids in the eye. Thus, severe visual impairments of individuals with null mutations in RDH12 may likely be caused by light damage1. 11-cis-Retinal, the chromophore of rhodopsin and cone pigments in photoreceptor cells, is essential for vision (1Matthews R.G. Hubbard R. Brown P.K. Wald G. J. Gen. Physiol. 1963; 47: 215-240Crossref PubMed Scopus (431) Google Scholar, 2Palczewski K. Annu. Rev. Biochem. 2006; 75: 743-767Crossref PubMed Scopus (561) Google Scholar). Photoactivation of rhodopsin and cone pigments causes isomerization of 11-cis-retinal to all-trans-retinal (2Palczewski K. Annu. Rev. Biochem. 2006; 75: 743-767Crossref PubMed Scopus (561) Google Scholar, 3Filipek S. Stenkamp R.E. Teller D.C. Palczewski K. Annu. Rev. Physiol. 2003; 65: 851-879Crossref PubMed Scopus (201) Google Scholar), which is recycled in a pathway termed the visual (retinoid) cycle (4McBee J.K. Palczewski K. Baehr W. Pepperberg D.R. Prog. Retin. Eye Res. 2001; 20: 469-529Crossref PubMed Scopus (316) Google Scholar, 5Lamb T.D. Pugh Jr., E.N. Prog. Retin. Eye Res. 2004; 23: 307-380Crossref PubMed Scopus (531) Google Scholar). The importance of retinol recycling is emphasized by the large number of retinal diseases associated with mutations in genes involved in the visual cycle (6Thompson D.A. Gal A. Prog. Retin. Eye Res. 2003; 22: 683-703Crossref PubMed Scopus (162) Google Scholar). Loss of function mutations in the retinol dehydrogenase 12 gene (RDH12) were recently reported to be associated with severe, early-onset autosomal recessive retinal dystrophy in several independent pedigrees (7Janecke A.R. Thompson D.A. Utermann G. Becker C. Hubner C.A. Schmid E. McHenry C.L. Nair A.R. Ruschendorf F. Heckenlively J. Wissinger B. Nurnberg P. Gal A. Nat. Genet. 2004; 36: 850-854Crossref PubMed Scopus (187) Google Scholar, 8Perrault I. Hanein S. Gerber S. Barbet F. Ducroq D. Dollfus H. Hamel C. Dufier J.L. Munnich A. Kaplan J. Rozet J.M. Am. J. Hum. Genet. 2004; 75: 639-646Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). RDH12 is a member of a novel subfamily of four retinol dehydrogenases (RDH11-14) active toward all-trans- and cis-retinals with C (15Ohguro H. Chiba S. Igarashi Y. Matsumoto H. Akino T. Palczewski K. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3241-3245Crossref PubMed Scopus (60) Google Scholar) pro-R specificity (9Haeseleer F. Jang G.F. Imanishi Y. Driessen C.A. Matsumura M. Nelson P.S. Palczewski K. J. Biol. Chem. 2002; 277: 45537-45546Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar) as well as other aldehydes (10Belyaeva O.V. Korkina O.V. Stetsenko A.V. Kim T. Nelson P.S. Kedishvili N.Y. Biochemistry. 2005; 44: 7035-7047Crossref PubMed Scopus (93) Google Scholar). Based on in situ hybridization, RDH12 expression was observed in photoreceptor cells (9Haeseleer F. Jang G.F. Imanishi Y. Driessen C.A. Matsumura M. Nelson P.S. Palczewski K. J. Biol. Chem. 2002; 277: 45537-45546Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). Thus, in the visual cycle, RDH12 can catalyze reduction of all-trans-retinal and 11-cis-retinal to their corresponding retinols. In vitro studies suggest that decreased 11-cis-retinal production due to disruption of the visual cycle (4McBee J.K. Palczewski K. Baehr W. Pepperberg D.R. Prog. Retin. Eye Res. 2001; 20: 469-529Crossref PubMed Scopus (316) Google Scholar, 5Lamb T.D. Pugh Jr., E.N. Prog. Retin. Eye Res. 2004; 23: 307-380Crossref PubMed Scopus (531) Google Scholar) can be a cause of the degeneration with RDH12 mutations (8Perrault I. Hanein S. Gerber S. Barbet F. Ducroq D. Dollfus H. Hamel C. Dufier J.L. Munnich A. Kaplan J. Rozet J.M. Am. J. Hum. Genet. 