Extracellular regulators of axonal growth in the adult central nervous system

Abstract

Robust axonal growth is required during development to establish neuronal connectivity. However, stable fibre patterns are necessary to maintain adult mammalian central nervous system (CNS) function. After adult CNS injury, factors that maintain axonal stability limit the recovery of function. Extracellular molecules play an important role in preserving the stability of the adult CNS axons and in restricting recovery from pathological damage. Adult axonal growth inhibitors include a group of proteins on the oligodendrocyte, Nogo-A, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein and ephrin-B3, which interact with axonal receptors, such as NgR1 and EphA4. Extracellular proteoglycans containing chondroitin sulphates also inhibit axonal sprouting in the adult CNS, particularly at the sites of astroglial scar formation. Therapeutic perturbations of these extracellular axonal growth inhibitors and their receptors or signalling mechanisms provide a degree of axonal sprouting and regeneration in the adult CNS. After CNS injury, such interventions support a partial return of neurological function.

Figure 1

Molecular regulation of axonal guidance, plasticity and regeneration. A schematic summarizes the shift of CNS axons through three phases of development. In the embryonic period, there is rapid axonal growth and the premium is on guidance. In the neonatal and juvenile phase, connectivity is plastic and undergoes refinement. In the third adult phase, axons are stable with myelin and CSPGs playing crucial roles in limiting rearrangements. The extracellular molecules and receptors most critical in each stage of this developmental progression are listed. Axonal growth, plasticity and regeneration in the injured adult CNS may be achieved by perturbing the function of those extracellular molecules limiting axonal growth in the adult setting.

Figure 2

Ligand–receptor interactions limiting adult CNS axon growth. The myelin-associated ligands ephrin-B3, MAG, Nogo-A and OMgp are expressed by the oligodendrocyte. Ephrin-B3 signals through the neuronal Eph receptors including EphA4. MAG binds NgR1 and specific gangliosides such as GT1b. Nogo has two inhibitory domains; Nogo-66 (dark blue)/Nogo-24 (purple) binds to the neuronal NgR1, while Δ20 (light blue) bind to a distinct putative amino-Nogo receptor (turquoise). OMgp is expressed by oligodendrocytes and signals through NgR1. NgR1 (crystal structure of the ligand-binding domain depicted) is a GPI-anchored protein that signals through multiple transducers (listed). The NgR1 residues necessary for binding of all the three myelin ligands are shown in red. CSPGs are membrane bound or attached to specific matrix protein such as tenascin (yellow). The core protein (light orange) is covered with inhibitory GAGs (burgundy) that limit axon sprouting and outgrowth by an undefined mechanism. These inhibitory molecules activate downstream signalling pathways that prevent neurite outgrowth in vitro and impede axon growth in vivo.