Integrin signalling and traffic during axon growth and regeneration
Graphical abstract
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
References (56)
Integrins: bidirectional, allosteric signaling machines
Cell
(2002)- et al.
Stabilising influence: integrins in regulation of synaptic plasticity
Neurosci Res
(2011) - et al.
Intrinsic mechanisms regulating axon regeneration: an integrin perspective
Int Rev Neurobiol
(2012) Structure and function of focal adhesions
Curr Opin Cell Biol
(2012)- et al.
p130Cas: a versatile scaffold in signaling networks
Trends Cell Biol
(2006) - et al.
Mechanisms of integrin activation and trafficking
Curr Opin Cell Biol
(2011) - et al.
Regulation of adhesion site dynamics by integrin traffic
Curr Opin Cell Biol
(2012) - et al.
Distinct roles of talin and kindlin in regulating integrin alpha5beta1 function and trafficking
Curr Biol CB
(2012) - et al.
Studies on integrins in the nervous system
Methods Enzymol
(2007) - et al.
Integrin signaling switches the cytoskeletal and exocytic machinery that drives neuritogenesis
Dev Cell
(2010)