Abstract

Familial exudative vitreoretinopathy (FEVR) is a human disease characterized by defective retinal angiogenesis and associated complications that can result in vision loss. Defective Wnt/β-catenin signaling is an established cause of FEVR, whereas other molecular alterations contributing to the disease remain insufficiently understood. Here, we show that integrin-linked kinase (ILK), a mediator of cell-matrix interactions, is indispensable for retinal angiogenesis. Inactivation of the murine Ilk gene in postnatal endothelial cells results in sprouting defects, reduced endothelial proliferation and disruption of the blood-retina barrier, resembling phenotypes seen in established mouse models of FEVR. Retinal vascularization defects are phenocopied by inducible inactivation of the gene for α-parvin (Parva), an interactor of ILK. Screening genomic DNA samples from exudative vitreoretinopathy patients identifies three distinct mutations in human ILK, which compromise the function of the gene product in vitro. Together, our data suggest that defective cell-matrix interactions are linked to Wnt signaling and FEVR.

Highlights

  • Familial exudative vitreoretinopathy (FEVR) is a human disease characterized by defective retinal angiogenesis and associated complications that can result in vision loss

  • Knockdown of integrin-linked kinase (ILK) expression impairs the migration of human umbilical vein endothelial cell (EC) (HUVECs) toward vascular endothelial growth factor (VEGF) and pharmacological ILK inhibition leads to reduced tumor growth and angiogenesis in a xenograft model[21]

  • Tamoxifen was initially administered at postnatal day (P1) to P3 followed by analysis of the resulting Pdgfb-iCre+/− Ilklox/lox (IlkiECKO) mutant and Cre-negative control littermate retinas at P6 (Fig. 1a), which allows detailed analysis of the growing superficial vascular plexus

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Summary

Introduction

Familial exudative vitreoretinopathy (FEVR) is a human disease characterized by defective retinal angiogenesis and associated complications that can result in vision loss. Inactivation of the murine Ilk gene in postnatal endothelial cells results in sprouting defects, reduced endothelial proliferation and disruption of the blood-retina barrier, resembling phenotypes seen in established mouse models of FEVR. Among the genes associated with FEVR, components of the Wnt/β-catenin signaling pathway are highly prevalent These are the genes encoding the growth factor Norrin (NDP), the receptor Frizzled-4 (FZD4), the low-density lipoprotein receptor-related protein 5 (LRP5), and tetraspanin-12 (TSPAN12), which forms transmembrane receptor complexes with LRP5 and Frizzled-42,3. We identify three loss-of-function mutations in human ILK in genomic DNA samples from exudative retinopathy patients, which links defective cell–matrix interactions to the development of this disease

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