Retinal expression of Wnt-pathway mediated genes in low-density lipoprotein receptor-related protein 5 (Lrp5) knockout mice

PLoS One. 2012;7(1):e30203. doi: 10.1371/journal.pone.0030203. Epub 2012 Jan 17.

Abstract

Mutations in low-density lipoprotein receptor-related protein 5 (Lrp5) impair retinal angiogenesis in patients with familial exudative vitreoretinopathy (FEVR), a rare type of blinding vascular eye disease. The defective retinal vasculature phenotype in human FEVR patients is recapitulated in Lrp5 knockout (Lrp5(-/-)) mouse with delayed and incomplete development of retinal vessels. In this study we examined gene expression changes in the developing Lrp5(-/-) mouse retina to gain insight into the molecular mechanisms that underlie the pathology of FEVR in humans. Gene expression levels were assessed with an Illumina microarray on total RNA from Lrp5(-/-) and WT retinas isolated on postnatal day (P) 8. Regulated genes were confirmed using RT-qPCR analysis. Consistent with a role in vascular development, we identified expression changes in genes involved in cell-cell adhesion, blood vessel morphogenesis and membrane transport in Lrp5(-/-) retina compared to WT retina. In particular, tight junction protein claudin5 and amino acid transporter slc38a5 are both highly down-regulated in Lrp5(-/-) retina. Similarly, several Wnt ligands including Wnt7b show decreased expression levels. Plasmalemma vesicle associated protein (plvap), an endothelial permeability marker, in contrast, is up-regulated consistent with increased permeability in Lrp5(-/-) retinas. Together these data suggest that Lrp5 regulates multiple groups of genes that influence retinal angiogenesis and may contribute to the pathogenesis of FEVR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Amino Acid Transport Systems, Neutral / genetics
  • Animals
  • Carrier Proteins / genetics
  • Disease Models, Animal
  • Dishevelled Proteins
  • Eye Proteins / genetics
  • Frizzled Receptors / genetics
  • Gene Expression Profiling*
  • Gene Expression Regulation, Developmental
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-5 / deficiency
  • Low Density Lipoprotein Receptor-Related Protein-5 / genetics*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Oligonucleotide Array Sequence Analysis
  • Phosphoproteins / genetics
  • Proto-Oncogene Proteins / genetics
  • Retina / growth & development
  • Retina / metabolism*
  • Retinal Vessels / growth & development
  • Retinal Vessels / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vitreoretinopathy, Proliferative / genetics
  • Wnt Proteins / genetics
  • Wnt Signaling Pathway / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Transport Systems, Neutral
  • Carrier Proteins
  • Dishevelled Proteins
  • Eye Proteins
  • Frizzled Receptors
  • Fzd4 protein, mouse
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Lrp5 protein, mouse
  • Membrane Proteins
  • Ndph protein, mouse
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Plvap protein, mouse
  • Proto-Oncogene Proteins
  • Wnt Proteins
  • Wnt7b protein, mouse

Associated data

  • GEO/GSE32145