2004; 75: 639-646Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 11Yzer S. Leroy B.P. De Baere E. de Ravel T.J. Zonneveld M.N. Voesenek K. Kellner U. Ciriano J.P. de Faber J.T. Rohrschneider K. den Roepman R. Hollander A.I. Cruysberg J.R. Meire F. Casteels I. Allikmets R. Cremers F.P. van den Born L.I. van Moll-Ramirez N.G. Investig. Ophthalmol. Vis. Sci. 2006; 47: 1167-1176Crossref PubMed Scopus (78) Google Scholar, 12Thompson D.A. Janecke A.R. Lange J. Feathers K.L. Hubner C.A. McHenry C.L. Stockton D.W. Rammesmayer G. Lupski J.R. Antinolo G. Ayuso C. Baiget M. Gouras P. den Heckenlively J.R. Hollander A. Jacobson S.G. Lewis R.A. Sieving P.A. Wissinger B. Yzer S. Zrenner E. Utermann G. Gal A. Hum. Mol. Genet. 2005; 14: 3865-3875Crossref PubMed Scopus (81) Google Scholar). Deletion of RDH8 (also known as prRDH), another all-trans-RDH present in photoreceptor cells (13Rattner A. Smallwood P.M. Nathans J. J. Biol. Chem. 2000; 275: 11034-11043Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar), caused only a mild phenotype exhibiting delayed dark adaptation (14Maeda A. Maeda T. Imanishi Y. Kuksa V. Alekseev A. Bronson J.D. Zhang H. Zhu L. Sun W. Saperstein D.A. Rieke F. Baehr W. Palczewski K. J. Biol. Chem. 2005; 280: 18822-18832Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). No RDH8 mutations have yet been identified in patients with retinal diseases. Thus, RDH12 is possibly a key enzyme in the visual cycle pathway. Rdh12-/- Mice, Genotyping, and PCR—Rdh12-/- mice were generated by standard procedures (Ingenious Targeting, Inc., Rochester, NY). The targeting vector was constructed by replacing exons 1, 2, and 3 with the neo cassette (supplemental Fig. S1). The Rdh12-/- genotype was maintained in a mixed background of C57BL/6J and 129Sv/Ev mice, and siblings were used for the majority of experiments. Genotyping was carried out by PCR using primers RDH12U5, 5′-GCTGAGCCACTTTCCCTGCCCT-3′, and RDH12d5, 5′-AGAGCCGCCAGAGCACAGCCT-3′, for wild type (751 bp) and RDH12U5 and neoa1, 5′-GCCCCGACTGCATCTGCGTGTT-3′, for targeted deletion (468 bp). PCR products were cloned and sequenced to verify their identity. 129Sv/Ev (Leu-450; RPE65) 2The abbreviations used are: RPE, retinal pigment epithelium; A2E, (2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hydroxyethyl)-4-[4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium); ERG, electroretinogram; HPLC, high pressure liquid chromatography; LD, light damage; RDH, retinol dehydrogenase; ROS, rod outer segment(s); cd, candela. and C57Bl/6J (Met-450; RPE65) mice were purchased from Taconic Inc. and The Jackson Laboratory. The RPE65 variant was verified by direct sequencing. Rdh12-/- mice were fertile, developed normally, and reached similar body weights in both sexes. All animal experiments employed procedures approved by the Case Western Reserve University Animal Care Committee and conformed to both the recommendations of the American Veterinary Medical Association Panel on Euthanasia and the Association of Research for Vision and Ophthalmology. Mice were maintained in a 12-h light/12-h dark (6 a.m./6 p.m.) cycle and were reared under less than 10 lux white light. All manipulations were done under dim red light employing a Kodak No. 1 safelight filter (transmittance >560 nm). Total RNA was isolated from 3-month-old Rdh12-/-, Rdh8-/-, and Rdh12+/+ mouse retinas and the RPE. First-strand cDNA was synthesized by using SuperScript First-Strand Synthesis system for reverse transcription-PCR (Invitrogen). Primers for mouse RDH12 (Mm01307472_m1) and RDH8 (Mm01178944_m1) were ordered from Applied Biosystems. All samples were triple-loaded and 18 S rRNA was used as the internal control. The results are presented with S.E., and n was between 3 and 5. Immunoblots and Antibodies—Immunoblotting was done according to standard protocols using Immobilon-P to adsorb proteins (polyvinylidene difluoride; Millipore Corp.) (15Ohguro H. Chiba S. Igarashi Y. Matsumoto H. Akino T. Palczewski K. