This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Driessen, C. A. G. G.
Right arrow Articles by Janssen, J. J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Driessen, C. A. G. G.
Right arrow Articles by Janssen, J. J. M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 2000, p. 4275-4287, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Disruption of the 11-cis-Retinol Dehydrogenase Gene Leads to Accumulation of cis-Retinols and cis-Retinyl Esters

Carola A. G. G. Driessen,1,* Huub J. Winkens,1 Kirstin Hoffmann,2 Leonoor D. Kuhlmann,1 Bert P. M. Janssen,1 Anke H. M. Van Vugt,1 J. Preston Van Hooser,3 B. E. Wieringa,4 August F. Deutman,1 Krzysztof Palczewski,3,5,6 Klaus Ruether,2 and Jacques J. M. Janssen1

Department of Ophthalmology, University of Nijmegen, 6525 EX Nijmegen, The Netherlands1; Department of Ophthalmology, Humboldt University, 15553 Berlin, Germany2; Departments of Ophthalmology,3 Chemistry,5 and Pharmacology,6 University of Washington, Seattle, Washington 98195; and Department of Cell Biology, University of Nijmegen, 6500 HB Nijmegen, The Netherlands4

Received 28 January 2000/Accepted 13 March 2000

To elucidate the possible role of 11-cis-retinol dehydrogenase in the visual cycle and/or 9-cis-retinoic acid biosynthesis, we generated mice carrying a targeted disruption of the 11-cis-retinol dehydrogenase gene. Homozygous 11-cis-retinol dehydrogenase mutants developed normally, including their retinas. There was no appreciable loss of photoreceptors. Recently, mutations in the 11-cis-retinol dehydrogenase gene in humans have been associated with fundus albipunctatus. In 11-cis-retinol dehydrogenase knockout mice, the appearance of the fundus was normal and punctata typical of this human hereditary ocular disease were not present. A second typical symptom associated with this disease is delayed dark adaptation. Homozygous 11-cis-retinol dehydrogenase mutants showed normal rod and cone responses. 11-cis-Retinol dehydrogenase knockout mice were capable of dark adaptation. At bleaching levels under which patients suffering from fundus albipunctatus could be detected unequivocally, 11-cis-retinol dehydrogenase knockout animals displayed normal dark adaptation kinetics. However, at high bleaching levels, delayed dark adaptation in 11-cis-retinol dehydrogenase knockout mice was noticed. Reduced 11-cis-retinol oxidation capacity resulted in 11-cis-retinol/13-cis-retinol and 11-cis-retinyl/13-cis-retinyl ester accumulation. Compared with wild-type mice, a large increase in the 11-cis-retinyl ester concentration was noticed in 11-cis-retinol dehydrogenase knockout mice. In the murine retinal pigment epithelium, there has to be an additional mechanism for the biosynthesis of 11-cis-retinal which partially compensates for the loss of the 11-cis-retinol dehydrogenase activity. 11-cis-Retinyl ester formation is an important part of this adaptation process. Functional consequences of the loss of 11-cis-retinol dehydrogenase activity illustrate important differences in the compensation mechanisms between mice and humans. We furthermore demonstrate that upon 11-cis-retinol accumulation, the 13-cis-retinol concentration also increases. This retinoid is inapplicable to the visual processes, and we therefore speculate that it could be an important catabolic metabolite and its biosynthesis could be part of a process involved in regulating 11-cis-retinol concentrations within the retinal pigment epithelium of 11-cis-retinol dehydrogenase knockout mice.

* Corresponding author. Mailing address: Department of Ophthalmology, University of Nijmegen, Philips van Leijdenlaan 15, 6525 EX Nijmegen, The Netherlands. Phone: 31243615160. Fax: 31243540522. E-mail: c.driessen{at}ohk.azn.nl.

