Identification of gene expression changes associated with the progression of retinal degeneration in the rd1 mouse.
OBJECTIVE
One approach to gaining insight into the biological pathways contributing to rod and cone photoreceptor death is to identify patterns of gene expression changes. In the present study, a custom retinal microarray was developed to analyze the rd1 mouse, a well-characterized animal model of human retinal degeneration.


METHODS
A microarray was constructed containing cDNA fragments corresponding to genes known or postulated to be involved in normal retinal function, development, and disease. Gene expression in rd1 retina was compared with age-matched control retinas at three time points: the peak of rod degeneration (postnatal day [P]14), early in cone degeneration (P35), and during cone degeneration (P50). Selected microarray results were confirmed with real-time PCR. The cellular distribution of one of the differentially expressed genes, dickkopf 3 (Dkk3), was assessed by in situ hybridization.


RESULTS
At each stage of degeneration, there was only limited overlap of the genes that showed increased expression, suggesting the involvement of temporally distinct molecular pathways. Genes active in transport mechanisms and in signaling pathways were differentially expressed during rod degeneration, whereas genes with functions in protein modification and cellular metabolism were differentially expressed during cone degeneration. Increased expression of genes involved in cell proliferation pathways and oxidative stress was observed at each time point.


CONCLUSIONS
These microarray results provide clues to understanding the molecular pathways underlying photoreceptor degeneration and indicate directions for future studies. In addition, comparisons of normal and degenerated retina identified numerous genes and ESTs that are potentially enriched in rod photoreceptors.
Hackam
Abigail S
AS
Guerrieri Center for Genetic Engineering and Molecular Ophthalmology at the Wilmer Eye Institute, John Hopkins University School of medicine, Baltimore MD 21287, USA.
Strom
Richelle
R
Liu
Dongmei
D
Qian
Jiang
J
Wang
Chenwei
C
Otteson
Deborah
D
Gunatilaka
Tushara
T
Farkas
Ronald H
RH
Chowers
Itay
I
Kageyama
Masaaki
M
Leveillard
Thierry
T
Sahel
Jose-Alain
JA
Campochiaro
Peter A
PA
Parmigiani
Giovanni
G
Zack
Donald J
DJ
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism; D012160:Retina / Q000503:physiopathology; D012162:Retinal Degeneration / Q000235:genetics / Q000503:physiopathology*; D017948:Retinal Rod Photoreceptor Cells / Q000503:physiopathology; D016324:Sequence Tagged Sites; D013997:Time Factors; D014018:Tissue Distribution
D048868:Adaptor Proteins, Signal Transducing; C405061:Dkk3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins