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
• extracellular matrix
• hyaluronan
• TGFβ
• versican

Acknowledgments

We wish to thank Ms. Hara, Ms. Fuwa, and Ms. Okitani for their technical assistance.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

Funding

This work was supported in part by a Grant-in-Aid for Scientific Research (B) (KAKENHI to H.W.), Supported Program for the Strategic Research Foundation at Private Universities 2011–2015 (S1101027) from the Ministry of Education, Culture, Sports Science and Technology, Japan, and by Seikagaku Corporation.

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Additional information

Funding

This work was supported in part by a Grant-in-Aid for Scientific Research (B) (KAKENHI to H.W.), Supported Program for the Strategic Research Foundation at Private Universities 2011–2015 (S1101027) from the Ministry of Education, Culture, Sports Science and Technology, Japan, and by Seikagaku Corporation.