Date of this Version
Molecular components of the extracellular matrix (ECM) are critical for matrix stabilization, cellular differentiation, and tissue morphogenesis. Once thought to function only as the extracellular glue that primarily binds cells together, proteoglycans in the ECM carry out a diverse array of activities and can be grouped into five functionally based families: (i) hyalectins (lecticans), which contain lectin-like carbohydrate-recognition domains (CRDs) and bind hyaluronan (HA); (ii) heparan sulfate (HS) proteoglycans that sequester growth factors via their HS chains; (iii) small leucine-rich proteoglycans (SLRPs) containing leucine-rich domains that interact with collagens and other ECM proteins; (iv) phosphacans that function primarily as receptor-like protein-tyrosine phosphatases; and (v) part-time proteoglycans that reside both on the cell surface and in the ECM. More than 40 cDNAs encoding proteoglycan core proteins have been discovered thus far . For the sake of brevity, this chapter will focus only on the four lecticans that bind HA (Figure 1): Aggrecan, neurocan, brevican, and versican.
All lecticans have two N-terminal Link domains, one immunoglobulin-like module, a central glycosaminoglycan (GAG)-attachment region, and one or more EGF-like domains in the C-terminus. The lecticans are post-translationally modified by O-Linked GAG chains on Ser residues of multiple Ser-Gly dipeptide repeats. Aggrecan, versican, neurocan, and brevican contain 120, 20, 7, and 3 potential sites, respectively. Generally, the CS chains of the lecticans maintain structural integrity of the tissue ECM by serving as barrier functions to limit the growth and migration of cells. For example, the CS chains of neurocan and brevican act as barriers to inhibit neurite outgrowth and migration so that, hypothetically, dendrites are available for longer periods of time in their local environment to make the correct synaptic junctions and set up guidance cues for migration. The barrier functions of the lecticans exist on two levels: (i) as mechanical barriers, the proteoglycans form neuronal nets to physically constrain neurite outgrowth and (ii) as cell signaling barriers, the proteoglycans can activate intracellular signaling pathways regulated by the Rho-family GTPases to promote the disruption of the actin cytoskeleton and growth cone collapse. In addition to the barrier functions, GAGs in close proximity may also serve to sequester water to maintain tissue hydration.
Neurocan and brevican are primarily neural ECM lecticans, whereas aggrecan is found mainly in cartilage and versican is in vascular vessel walls. Aggrecan and versican play minor, albeit important and sometimes transient, functions in central nervous system (CNS) development and ECM composition. Aggrecan, versican, and brevican are proteolytically degraded by ADAMTS-1/4 (a disintegrin and metalloproteinase with thrombospondin motifs) metalloproteases, whereas neurocan is processed by matrix metalloproteinases 2 (MMP-2). Metalloprotease cleavage of the lecticans is part of their normal turnover process and an increase in metalloprotease activity in tissues such as the brain may be a prerequisite for diseases such as Alzheimer’s disease and epilepsy. Numerous reviews have described the biology, chemistry, and physiological impact of these lecticans, their splice variants, and their cohorts of interacting partners on matrix and cellular composition in tissues.