Versican A-subdomain is required for its adequate function in dermal development

Abstract

Versican, a large chondroitin sulfate (CS) proteoglycan, serves as a structural macromolecule of the extracellular matrix (ECM) and regulates cell behavior. We determined the function of versican in dermal development using Vcan^Δ3/Δ3 mutant mice expressing versican with deleted A-subdomain of the N-terminal G1 domain. The mutant versican showed a decreased hyaluronan (HA)-binding ability and failed to accumulate in the ECM. In the early developmental stage, Vcan^Δ3/Δ3 dermis showed a decrease in versican expression as compared with WT. As development proceeded, versican expression further decreased to a barely detectable level, and Vcan^Δ3/Δ3 mice died at the neonatal period (P0). At P0, Vcan^Δ3/Δ3 dermis exhibited an impaired ECM structure and decreased cell density. While the level of collagen deposition was similar in both genotypes, collagen biosynthesis significantly decreased in Vcan^Δ3/Δ3 fibroblasts as compared with that in wild type (WT). Transforming growth factor β (TGFβ) signaling mediated through the Smad2/3-dependent pathway was down-regulated in Vcan^Δ3/Δ3 fibroblasts and a reduced TGFβ storage in the ECM was observed. Microarray analysis revealed a decrease in the expression levels of transcription factors, early growth response (Egr) 2 and 4, which act downstream of TGFβ signaling. Thus, our results suggest that A-subdomain is necessary for adequate versican expression in dermis and that versican is involved in the formation of the ECM and regulation of TGFβ signaling.

Keywords: Collagen; TGFβ; extracellular matrix; hyaluronan; versican.