Versican is encoded by a single gene and is located on chromosome 5q12-14 in the human genome. The human VCAN gene is divided into 15 exons over 90-100 kb. The structure of versican was originally deduced by the analysis of cDNA from a human placental library (Naso et al., 1994). The entire primary structures of versican have been generated from human, murine, bovine and chick cDNA clones. The chick form was originally named PG-M (Shinomura et al., 1993).

RNA splicing occurs in the two large exons encoding the GAG attachment sites. The region encoded by exon 7 is called GAG alpha, the region encoded by exon 8, GAG beta. Four mRNA transcripts arise from alternative splicing, giving rise to V0, V1, V2 and V3. V0 possesses both exon 7 and exon 8, V1 possesses exon 8 but not exon 7, V2 possesses exon 7 but not exon 8; and V3 possesses neither exon 7 nor exon 8 (Wight, 2002).
The expression of the versican gene (CSPG2) is regulated by a promoter that harbors a typical TATA box and potential binding sites for several transcription factors, including AP1, AP2, CCAAT enhancer protein, TCF-4 and cAMP-responsive element (Naso et al., 1994; Rahmani et al., 2006; Domenzain-Reyna et al., 2009). Regulation of the versican gene through an androgen response element in the proximal promoter has been reported in prostate (Read et al., 2007).

Versican belongs to the extracellular matrix chondroitin sulphate proteoglycan family.
The largest versican isoform (V0) consists of 3396 aa. The core protein can be divided into three domains: the globular N-terminal domain (G1), the central domain (G2) where glycosaminoglycan (GAG) chains attach, and the globular C-terminal domain (G3). The G1 domain is composed of an immunoglobulin-like motif, followed by two tandem repeats which bind hyaluronan (HA). The G3 domain contains two EGF-like repeats, a lectin-like subdomain and a complement binding protein (CBP)-like subdomain. The central domain G2 can be alternatively spliced to give rise to the four versican isoforms: V0 (containing both GAG alpha and GAG beta), V1 (containing GAG beta), V2 (containing GAG alpha) and V3, lacking any GAG subdomain (Wight, 2002).
A new alternatively spliced versican isoform, referred to as V4, has been identified and found to be upregulated in human breast cancer (Kischel et al., 2010).

Posttranslational modifications (PTM): the consensus sequence for chondroitin sulphate attachment sites reveals the number of potential GAG attachment sites: the number of GAG chains attached to the protein core depends on the isoforms since the GAG alpha subdomain bears 12-17 chondroitin sulphate (CS) chains, whereas the GAG beta subdomain bears 5-8 CS chains (Ricciardelli et al., 2009).

Versican was initially identified in the culture medium of human IMR-90 lung fibroblasts (Zimmermann and Ruoslahti, 1989).
Versican is highly expressed in tissue compartments undergoing active cell proliferation and migration. V0 and V1 isoforms are highly expressed during embryonic development, and their expression decreases after tissue maturation. In adult tissues, versican is present in the loose connective tissues of various organs and often associated with the elastic fibre network. It is localized in most smooth muscle tissues, in cartilage, in the basal layer of the epidermis, and in blood vessels (Bode-Lesniewska et al., 1996). Versican V2 is abundant in the central nervous system (Schmalfeldt et al., 2000). The V3 isoform has been identified at the mRNA levels but very scarcely at the protein level (Cattaruzza et al., 2002).

Versican is a component of the extracellular matrix.

The name versican comes from versatile, with regard to the diversity of biological actions of this highly interactive molecule that can be attributed both to the amino- and carboxy-terminal domains and to the GAGs side chains attached to the middle portion of the core protein. Versican is involved in the control of cell adhesion, proliferation, migration, apoptosis and in ECM assembly (Wight, 2002; Theocharis, 2008; Ricciardelli et al., 2009). Its domain organization allows modulation of a large variety of cell behaviours through interaction with a wide range of binding partners, including ECM components (HA, type I collagen, tenascin and fibronectin among others), chemokines, and cell surface proteins (CD44, integrin beta1, epidermal growth factor receptor) (Wu et al., 2005).

