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Nathan M. Krah, Jing Chen, Molly R. Seaward, Chris M. Aderman, Keirnan L. Willett, Roberta J. Dennison, Colman J. Hatton, Aimee M. Juan, Lois E. Smith; Retinal Gene Profiles Of Low-density Lipoprotein Receptor-related Protein 5 (Lrp5) Null Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4852.
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Mutations in the Wnt signaling cascade have been linked to defects in the retinal vasculature both in human patients and mouse models. Familial exudative vitreoretinopathy (FEVR), Norrie disease and Coats’ disease, are all Wnt-related genetic diseases characterized by poor retinal vascular development, which leads to pathological retinal neovascularization and vascular leakage. However, the molecular mechanisms behind these diseases remain poorly understood. In order to further characterize the role of specific sub-cellular pathways in these diseases, we analyzed the retinal gene expression of mice lacking Lrp5, a Wnt co-receptor, as a model for FEVR.
Retinas from P8 Lrp5-/- and wild type (WT) mice were dissected and processed for either lectin-staining for vessel quantification; or RNA isolation using RNase free techniques (n=6 per group). Total RNA was extracted and prepared for Illumina microarray analysis using the Mouse-ref 6 chip. Data was acquired using the Illumina BeadStudio software and further analysis was performed using Significance Analysis of Microarray (SAM), Gene Set Enrichment Analysis (GSEA), and J-Express Pro 2.7 software. A set of differentially expressed genes were validated with real-time PCR.
Lrp5-/- retina showed a significant delay in vessel growth compared with WT retinas at P8 (WT: 92.2±1.6% vs. Lrp5-/- : 69.3+2.7%; p≤0.0001). We found that selected groups of cell adhesion and junction proteins, and membrane transporters were significantly downregulated in Lrp5 null mice. Illumina microarray analysis revealed a 2-8 fold downregulation of Claudin5, Slc38a5, Von Willebrand factor homolog, and secreted phosphoprotein 1, as well as a 2 fold upregulation of plasmalemma vesicle associated protein.
These findings suggest that the downregulation of cell adhesion/tight junction molecules and increase in vessel permeability markers in Lrp5 null mice may contribute in part to the observed retinal vascular defects. These findings may also have implications in understanding the vascular defects in patients with FEVR.
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