Molecular and Cellular Biology, June 2000, p. 4275-4287, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Maeda, A., Maeda, T., Sun, W., Zhang, H., Baehr, W., Palczewski, K. (2007). Redundant and unique roles of retinol dehydrogenases in the mouse retina. Proc. Natl. Acad. Sci. USA 104: 19565-19570 [Abstract] [Full Text]  
  • Kurth, I., Thompson, D. A., Ruther, K., Feathers, K. L., Chrispell, J. D., Schroth, J., McHenry, C. L., Schweizer, M., Skosyrski, S., Gal, A., Hubner, C. A. (2007). Targeted Disruption of the Murine Retinal Dehydrogenase Gene Rdh12 Does Not Limit Visual Cycle Function. Mol. Cell. Biol. 27: 1370-1379 [Abstract] [Full Text]  
  • Wenzel, A., von Lintig, J., Oberhauser, V., Tanimoto, N., Grimm, C., Seeliger, M. W. (2007). RPE65 Is Essential for the Function of Cone Photoreceptors in NRL-Deficient Mice. IOVS 48: 534-542 [Abstract] [Full Text]  
  • Jacobson, S. G., Cideciyan, A. V., Aleman, T. S., Sumaroka, A., Schwartz, S. B., Windsor, E. A. M., Roman, A. J., Heon, E., Stone, E. M., Thompson, D. A. (2007). RDH12 and RPE65, Visual Cycle Genes Causing Leber Congenital Amaurosis, Differ in Disease Expression. IOVS 48: 332-338 [Abstract] [Full Text]  
  • Maeda, A., Maeda, T., Imanishi, Y., Sun, W., Jastrzebska, B., Hatala, D. A., Winkens, H. J., Hofmann, K. P., Janssen, J. J., Baehr, W., Driessen, C. A., Palczewski, K. (2006). Retinol Dehydrogenase (RDH12) Protects Photoreceptors from Light-induced Degeneration in Mice. J. Biol. Chem. 281: 37697-37704 [Abstract] [Full Text]  
  • Maeda, A., Maeda, T., Palczewski, K. (2006). Improvement in Rod and Cone Function in Mouse Model of Fundus albipunctatus after Pharmacologic Treatment with 9-cis-Retinal.. IOVS 47: 4540-4546 [Abstract] [Full Text]  
  • Liden, M., Eriksson, U. (2006). Understanding Retinol Metabolism: Structure and Function of Retinol Dehydrogenases. J. Biol. Chem. 281: 13001-13004 [Full Text]  
  • Redmond, T. M., Poliakov, E., Yu, S., Tsai, J.-Y., Lu, Z., Gentleman, S. (2005). Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proc. Natl. Acad. Sci. USA 102: 13658-13663 [Abstract] [Full Text]  
  • Wenzel, A., Oberhauser, V., Pugh, E. N. Jr., Lamb, T. D., Grimm, C., Samardzija, M., Fahl, E., Seeliger, M. W., Reme, C. E., von Lintig, J. (2005). The Retinal G Protein-coupled Receptor (RGR) Enhances Isomerohydrolase Activity Independent of Light. J. Biol. Chem. 280: 29874-29884 [Abstract] [Full Text]  
  • Strauss, O. (2005). The Retinal Pigment Epithelium in Visual Function. Physiol. Rev. 85: 845-881 [Abstract] [Full Text]  
  • Maeda, 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. (2005). Role of Photoreceptor-specific Retinol Dehydrogenase in the Retinoid Cycle in Vivo. J. Biol. Chem. 280: 18822-18832 [Abstract] [Full Text]  
  • Niwa, Y., Kondo, M., Ueno, S., Nakamura, M., Terasaki, H., Miyake, Y. (2005). Cone and Rod Dysfunction in Fundus Albipunctatus with RDH5 Mutation: An Electrophysiological Study. IOVS 46: 1480-1485 [Abstract] [Full Text]  
  • Kim, T. S., Maeda, A., Maeda, T., Heinlein, C., Kedishvili, N., Palczewski, K., Nelson, P. S. (2005). Delayed Dark Adaptation in 11-cis-Retinol Dehydrogenase-deficient Mice: A ROLE OF RDH11 IN VISUAL PROCESSES IN VIVO. J. Biol. Chem. 280: 8694-8704 [Abstract] [Full Text]  
  • Nadauld, L. D., Sandoval, I. T., Chidester, S., Yost, H. J., Jones, D. A. (2004). Adenomatous Polyposis Coli Control of Retinoic Acid Biosynthesis Is Critical for Zebrafish Intestinal Development and Differentiation. J. Biol. Chem. 279: 51581-51589 [Abstract] [Full Text]  
  • Gollapalli, D. R., Rando, R. R. (2004). The specific binding of retinoic acid to RPE65 and approaches to the treatment of macular degeneration. Proc. Natl. Acad. Sci. USA 101: 10030-10035 [Abstract] [Full Text]  
