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J. Biol. Chem., Vol. 279, Issue 40, 42211-42220, October 1, 2004

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Altered Expression of Genes of the Bmp/Smad and Wnt/Calcium Signaling Pathways in the Cone-only Nrl^-/- Mouse Retina, Revealed by Gene Profiling Using Custom cDNA Microarrays^*

From the Departments of ^aOphthalmology and Visual Sciences, ^bBiomedical Engineering, ^eBiostatistics, and ^hHuman Genetics, University of Michigan, Ann Arbor, Michigan 48015, the ^dTranslational Research Center, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan, and the ^gLaboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM U.592, 67091 Strasbourg Cedex, France

Many mammalian retinas are rod-dominant, and hence our knowledge of cone photoreceptor biology is relatively limited. To gain insights into the molecular differences between rods and cones, we compared the gene expression profile of the rod-dominated retina of wild type mouse with that of the cone-only retina of Nrl^-/- (Neural retina leucine zipper knockout) mouse. Our analysis, using custom microarrays of eye-expressed genes, provided equivalent data using either direct or reference-based experimental designs, confirmed differential expression of rod- and cone-specific genes in the Nrl^-/- retina and identified novel genes that could serve as candidates for retinopathies or for functional studies. In addition, we detected altered expression of several genes that encode cell signaling or structural proteins. Prompted by these findings, additional real-time PCR analysis revealed that genes belonging to the Bmp/Smad and Wnt/Ca²⁺ signaling pathways are expressed in the mature wild type retina and that their expression is significantly altered in the Nrl^-/- retina. Chromatin immunoprecipitation analysis of adult retina identified Bmp4 and Smad4, which are down-regulated in the Nrl^-/- retina, as possible direct transcriptional targets of Nrl. Consistent with these studies, Bmp4 and Smad4 are expressed in the mature rod photoreceptors of mouse retina. Modulation of Bmp4 and/or Smad4 by Nrl may provide a mechanism for integrating diverse cell signaling networks in rods. We hypothesize that Bmp/Smad and Wnt/Ca²⁺ pathways participate in cell-cell communication in the mature retina, and expression changes observed in the Nrl^-/- retina reflect their biased utilization in rod versus cone homeostasis.

Received for publication, July 20, 2004

^* This research was supported in part by National Institutes of Health Grants EY11115 (including administrative supplements), EY07003, and GM72007, by The Foundation Fighting Blindness (Owings Mills, MD), by Research to Prevent Blindness (RPB, New York, NY), by the Macula Vision Research Foundation (West Conshohocken, PA), and by the British Retinitis Pigmentosa Society. 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.

^c A recipient of Foundation Fighting Blindness-Canada Post-Doctoral Fellowship.

^f Current address: University of Ottawa Eye Institute, Ottawa Health Research Institute, Ottawa, Ontario K1H 8L6, Canada.

ⁱ To whom correspondence should be addressed: W. K. Kellogg Eye Center, University of Michigan, 1000 Wall St., Ann Arbor, MI 48105. Tel.: 734-615-2246; Fax: 734-647-0228; E-mail: swaroop{at}umich.edu.

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