Genome-wide expression profiling of the retinoschisin-deficient retina in early postnatal mouse development.
Invest Ophthalmol Vis Sci, 2007/2;48(2):891-900.
Gehrig A[1], Langmann T, Horling F, Janssen A, Bonin M, Walter M, Poths S, Weber BH
Affiliations
PMID: 17251492
Impact factor: 4.925
Abstract
purpose: The Rs1h knockout mouse displays retinal features typical for X-linked juvenile retinoschisis (RS). Consequently, this mouse line represents an excellent model to study early molecular events in RS.
methods: Whole genome expression profiling using DNA-microarrays was performed on total RNA extracts from retinoschisin-deficient and wild-type murine retinas from postnatal days 7, 9, 11, and 14. Quantitative real-time RT-PCR (qRT-PCR) analysis of additional time points facilitated the refinement of the temporal expression profile of differentially regulated transcripts. Differential protein expression was confirmed by Western blot analysis.
results: Based on biostatistic and knowledge-based DNA-microarray analyses we have identified differentially regulated retinal genes in early postnatal stages of the Rs1h-deficient mouse defining key molecular pathways including adhesion, cytoskeleton, vesicular trafficking, and immune response. A significant upregulation of Egr1 at P11 and several microglia/glia-related transcripts starting at P11 with a peak at P14 were identified in the diseased retina. The results provided evidence that macrophage/microglia activation precedes apoptotic photoreceptor cell death. Finally, the role of Egr1 in the pathogenesis of Rs1h-deficiency was investigated, and the results indicated that activation of the MAPK Erk1/2 pathway occurs as early as P7. Analyses of Rs1h(-/Y)/Egr1(-/-) double-knockout mice suggest that Egr1 upregulation is not a prerequisite for macrophage/microglia activation or apoptosis.
conclusions: The findings imply that microglia/glia activation may be triggering events in the photoreceptor degeneration of retinoschisin-deficient mice. Furthermore, the data point to a role of Erk1/2-Egr1 pathway activation in RS pathogenesis.
MeSH terms
Animals; Blotting, Western; Cell Adhesion Molecules; Disease Models, Animal; Early Growth Response Protein 1; Electrophoresis, Polyacrylamide Gel; Eye Proteins; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genome; In Situ Nick-End Labeling; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Oligonucleotide Array Sequence Analysis; Retina; Retinoschisis; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation
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