  • Batten, M. L., Imanishi, Y., Maeda, T., Tu, D. C., Moise, A. R., Bronson, D., Possin, D., Van Gelder, R. N., Baehr, W., Palczewski, K. (2004). Lecithin-retinol Acyltransferase Is Essential for Accumulation of All-trans-Retinyl Esters in the Eye and in the Liver. J. Biol. Chem. 279: 10422-10432 [Abstract] [Full Text]  
  • Molotkov, A., Duester, G. (2003). Genetic Evidence That Retinaldehyde Dehydrogenase Raldh1 (Aldh1a1) Functions Downstream of Alcohol Dehydrogenase Adh1 in Metabolism of Retinol to Retinoic Acid. J. Biol. Chem. 278: 36085-36090 [Abstract] [Full Text]  
  • Radu, R. A., Mata, N. L., Nusinowitz, S., Liu, X., Sieving, P. A., Travis, G. H. (2003). From the Cover: Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc. Natl. Acad. Sci. USA 100: 4742-4747 [Abstract] [Full Text]  
  • Qtaishat, N. M., Redmond, T. M., Pepperberg, D. R. (2003). Acute Radiolabeling of Retinoids in Eye Tissues of Normal and Rpe65-Deficient Mice. IOVS 44: 1435-1446 [Abstract] [Full Text]  
  • Haeseleer, F., Jang, G.-F., Imanishi, Y., Driessen, C. A. G. G., Matsumura, M., Nelson, P. S., Palczewski, K. (2002). Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina. J. Biol. Chem. 277: 45537-45546 [Abstract] [Full Text]  
  • Molotkov, A., Fan, X., Deltour, L., Foglio, M. H., Martras, S., Farres, J., Pares, X., Duester, G. (2002). Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3. Proc. Natl. Acad. Sci. USA 99: 5337-5342 [Abstract] [Full Text]  
  • Molotkov, A., Deltour, L., Foglio, M. H., Cuenca, A. E., Duester, G. (2002). Distinct Retinoid Metabolic Functions for Alcohol Dehydrogenase Genes Adh1 and Adh4 in Protection against Vitamin A Toxicity or Deficiency Revealed in Double Null Mutant Mice. J. Biol. Chem. 277: 13804-13811 [Abstract] [Full Text]  
  • Shang, E., Lai, K., Packer, A. I., Paik, J., Blaner, W. S., de Morais Vieira, M., Gouras, P., Wolgemuth, D. J. (2002). Targeted disruption of the mouse cis-retinol dehydrogenase gene: visual and nonvisual functions. J. Lipid Res. 43: 590-597 [Abstract] [Full Text]  
  • McBee, J. K., Van Hooser, J. P., Jang, G.-F., Palczewski, K. (2001). Isomerization of 11-cis-Retinoids to All-trans-retinoids in Vitro and in Vivo. J. Biol. Chem. 276: 48483-48493 [Abstract] [Full Text]  
  • Sieving, P. A., Chaudhry, P., Kondo, M., Provenzano, M., Wu, D., Carlson, T. J., Bush, R. A., Thompson, D. A. (2001). Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc. Natl. Acad. Sci. USA 10.1073/pnas.041606498v1 [Abstract] [Full Text]  
  • Jang, G.-F., McBee, J. K., Alekseev, A. M., Haeseleer, F., Palczewski, K. (2000). Stereoisomeric Specificity of the Retinoid Cycle in the Vertebrate Retina. J. Biol. Chem. 275: 28128-28138 [Abstract] [Full Text]  
  • Tryggvason, K., Romert, A., Eriksson, U. (2001). Biosynthesis of 9-cis-Retinoic Acid in Vivo. THE ROLES OF DIFFERENT RETINOL DEHYDROGENASES AND A STRUCTURE-ACTIVITY ANALYSIS OF MICROSOMAL RETINOL DEHYDROGENASES. J. Biol. Chem. 276: 19253-19258 [Abstract] [Full Text]  
  • Jang, G.-F., Van Hooser, J. P., Kuksa, V., McBee, J. K., He, Y.-G., Janssen, J. J. M., Driessen, C. A. G. G., Palczewski, K. (2001). Characterization of a Dehydrogenase Activity Responsible for Oxidation of 11-cis-Retinol in the Retinal Pigment Epithelium of Mice with a Disrupted RDH5 Gene. A MODEL FOR THE HUMAN HEREDITARY DISEASE FUNDUS ALBIPUNCTATUS. J. Biol. Chem. 276: 32456-32465 [Abstract] [Full Text]  
  • Liden, M., Romert, A., Tryggvason, K., Persson, B., Eriksson, U. (2001). Biochemical Defects in 11-cis-Retinol Dehydrogenase Mutants Associated with Fundus Albipunctatus. J. Biol. Chem. 276: 49251-49257 [Abstract] [Full Text]  
  • Sieving, P. A., Chaudhry, P., Kondo, M., Provenzano, M., Wu, D., Carlson, T. J., Bush, R. A., Thompson, D. A. (2001). Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc. Natl. Acad. Sci. USA 98: 1835-1840 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»