Deletion of versican V0/V2 isoforms in mice leads to retinal dysplasia.

Abstract

Versican, a chondroitin sulfate proteoglycan, is a component of the interphotoreceptor matrix (IPM) and vitreous body in both mouse and human eyes. Mutations in VCAN, the gene encoding the versican core protein, cause Wagner vitreoretinopathy, a disorder characterized by vitreous syneresis, progressive chorioretinal atrophy, and early-onset retinal detachment. Versican exists in four isoforms (V0, V1, V2, V3), which differ in their glycosaminoglycan (GAG) attachment domains. To investigate isoform-specific functions of versican in retinal development and homeostasis, we examined VCANmice, which lack the V0 and V2 isoforms. Retinal development was assessed at postnatal days 1, 5, and 15, and at 4 and 8 weeks of age using light and transmission electron microscopy, morphometric analyses, and immunohistochemistry for RPE65, laminin, and collagen IV. Hyaluronan distribution was assessed using biotinylated versican G1 hyaluronan-binding protein, and in situ hybridization localized isoform-specific mRNA expression. Loss of V0 and V2 resulted in early-onset retinal infoldings, visible by P1, with fold cores containing cellular debris and retinal pigmented epithelium (RPE)-derived melanosomes. However, the RPE monolayer remained structurally intact, and no differences in RPE cell number or size were detected between wild-type and mutant animals. In wild-type mice, V0 and V2 transcripts were present throughout all retinal layers and the RPE. No morphological abnormalities were observed in Bruch's membrane or the vitreoretinal border based on staining for collagen IV, laminin, or hyaluronan. These findings suggest that V0/V2 isoforms play a critical role in maintaining adhesion between the neural retina and the RPE, likely through regulation of the IPM microenvironment. Based on these results, it is plausible that photoreceptor degeneration and dysfunction in Wagner vitreoretinopathy arises from isoform-specific disturbances in the IPM secondary to versican deficiency or dysfunction.