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J. Biol. Chem., Vol. 279, Issue 40, 41903-41910, October 1, 2004

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Multidestructive Pathways Triggered in Photoreceptor Cell Death of the RD Mouse as Determined through Gene Expression Profiling^*

Baerbel Rohrer¶, Francisco R. Pinto||**, Kathryn E. Hulse, Heather R. Lohr, Li Zhang, and Jonas S. Almeida||

From the Departments of Ophthalmology, Physiology and Neuroscience, and ^||Biostatistics, Bioinformatics, and Epidemiology, Medical University of South Carolina, Charleston, South Carolina 29425, the ^**Biomathematics Group, Instituto de Tecnologia Química e Biológica, University Nova Lisboa, 2780 Oeiras, Portugal, and the M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030

In the rd/rd mouse, photoreceptor degeneration is due to a mutation of the rod-specific enzyme cGMP phosphodiesterase, resulting in permanently opened cGMP-gated cation channels in the rod outer segment membrane that allow Na⁺ and Ca²⁺ ions to enter the cell, resulting in possibly toxic levels of Ca²⁺. To identify pathways involved in cell death of the rd/rd rods, we evaluated gene expression in the rd/rd and wild type (wt) mouse retina (U74A oligonucleotide arrays (Affymetrix)) over the known time course of photoreceptor degeneration. 181 genes passed the selection criteria (low standard deviation and high correlation between replicates), falling into six clusters. For any given pair of genes, an expression profile correlation distance and a semantic distance (one for each class of gene ontology terms) were established using newly designed software. Gene expression in rd/rd started to deviate from wt by postnatal day 10. The reduction in photoreceptor-specific genes followed the known time course of photoreceptor degeneration. Likewise the increase in transcription factors and apoptosis- and neuroinflammation-specific genes followed the kinetics of the rise in intracellular cGMP in the rod photoreceptors. In addition, genes coding for calcium-binding proteins and those implicated in tissue and vessel remodeling were increased. These results suggest that photoreceptor degeneration in the rd/rd mouse is a process starting with Ca²⁺ toxicity followed by secondary insults involving multidestructive pathways such as apoptosis and neuroinflammation, presumably boosting morphological changes. All of these components need to be addressed if rods are to be successfully protected.

Received for publication, May 7, 2004 , and in revised form, June 24, 2004.

^* This work was supported in part by National Institutes of Health Grants EY-13520 (to B. R.) and EY-14793 (Core Grant for Vision Research at Medical University of South Carolina (MUSC)), the NHLBI, National Institutes of Health Proteomics Initiative through Contract N01-HV-28181 (to J. S. A.), Portuguese Foundation for Science and Technology Grant SFRH/BD/6488/2001 (to F. R. P.), Fundação para a Ciência e a Tecnologia of the Portuguese Ministério da Ciência e do Ensino Superior Grant SAPIENS/34794/99 (to J. S. A.), the Kirchgessner Foundation (to B. R.), and an unrestricted grant to MUSC from Research to Prevent Blindness, Inc., New York. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Worksheets 1 (data and cluster assignment), 2 (legend list), and 3 (over-represented GO terms).

^¶ To whom correspondence should be addressed: Dept. of Ophthalmology, Medical University of South Carolina, 167 Ashley Ave., Charleston, SC 29425. Tel.: 843-792-5086; Fax: 843-792-1723; E-mail: rohrer{at}musc.edu.

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