title: Genome-wide expression profiling of the retinoschisin-deficient retina in early postnatal mouse development.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gehrig
authors.forename: Thomas
authors.initials: T
authors.lastname: Langmann
authors.forename: Franziska
authors.initials: F
authors.lastname: Horling
authors.forename: Andreas
authors.initials: A
authors.lastname: Janssen
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.forename: Sven
authors.initials: S
authors.lastname: Poths
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000502:physiology*; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005136:Eye Proteins / Q000502:physiology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012160:Retina / Q000378:metabolism*; D041441:Retinoschisis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D015815:Cell Adhesion Molecules; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D005136:Eye Proteins; C491843:RS1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3