Abstract
Purpose :
Versican is a large chrondroitin sulphate proteoglycan and major component of the extracellular matrix. It consists of four isoforms (V0, V1, V2, V3) that show molecular differences in their respective glycosaminoglycan (GAG) attachment domain. To learn more about the specific function of versican and its isoforms in the retina, we analyzed mutant mice with deficiency in V0 and V2.
Methods :
VCAN(tm1Zim) mice were investigated with a splice-variant specific gene inactivation of V0 and V2 resulting in GAG-α domain deficiency. Four- and eight-week-old versicanV0/V2-/- and versicanV0/V2+/- mice were analyzed and compared with wildtype littermates. Semithin sections were investigated by light microscopy. Retinal thickness and the number of optic nerve (ON) axons was quantified. The distribution and expression of GFAP and of the major versican binding partners fibronectin and hyaluronan was investigated by immunohistochemistry.
Results :
The loss of V0 and V2 isoforms resulted in the formation of retinal rosettes, affecting the outer nuclear layer, and photoreceptor inner and outer segments. The defects were first seen in 4-week-old homozygous mice. Essentially similar defects were seen in heterozygous mice, though with later onset (8 wks of age). Rosette formation was frequently associated with detachment of the sensory retina. Analysis of the anterior chamber showed a wide-open angle with no obvious structural changes in the trabecular meshwork outflow pathways. GFAP immunoreactivity in Müller cells of mutant mice was identical to that seen in wildtype littermates, even in mutant eyes with rosette formation and retinal detachment. Immunoreactivity for fibronectin was dramatically reduced in the retina of mutant mice but unchanged in the chamber angle. Reactivity for hyaluronan was markedly decreased in the inner plexiform layer but increased in the ganglion cell layer and the vitreous of versican V0/V2-/- mice. Retinal thickness and number of ON axons showed no difference in versican V0/V2-/- mice compared to wildtype littermates.
Conclusions :
Deficiency of the versican isoforms V0 and V2 causes retinal changes that indicate its critical role for attachment of the sensory retina to the retinal pigment epithelium.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.