Versican belongs to the hyalectan family, characterized by its ability to bind hyaluronan. The overall consensus is that versican together with hyaluronan forms a pericellular matrix that modulates cell proliferation, adhesion and migration in conditions such as in development and wound healing cell. Some of these actions have been ascribed to specific domains in the molecule. Thus, overexpression of versican G1 domain can enhance cell proliferation and reduce cell adhesion (Ang et al., 1999; Zhang et al., 1999). G3 domain has also been involved in several processes like cell proliferation and invasion (Zhang et al., 1998; Yang et al., 2003; Zheng et al., 2004; Yee et al., 2007), and GAG chains have been considered partially responsible for the antiadhesive properties of versican (Yamagata and Kimata, 1994; Sakko et al., 2003).

Cell proliferation. Versican is associated with a proliferative cell phenotype and it is often found in tissues showing elevated proliferation such as in development and in a variety of tumours (Wight, 2002; Ricciardelli et al., 2009). Purified versican added to the culture media in a melanoma cell line induces proliferation (Touab et al., 2002). Silencing experiments with siRNA have lead to the same conclusion in vascular smooth muscle cells (Huang et al., 2006) and preadipocytes (Zizola et al., 2007).

Cell adhesion. Versican is an anti-adhesive substrate (Yamagata and Kimata, 1994). The anti-adhesive role of versican has been also shown in melanoma cells (Touab et al., 2002), prostate carcinoma cells (Sakko et al., 2003) or neural crest cells (Dutt et al., 2006). This inhibitory effect on cell adhesion may be mainly due to the presence of the GAG chains that might create a more hydrated extracellular matrix less suitable for cell adhesion.
Nevertheless, the G3 domain of versican has pro-adhesive properties raising the possibility that different breakdown products might differentially affect cell adhesion (Wu et al., 2002).

Cell migration and invasion. Versican can increase cell motility in embryonic as well as tumour cells. This activity may be mostly associated with its antiadhesive activities. Silencing of V0/V1 versican expression reduces cell migration in wound healing assays in smooth muscle cells (Huang et al., 2006), or in prostate cancer cells, where addition of purified versican to the cells caused an increase in the invasion ability (Ricciardelli et al., 2007). In glioma, treatment of the cells with TGF-beta2 caused an increase in cell migration associated to an increase in versican production (Arslan et al., 2007). In the nervous system and in axonal growth, the V2 splice variant inhibits axonal growth and migration (Schmalfeldt et al., 2000).

Apoptosis. The effect of versican on apoptosis is complex and anti- as well as pro-apoptotic functions have been reported. Overexpression of the V1 versican isoform in cultured fibroblasts increases apoptotic resistance, but cells were also sensitized to a wide range of cytotoxic agents (LaPierre et al., 2007).

Cell differentiation and epithelial-mesenchymal transition (EMT). Versican modulates cell differentiation and morphogenesis, since it is involved in EMT interactions and in mesenchymal cell condensation required for organogenesis. V1 (but not V2) has been shown to trigger MET in fibroblasts by inducing a switch from N-cadherin to E-cadherin and subsequent acquirement of epithelioid phenotype. Silencing of endogenous versican prevents condensation and MET in metanephric mesenchyme (Sheng et al., 2006). Versican is highly expressed in the mesenchymal cell condensation area during development of cartilage, heart, hair follicles and kidney, and in vitro evidences show that versican V0 and V1 isoforms are involved in the process of precartilage mesenchymal condensation and subsequent chondrogenesis (Kamiya et al., 2006). The requirement of versican in development is highlighted by the finding that deficiency of versican in a transgenic mouse model is embryonic lethal, due to defects on cardiac formation, limb mesenchymal aggregation and chondrogenesis (Williams et al., 2005).

Others. In neural cells, versican plays an important role in regulating axonal guidance (Perissinotto et al., 2000). It is also an important molecule in inflammatory processes since it is able to interact with immune cell receptors and chemokines (Hirose et al., 2001).

Versican belongs to the hyalectan gene family of proteoglycans that include aggrecan, neurocan and brevican.

No missense, regulatory, small and gross deletions and insertions, complex rearrangements, or repeat variations have been described.
In this context, disruption of the versican gene in mouse and chick leads to severe cardiac defects and alterations in chondrogenesis in the hdf (heart defect) mouse. This animal model has lead to the conclusion that normal expression of the VCAN (Cspg2) gene is required for the successful development of the heart and for cartilage differentiation, leading to correct limb chondrogenesis (Mjaatvedt et al., 1998).

Only mutations affecting the splicing of exons 7 and 8 have been described associated to Wagner syndrome, a rare disorder belonging to the group of hereditary vitreoretinal degenerations (Miyamoto et al., 2005; Kloeckener-Gruissem et al., 2006).