This provides both a surface on which to traverse and a source of intracellular signalling activation. The ECM
can act as a supportive, adhesive substrate (in addition to other cells/cell surface bound factors), as well as providing guidance signals directly, and via localization of other soluble factors R428 (reviewed in [81]). The ECM contains both permissive and inhibitory context-dependent cues to growth cones. Neuronal preference for substrata and cues is determined by the expression of appropriate receptors by the growth cone. In addition, ECM-derived ligand binding also induces changes in receptor expression to regulate motility [82]. It should be noted that in the developing CNS, ECM molecules such as reelin and those of the thrombospondin type-1 repeat superfamily are crucially involved in migration and lamination, binding to neurones and retinal ganglion cells and initiating diverse signalling cascades required for radial and chain migration [83], but will not be discussed further here as we focus on ECM molecules with typical additional relevance to repair and plasticity following CNS injury Selumetinib chemical structure or disorder. As a major component of the basal laminae, laminin is crucial for layer formation in the developing neocortex. It influences neural positionning directly, acting through integrin and dystroglycan receptors, or indirectly via associated radial glial cells (reviewed
in [84]). Laminin isoforms vary in their tissue distribution and ability to promote migration and axon elongation. Laminin-1 (LN-1) mediates permissive outgrowth, primarily by binding to appropriate
growth cone integrins. Knockout of laminin γ1 in the mouse cerebral cortex leads to defects in neuritogenesis and neuronal migration resulting in defects in cortical layering and axonal pathfinding, suggested to occur via integrin signalling through the AKT/GSK-3β pathway [85]. A number of in vitro studies have demonstrated that LN-1 acts not only as a permissive substrate but also as a chemoattractive cue if applied locally to the growth cone [86]. Laminin can also modulate the ability of other guidance cues to inhibit growth cones. For example, the repulsive role of ephrin-A5 in controlling retinotectal P-type ATPase mapping in a fibronectin-rich environment is reversed when cultured on laminin [87]. This phenomenon has particular relevance to repair where the growth cone repulsive nature of myelin-associated glycoprotein is attenuated upon addition of laminin substrate and enhanced neurite outgrowth observed on glial scar cultures following removal of inhibitory CSPGs is reversed following application of a laminin neutralizing antibody [88]. Expression of fibronectin is widespread within the developing CNS and it is suggested to have various supportive roles in adhesion, migration and axon elongation.