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J. Biol. Chem., Vol. 280, Issue 21, 20413-20420, May 27, 2005

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Functional Characterization of Mouse RDH11 as a Retinol Dehydrogenase Involved in Dark Adaptation in Vivo^*

Anne Kasus-Jacobi¶, Jiafu Ou, David G. Birch||, Kirsten G. Locke||, John M. Shelton**, James A. Richardson, Andrew J. Murphy, David M. Valenzuela, George D. Yancopoulos, and Albert O. Edwards¶¶

From the Departments of Molecular Genetics, ^**Internal Medicine, Pathology and Molecular Biology, and ^¶¶Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, the Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, the ^||Retina Foundation of the Southwest, Dallas, Texas 75231, and Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York 10591

We previously cloned mouse RDH11 (mRDH11) as a gene regulated by the transcription factor sterol regulatory element-binding proteins and showed that it is a retinol dehydrogenase expressed in non-ocular tissues such as the liver and testis and in the retina (Kasus-Jacobi, A., Ou, J., Bashmakov, Y. K., Shelton, J. M., Richardson, J. A., Goldstein, J. L., and Brown, M. S. (2003) J. Biol. Chem. 278, 32380–32389). It was proposed to function in the recycling of the visual chromophore 11-cis-retinal after photoisomerization by a bleaching light, a pathway referred to as the visual cycle. In this work, we describe our studies on the ocular function of mRDH11. We created a knockout mouse by replacing the mrdh11 coding sequence with the lacZ reporter gene for expression profiling. 5-Bromo-4-chloro-3-indolyl--D-galactopyranoside (X-Gal) staining demonstrated active transcription of this gene in photoreceptor cells. We show by immunoblot analysis that mRDH11 is associated with retinal membranes purified from a non-outer segment fraction of the retina. No obvious retinal defect was found during development and aging of RDH11-deficient mice. The functional consequences of mRDH11 disruption were investigated by electroretinography. Dark adaptation was delayed by a factor of 2.5–3 compared with wild-type mice. However, the kinetics of 11-cis-retinal recycling during dark adaptation was not affected, suggesting that mRDH11 is not involved in the visual cycle. We propose that mRDH11 disruption affects retinoid metabolism in photoreceptor inner segments and delays the kinetics of dark adaptation through modulation of calcium homeostasis.

Received for publication, December 7, 2004 , and in revised form, March 16, 2005.

^* This work was supported by National Institutes of Health Grant HL 20948 and by grants from the Moss Heart Fund and the Perot Family Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Ophthalmology, University of Oklahoma Health Sciences Center, Dean A. McGee Eye Inst., 608 Stanton L. Young Blvd., Oklahoma City, OK 73104. Tel.: 405-271-8244; Fax: 405-271-3548; E-mail: anne-kasus-jacobi{at}ouhsc.edu.

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