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3241-3245Crossref PubMed Scopus (60) Google Scholar). Mouse polyclonal antibodies against bacterially expressed full-length mouse RDH12 were raised in BALB/c mice as (15Ohguro H. Chiba S. Igarashi Y. Matsumoto H. Akino T. Palczewski K. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3241-3245Crossref PubMed Scopus (60) Google Scholar). specificity was verified by using bacterially RDH12 and polyclonal antibodies against RDH8 were generated against bacterially expressed as I. Baehr W. Palczewski K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and was purchased from Inc. were used as were with and were in for 18 in and in with in were with and with for were (9Haeseleer F. Jang G.F. Imanishi Y. Driessen C.A. Matsumura M. Nelson P.S. Palczewski K. J. Biol. Chem. 2002; 277: 45537-45546Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). were with a were as (9Haeseleer F. Jang G.F. Imanishi Y. Driessen C.A. Matsumura M. Nelson P.S. Palczewski K. J. Biol. Chem. 2002; 277: 45537-45546Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). which were as with in was used for and were 10 were for in in by a in for was carried out with the in for were as employing mice were as reported (14Maeda A. Maeda T. Imanishi Y. Kuksa V. Alekseev A. Bronson J.D. Zhang H. Zhu L. Sun W. Saperstein D.A. Rieke F. Baehr W. Palczewski K. J. Biol. Chem. 2005; 280: 18822-18832Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, T. J.P. Driessen C.A. S. Palczewski K. J. 2003; PubMed Scopus Google Scholar). of Mouse and procedures to and of retinoids from mouse were carried out as T. J.P. Driessen C.A. S. Palczewski K. J. 2003; PubMed Scopus Google Scholar). Mouse was done according to procedures (14Maeda A. Maeda T. Imanishi Y. Kuksa V. Alekseev A. Bronson J.D. Zhang H. Zhu L. Sun W. Saperstein D.A. Rieke F. Baehr W. Palczewski K. J. Biol. Chem. 2005; 280: 18822-18832Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). of was with a known of C.A. M. K. J. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). of from mice was done as reported (14Maeda A. Maeda T. Imanishi Y. Kuksa V. Alekseev A. Bronson J.D. Zhang H. Zhu L. Sun W. Saperstein D.A. Rieke F. Baehr W. Palczewski K. J. Biol. Chem. 2005; 280: 18822-18832Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). The of rhodopsin was the by the in using the mouse were of the and were by the production of of as reported (14Maeda A. Maeda T. Imanishi Y. Kuksa V. Alekseev A. Bronson J.D. Zhang H. Zhu L. Sun W. Saperstein D.A. Rieke F. Baehr W. Palczewski K. J. Biol. Chem. 2005; 280: 18822-18832Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). was as A. F. C. J. 2001; PubMed Google Scholar) with Mice were for and was with by to lux white light on was from retinas with a samples were on was carried out and were under light. of the in Mice and Here we to the role of RDH12 in vision by disruption of function to retinal degeneration in a mouse targeted we generated Rdh12-/- mouse in which exons of the mouse gene were by a neo cassette (supplemental Fig. S1). The expression of RDH12 was in the of Rdh12-/- mice as by and PCR RDH8 expression was in Rdh12-/- of RDH12 in the photoreceptor inner suggesting the RDH12 is to both cone and rod inner studies be to the of RDH12 in cone photoreceptor and between mice from were for than The results are presented with S.E., and n was between 3 and 5. and retinoids were as under and was as under and The results are presented with S.E., and n was between 3 and was as under and PCR was carried out in the and PCR of Case Western Reserve Mice were for than The results are presented with S.E., and n was between 3 and 5. and retinoids were as under and was as under and The results are presented with S.E., and n was between 3 and was as under and PCR was carried out in the and PCR of Case Western Reserve in a we rhodopsin in and Rdh12-/- mice and that were we disruption of the gene reduction of was to the and all-trans-RDH was from the of production and from and Rdh12-/- mice all-trans-RDH The all-trans-RDH of expressed RDH8 and RDH12 in cells also (9Haeseleer F. Jang G.F. Imanishi Y. Driessen C.A. Matsumura M. Nelson P.S. Palczewski K. J. Biol. Chem. 2002; 277: 45537-45546Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). from Rdh12+/+ and Rdh12-/- mice similar in the of Thus, deletion of RDH12 the all-trans-RDH in the and and that other are to a majority of all-trans-retinal in mouse that RDH12 is a enzyme in inner However, RDH12 is a to the in the the of the of RDH12 on of we used on the were to a and for the of were observed in from Rdh12+/+ and Rdh12-/- mice, Fig. suggested that RDH12 of the chromophore from the in are also with RDH12 to photoreceptor inner segments and of Rdh12-/- in the retinas of Rdh12-/- mice raised in 12-h light The were similar in in Rdh12-/-, and Rdh12+/+ mice 1 The of in the was also similar in In light that the the of the from the were in in Rdh12-/- mice In the of in the from the of the was similar in the and light we Rdh12-/- mice using The of the a and were in and Rdh12-/-, and Rdh12+/+ mice of 2, A and also were similar for and mice (supplemental Fig. Thus, RDH12 deletion have a on the of and to light of the was also by the of the to for 3 of the was in Rdh12-/- mice with Rdh12+/+ mice Fig. mice dark adaptation in the their adaptation kinetics similar to Rdh12+/+ mice by the of all-trans-retinal and 11-cis-retinal the that the was with the of all-trans-retinal suggested that of all-trans-retinal in Rdh12-/- mice is than production of 11-cis-retinal dark adaptation. of in Rdh12-/- Mice to a of RDH12 the flow the visual cycle, we retinoids by caused the of of which decreased with was to and The reduction kinetics were in Rdh12-/- in than in Rdh12+/+ reduction was also observed in retinas Mice also reduction and the in mice was with that in Rdh12-/- mice (14Maeda A. Maeda T. Imanishi Y. Kuksa V. Alekseev A. Bronson J.D. Zhang H. Zhu L. Sun W. Saperstein D.A. Rieke F. Baehr W. Palczewski K. J. Biol. Chem. 2005; 280: 18822-18832Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). The kinetics of 11-cis-retinal were in Rdh12-/- than in Rdh12+/+ mice that the reduction of the of all-trans-retinal to in Rdh12-/- mice was 11-cis-retinal in the visual cycle was mice with all-trans-retinal reduction show accelerated 11-cis-retinal production (14Maeda A. Maeda T. Imanishi Y. Kuksa V. Alekseev A. Bronson J.D. Zhang H. Zhu L. Sun W. Saperstein D.A. Rieke F. Baehr W. Palczewski K. J. Biol. Chem. 2005; 280: 18822-18832Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Total of retinoids in the were and in and Rdh12-/- mice of the in Rdh12-/- Mice to employed light to the of 11-cis-retinal in Rdh12-/- mice light that of accelerated 11-cis-retinal production was observed in Rdh12-/- mice of the 11-cis-retinal was with 3 in Rdh12+/+ in the and the of that of rhodopsin is in Fig. was in the and in Rdh12-/- mice in Fig. in the and in the that reduction of all-trans-retinal was in Rdh12-/- mice in Rdh12-/- Mice to is another of the visual cycle involved in the isomerization of to G. Y. Y. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar, M. S. Sun H. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). also is a of light-induced retinal degeneration RPE65 null mice show to C. A. F. S. Nat. Genet. 