Elsevier

Current Opinion in Neurobiology

Volume 27, August 2014, Pages 179-185
Current Opinion in Neurobiology

Integrin signalling and traffic during axon growth and regeneration

https://doi.org/10.1016/j.conb.2014.03.018Get rights and content

Highlights

  • Integrins are subject to complex regulation by signalling and trafficking molecules.

  • Integrin activation occurs from inside and outside of the cell.

  • Integrins can mediate developmental CNS axon growth and axon regeneration in the PNS.

  • Activation of integrins can boost axon regeneration in the adult CNS in vivo.

  • Integrin traffic can be manipulated to increase axonal integrin expression and growth.

Adult corticospinal tract axons do not regenerate because they have low intrinsic growth ability, and are exposed to inhibitory molecules after injury. PNS axons have a better regenerative capacity, mediated in part by integrins (extracellular matrix receptors). These are subject to complex regulation by signalling and trafficking. Recent studies have found that integrin mediated axon growth relies on signalling via focal adhesion molecules, and that integrins are inactivated by inhibitory molecules in the CNS. Forced activation of integrins can overcome inhibition and increase axon regeneration, however integrins are not transported into some CNS axons. Studies of PNS integrin traffic have identified molecules that can be manipulated to increase axonal integrin expression, suggesting strategies for repairing the injured spinal cord.

Introduction

After injury to the spinal cord there is very little axonal regeneration. This is because there are inhibitory molecules at the site of injury, and because adult central nervous system (CNS) neurons have a low intrinsic capacity for axon growth. This is profoundly evident in adult corticospinal axons [1]. These axons project from the brain into the spinal cord in order to control voluntary skilled movement, and so damaging them leads to paralysis. In order to address this, research has focused on either overcoming the inhibitory environment, or enhancing the growth capacity of the injured axons. This review highlights how recent studies on integrins have helped to identify intrinsic growth-related mechanisms which can be manipulated to enhance axon growth and regeneration through an otherwise inhibitory environment.

Integrins are a large family of transmembrane receptors that bind to molecules in the extra cellular matrix (ECM). They transduce extracellular force-generating cues to the cytoskeleton, whilst activating intracellular signalling pathways that can regulate cell function, survival, morphology, motility, and the cell cycle. They exist as an α and a β subunit constituted from 18 α and 8 β subunits which form 24 heterodimers. The combination of dimers governs the specificity for their ligands, resulting in binding with differing affinities to ECM molecules such as fibronectin, collagen, laminin, tenascin and vitronectin [2]. ECM molecules and their integrin receptors have been implicated in a wide variety of biological functions during development and in adulthood, as well as in various disease states, and have been assigned roles in both the developing and mature nervous system (in most neurological cell types) and it is now widely accepted that integrins and the ECM are crucial for defining the laminar architecture of the brain by controlling aspects of axon growth and guidance, and are also important for axon regeneration in the peripheral nervous system (PNS) [3, 4, 5, 6, 7, 8].

Section snippets

Integrin regulation by signalling and traffic

Integrins are extremely complex molecules, not just because of their variety, but also because of the complex manner in which they are regulated by signalling and trafficking. Integrins convey information inside the cell regarding the environment outside the cell, by binding to their ligands. This is called outside-in signalling, and is reliant on numerous intracellular adapter proteins. This is for two reasons: firstly, integrins have no intrinsic enzymatic activity, so their ability to convey

Integrin signalling and axon growth and regeneration

It is now widely accepted that axon growth and extension is regulated in a large part by a balance between integrin and ECM expression which occurs during development, and there are some excellent recent reviews on this subject [4, 19, 20]. There is also substantial evidence to suggest that integrins are important for axon regeneration both during development and in the adult PNS; this literature has also been reviewed [7]. Understanding integrin dependent growth during development may

Integrin traffic and axon growth and regeneration

Integrin dependent axon regeneration depends on the transport of integrins and associated molecules to the site of axonal injury, and ultimately into the surface membrane. This is evident in the PNS [7] however in some adult CNS neurons, integrins are excluded from axons [21, 22]. It is therefore important to understand the processes that are involved in regulating axonal integrin transport. Studies into axonal integrin traffic have focused on endosomal trafficking pathways regulated by small

Summary

Recent studies are therefore confirming that successful axon growth can be mediated by integrin interaction with the ECM, transduced by focal adhesion proteins and regulated by trafficking and activation molecules. In the adult CNS these mechanisms are not evident, and after injury axons do not regenerate. Is it possible to influence axon regeneration via integrin manipulation in vivo? Is this a realistic therapeutic strategy? It is evident that any intervention will need to address both the

Conflicts of interest statement

James Fawcett is a paid consultant for Acorda Therapeutics. Richard Eva has no conflicts of interest.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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