Integrins promote axonal regeneration after injury of the nervous system

Abstract

Integrins are cell surface receptors that form the link between extracellular matrix molecules of the cell environment and internal cell signalling and the cytoskeleton. They are involved in several processes, e.g. adhesion and migration during development and repair. This review focuses on the role of integrins in axonal regeneration. Integrins participate in spontaneous axonal regeneration in the peripheral nervous system through binding to various ligands that either inhibit or enhance their activation and signalling. Integrin biology is more complex in the central nervous system. Integrins receptors are transported into growing axons during development, but selective polarised transport of integrins limits the regenerative response in adult neurons. Manipulation of integrins and related molecules to control their activation state and localisation within axons is a promising route towards stimulating effective regeneration in the central nervous system.

Keywords: axon regeneration; integrin; kindlin; receptor activation state; selective polarised transport; traumatic injury of the nervous system.

Figure 1

Integrins are localised to the growth cone of immature and peripheral nervous system neurons. Active and inactive integrins are present on the surface of the neuronal growth cone. However, only active integrins bind molecules of the extracellular matrix.

Figure 2

Molecular mechanisms of integrin inactivation after trauma in the nervous system. Integrins at the growth cones of regenerating axons are exposed to the extracellular environment of the lesion site. Integrins recruit focal adhesion kinases (FAKs) among others, which in turn, activate downstream signalling molecules such as protein kinase B (Akt3), phosphoinositide 3‐kinase (PI3K), Ras homolog gene family member A (RhoA), and Src kinase. However, most integrins exist in a bent, inactive state at the cell surface. The lesion site is rich in axon‐repulsive molecules, including Nogo‐A, myelin‐associated glycoprotein (MAG), class III semaphorins (Sema3s), and chondroitin sulphate proteoglycans (CSPGs). These molecules bind to several receptors, such as leukocyte common antigen‐related phosphatase (LAR), Nogo receptors (NgR1, NgR2), the plexin/neuropilin (PLXN/NRP) complex and protein tyrosine phosphatase σ (PTPσ), to suppress integrin signalling and axon regeneration. Nogo‐A binds to NgR1 and inhibits the phosphorylation of FAK. MAG is a direct ligand for integrins and stimulates integrin signalling. However, MAG also has an opposing effect by NgRs signalling that indirectly elevates intracellular calcium levels and stimulates clathrin‐mediated endocytosis of integrins. Most Sema3s mediate signalling via the PLXN/NRP receptor complex that results in inactivation of R‐Ras, which in turn interferes with integrin signalling, and activates ADP‐ribosylation factor 6 (ARF6) to remove integrins from the cell surface. Sema3A signalling results in the phosphorylation (Tyr397, Tyr576, Tyr577, Tyr925) and de‐phosphorylation (Tyr407, Tyr861) of different residues of FAK for Sema3A‐mediated axonal remodelling. CSPGs interact with many receptors, including LAR, NgR1 and PTPσ. The CSPG aggrecan has been shown to reduce FAK signalling, but the exact mechanisms remain to be identified. Other ligands such as ephrins, netrins and slits are also known to interfere with integrin signalling. In addition, there is evidence that integrin activation by kindlins and talins is inhibited by various regulatory mechanisms (illustrated as x).

Figure 3

Molecular mechanisms for integrin activation. Integrins exist in two activation states on the cell surface: a bent inactive and a straight active state. There are several ways to activate integrins: (i) cations such as Ca²⁺ and Mn²⁺ interact with a metal ion‐binding site at the ectodomain of the integrin to activate the receptor; (ii) kindlins and talins are two families of intracellular proteins that bind to the cytoplasmic tail of β1 integrins to activate the heterodimeric complex; (iii) the monoclonal antibody TS2/16 binds to the ectodomain of human β1 integrins to induce a conformational change and receptor activation. Activated integrins have their ectodomain exposed and bind extracellular matrix ligands, which leads to intracellular signalling and changes of the cytoskeleton. Activation of certain integrins can result in cell adhesion and axonal regeneration. FAK, focal adhesion kinase; ILK, integrin‐linked kinase; PI3K, phosphoinositide 3‐kinase.

Figure 4

Comparison of immature and mature central nervous system neurons. (A) Immature neurons do not have a fully developed axon initial segment and their axons have been shown to transport integrins both antero‐ and retrograde to an equal extent. Vesicles bound to ADP‐ribosylation factor 6 (ARF6)‐ and Ras‐associated binding (Rab) protein 11 (Rab11)‐GTP are retrograde transported, while vesicles bound to ARF6‐ and Rab11‐GDP move in the anterograde direction. (B) Mature neurons have developed an axon initial segment and are characterised with predominant retrograde axonal transport of integrins.