2000; PubMed Scopus Google Scholar). RPE65 in which is by less production of and mice this are also to A. F. C. J. 2001; PubMed Google Scholar). The of Fig. the of 11-cis-retinal the light in Rdh12-/- to mice with of Mice with the of 11-cis-retinal as reported A. F. C. J. 2001; PubMed Google Scholar). However, deletion of RDH12 accelerated 11-cis-retinal production in both RPE65 experiments to in Fig. 3 were also done with background mice, that 11-cis-retinal was accelerated The of 11-cis-retinal susceptibility to LD, and the RPE65 due to 11-cis-retinal Rdh12-/- mice accelerated 11-cis-retinal and susceptibility to was to lux white light for the of Rdh12-/- the from the the light was and were A and were observed in the of No in the were in in Rdh12-/- mice were to present in mice, rhodopsin in Rdh12+/+ mice were similar to retinoids in were by HPLC, Rdh12-/- mice less retinoids with Rdh12-/- mice suggesting that photoreceptor outer in Rdh12-/- mice light. A light was also employed to in Rdh12-/- In Rdh12-/- mice with in cells were of of were for Rdh12+/+ mice with in RPE65 and Fig. was in only a cells in Rdh12+/+ mice with RPE65 of a large was in Rdh12-/- mice (supplemental Fig. and was by reduction in Rdh12-/- mice with of also suggesting that Rdh12-/- mice are to LD, with their light are to in the is a in the of Rdh12-/- all-trans-retinal can as observed in mice J. Full Text Full Text PDF PubMed Scopus Google Scholar). was in Rdh12-/- and Rdh12+/+ mice than in Rdh12+/+ mice was several than in mice J. Full Text Full Text PDF PubMed Scopus Google Scholar). in Rdh12-/- mice is to be the cause of observed mice with of only mild photoreceptor degeneration J. Full Text Full Text PDF PubMed Scopus Google Scholar). J. Full Text Full Text PDF PubMed Scopus Google Scholar), (14Maeda A. Maeda T. Imanishi Y. Kuksa V. Alekseev A. Bronson J.D. Zhang H. Zhu L. Sun W. Saperstein D.A. Rieke F. Baehr W. Palczewski K. J. Biol. 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Thus, as by be from the results of of of in the cycle are other that reduction of all-trans-retinal in the photoreceptor inner is for function of the visual Based on the results of and mice, that the all-trans-retinal to the inner is by is accelerated is with the retinoids present in the Thus, of rhodopsin and 11-cis-retinal are were in the mice, are from accelerated of retinol from the Thus, results suggest role of RDH12 for of all-trans-retinal in the RDH12 and the Rdh12-/- mice, all-trans-retinal present in the inner segments the RDH12 enzyme be The of all-trans-retinal in the inner segments be a for is observed in wild type inner segments are in and a role in and is essential to the inner segments of chromophore to accelerated 11-cis-retinal production in Rdh12-/- mice can also to the of all-trans-retinal in the inner segments under light and independent studies that mutations in the RDH12 gene are for severe of termed early-onset autosomal recessive (7Janecke A.R. Thompson D.A. Utermann G. Becker C. Hubner C.A. Schmid E. McHenry C.L. Nair A.R. Ruschendorf F. Heckenlively J. Wissinger B. Nurnberg P. Gal A. Nat. Genet. 2004; 36: 850-854Crossref PubMed Scopus (187) Google Scholar, 8Perrault I. Hanein S. Gerber S. Barbet F. Ducroq D. Dollfus H. Hamel C. Dufier J.L. Munnich A. Kaplan J. Rozet J.M. Am. J. Hum. Genet. 2004; 75: 639-646Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 12Thompson D.A. Janecke A.R. Lange J. Feathers K.L. Hubner C.A. McHenry C.L. Stockton D.W. Rammesmayer G. Lupski J.R. Antinolo G. Ayuso C. Baiget M. Gouras P. den Heckenlively J.R. Hollander A. Jacobson S.G. Lewis R.A. Sieving P.A. Wissinger B. Yzer S. Zrenner E. Utermann G. Gal A. Hum. Mol. Genet. 2005; 14: 3865-3875Crossref PubMed Scopus (81) Google Scholar). The mouse phenotype presented in this is from mice disruption of the cycle genes as retinol Y. D.W. Baehr W. Palczewski K. J. Biol. 2004; PubMed Scopus Google Scholar, Imanishi Y. Maeda T. D.C. A.R. Bronson D. 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