**6. Aggrecans Roles in Articular Cartilage, Fibrocartilages, Heart and Neural Tissues**

Aggrecan is a large KS and CS substituted lectican PG family member with important space filling and water imbibing properties. In weight-bearing articular cartilages aggrecan forms macro-aggregate structures through interaction of its N-terminal G1 domain with hyaluronan and link protein [2,5,6]. Aggrecan–HA aggregates have important water-imbibing properties that entrap water in tissues in a dynamic manner. These properties allow the aggrecan-rich tissues to resist compression and equips articulating tissues in synovial joints with their weight-bearing properties. Cartilage is also self-lubricating through moisture expelled at the cartilage surface when the joint is loaded arising from aggrecan associated water molecules. This is a dynamic process with moisture returning to the cartilage when load is reduced or removed from the joint. Aggrecan is widely distributed in the articular hyaline cartilages of diarthrodial joints, but also occurs in the elastic and fibrocartilages of rib, nasal and tracheal cartilages, larynx, outer ear and the epiglottis [84–87]. Aggrecan is also important in foetal heart development and is a functional ECM component, which contributes to the resilience of the endocardium, myocardium, epicardium and valve leaflets of mature heart tissue [17,88]. Aggrecan is also found in the CNS and PNS in perineuronal net (PNNs) structures. These are aggrecan–HA–tenascin C aggregate structures which localise around neurons during development, and are specialised forms of neural extracellular matrix (ECM), which have neuroprotective roles and control synaptic plasticity [20,21,89]. Several studies show that, similar to notochordal aggrecan, brain aggrecan does not contain KS; however since most of these studies were conducted in mice and murine cartilage aggrecan does not contain KS, the significance of this statement needs to be carefully evaluated [90–92]. Further studies on bovine, ovine and human aggrecan have shown that, while KS is present on brain aggrecan, its content is significantly reduced compared to cartilage aggrecan [90,92–94] (Figure 3e). The hydrodynamic size of brain aggrecan is smaller both due to this absence of KS chains and replacement of CS chains with the HNK-1 trisaccharide. Embryonic chick cartilage aggrecan contains KS however notochordal aggrecan does not. HNK-1 aggrecan is also found in early embryonic cartilage rudiments but it disappears with tissue maturation.

The notochord is a full-length embryonic midline structure found in the Chordata [95]. In vertebrates, the notochord is critical for development and defines the major axis of the embryo [96]. The notochord is a source of developmental signals that regulate the patterning of tissues surrounding the notochord [97]. Hedgehog proteins (Shh, Ihh and Dhh) secreted by the notochord are central regulators of embryonic development [98] and control the patterning of tissues and proliferation of cell populations which form a wide variety of organs including the brain, heart and kidneys. Aggrecan interacts with the hedgehog morphogens and has key roles in the regulation of cellular proliferation and tissue development by embryonic NCCs in these tissues. Morphogens orchestrate the actions of progenitor cell populations through the regulation of cellular behaviours including migration, proliferation and matrix deposition into the axial embryonic tissues and in the patterning of the surrounding connective tissues.
