The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis

Abstract

Embryonic development is an exceptionally dynamic process, requiring a provisional extracellular matrix that is amenable to rapid remodeling, and proteolytic or non-proteolytic mechanisms that can remodel the major components of this matrix. Versican is a chondroitin-sulfate proteoglycan that forms highly hydrated complexes with hyaluronan and is widely distributed in the provisional matrix of mammalian embryos. It has been extensively studied in the context of cardiovascular morphogenesis, neural crest cell migration and skeletal development. Analysis of Vcan transgenic mice has established the requirement for versican in cardiac development and its role in skeletogenesis. The ADAMTS family includes several versican-degrading proteases that are active during remodeling of the embryonic provisional matrix, especially during sculpting of versican-rich tissues. Versican is cleaved at specific peptide bonds by ADAMTS proteases, and the cleavage products are detectable by neo-epitope antibodies. Myocardial compaction, closure of the secondary palate (in which neural crest derived cells participate), endocardial cushion remodeling, myogenesis and interdigital web regression are developmental contexts in which ADAMTS-mediated versican proteolysis has been identified as a crucial requirement. ADAMTS proteases are expressed coordinately and function cooperatively in many of these contexts. In addition to versican clearance, ADAMTS proteases generate a bioactive versican fragment containing the N-terminal G1 domain, which we have named versikine. This review promotes the view that the embryonic extracellular matrix has evolved not only to provide a permissive environment for embryo growth and morphogenesis, but through its dissolution to influence and regulate cellular processes.

Keywords: A disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs; ADAMTS; Cardiac jelly; Cleft palate; Embryogenesis; Heart valve; Limb development; Melanoblast; Soft tissue syndactyly; Versican.

Fig. 1

Domain structure of versican splice variants: Each versican variant shown binds to hyaluronan through the G1 domain, and has additional interactions through the G3 domain. As shown, inclusion of the alternatively spliced CS-bearing GAGα (violet) and GAGβ (red) regions defines distinct splice variants. CS-chains are shown as wavy blue lines. The cartoons at the bottom define the subdomains identified within the G1 and G3 domains.

Fig. 2

Dual function of versican and versican proteolysis in provisional ECM: During early development, the HA–versican composite forms a loose hydrated matrix (left) that is permissive form orphogenesis and amenable to rapid remodeling. Specific ADAMTS proteases cleave versican, leading to compaction of this matrix (right) concurrent with removal of other components of the provisional matrix, such as hyaluronan by other mechanisms, and elaboration of specialized matrix components (black fibers). Versican proteolysis by ADAMTS proteases occurs at a specific peptide bond (center). In addition to versican clearance and ECM remodeling occurring via the ADAMTS activity, versican fragments, such as versikine, may influence cell proliferation and apoptosis locally.