Roles of Eph receptors and ephrins in the normal and damaged adult CNS

doi:10.1016/j.brainresrev.2006.04.006

Brain Research Reviews

Volume 52, Issue 2, September 2006, Pages 327-345

https://doi.org/10.1016/j.brainresrev.2006.04.006 Get rights and content

Abstract

Injury to the central nervous system (CNS) usually results in very limited regeneration of lesioned axons, which are inhibited by the environment of the injury site. Factors that have been implicated in inhibition of axonal regeneration include myelin proteins, astrocytic gliosis and cell surface molecules that are involved in axon guidance during development. This review examines the contribution of one such family of developmental guidance molecules, the Eph receptor tyrosine kinases and their ligands, the ephrins in normal adult CNS and following injury or disease. Eph/ephrin signaling regulates axon guidance through contact repulsion during development of the CNS, inducing collapse of neuronal growth cones. Eph receptors and ephrins continue to be expressed in the adult CNS, although usually at lower levels, but are upregulated following neural injury on different cell types, including reactive astrocytes, neurons and oligodendrocytes. This upregulated expression may directly inhibit regrowth of regenerating axons; however, in addition, Eph expression also regulates astrocytic gliosis and formation of the glial scar. Therefore, Eph/ephrin signaling may inhibit regeneration by more than one mechanism and modulation of Eph receptor expression or signaling could prove pivotal in determining the outcome of injury in the adult CNS.

Introduction

Mammalian central nervous system (CNS) neurons do not regenerate successfully after injury. The molecular mechanisms underlying the processes involved in the response to injury in the CNS are not fully understood. Intensive studies over the past few decades have indicated that the extracellular environment of the CNS plays a pivotal role in determining the nerve's ability to regenerate. Many cell activation systems may be involved in regeneration, some used previously during development and others specific to the type of insult (trauma, ischemia, etc.). Changes after CNS injury include diffuse inflammation, ischemic cell death, excitotoxic cell death and apoptotic cell death.

The lack of neuronal regeneration following CNS injuries may be explained in part by the lack of growth-promoting molecules required for axon outgrowth and guidance, together with inhibitory changes in the neural microenvironment. These include the presentation of myelin-derived inhibitors (Caroni and Schwab, 1988, McKerracher et al., 1994, Mukhopadhyay et al., 1994, Bandtlow and Schwab, 2000), the proliferation and activation of astrocytes, which leads to the formation of a glial scar at the site of injury as well as changes in the composition of the local extracellular matrix (ECM) (reviewed in Silver and Miller, 2004) that promote degeneration of axotomised neurons (Caroni, 1998).

In the last decade, the majority of research has focused on the role of myelin inhibitors and the astrocytic scar. Recently, developmental axon guidance molecules have also been implicated in inhibition of adult axon regrowth (De Winter et al., 2002, Goldshmit et al., 2004, Hashimoto et al., 2004). This review discusses how members of one such family of developmental guidance molecules, the Eph and the ephrin family, may play a role in adult CNS regeneration.

Section snippets

Eph and ephrins—membrane bound guidance molecules

Several families of membrane bound cell surface proteins have been implicated in the control of cell movement, which is crucial for tissue organization during development. These proteins include ligand-receptor systems that regulate cell adhesion and/or the assembly state of the actin cytoskeleton to elicit either attractive or repulsive responses during cell–cell contact, such as the Eph receptor tyrosine kinases (RTKs), or at a distance through diffusible signals. The Eph receptors and their

Eph and ephrins during CNS development

During the development of the nervous system, axons grow through specific pathways before establishing connections with their target cells. A variety of attractive and repulsive signals help to guide axonal processes along their complex migration pathways. In the developing nervous system, repulsive interactions are required between Eph receptors and their ligands in diverse areas, including anterior commissure formation (Henkemeyer et al., 1996, Orioli et al., 1996), spinal cord motor neuron

Eph/ephrin expression in adult brain

The majority of research on the Eph family has focused on development, during which changes in receptor and ligand expression levels are marked. Continued expression of Ephs and ephrins occurs in the CNS in adulthood, although often at a lower level than during development. The function of continued expression of Eph receptors and their ligands in adulthood remains unclear, although it is beginning to be elucidated. Like other receptor tyrosine kinases, such as epidermal growth factor (EGF) and

Eph receptors and ephrins in the adult CNS after injury and disease

In addition to its developmental roles, expression of Ephs and ephrins in the adult CNS also has implications for regeneration after injury. Indeed, it has been shown that many Eph receptors in adult CNS are upregulated after CNS injury (Miranda et al., 1999, Moreno-Flores and Wandosell, 1999, Rodger et al., 2001, Willson et al., 2002, Willson et al., 2003, Bundesen et al., 2003). Expression of Ephs and ephrins after CNS injury is summarized in Table 2.

Following damage to the CNS, different

Conclusions

Collectively, the observations described in this review provide evidence that Ephs and ephrins play a central role in determining regenerative outcomes following CNS injury and disease. Signaling through Eph–ephrin complexes directly inhibits axonal regeneration by stimulating growth cone collapse and is a key regulator of astrocyte reactivity and glial scar formation (Fig. 3). Interestingly, Benson et al. (2005) have recently reported ephrin-B3 expression on myelinated oligodendrocytes in vivo

Acknowledgments

We would like to thank the NH&MRC and SpinalCure Australia for their support. Y.G. is a SpinalCure Australia Research Fellow.

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ReviewRoles of Eph receptors and ephrins in the normal and damaged adult CNS

Abstract

Introduction

Section snippets

Eph and ephrins—membrane bound guidance molecules

Eph and ephrins during CNS development

Eph/ephrin expression in adult brain

Eph receptors and ephrins in the adult CNS after injury and disease

Conclusions

Acknowledgments

Cell

Neurosci. Lett.

Dev. Biol.

Curr. Opin. Neurobiol.

Neuron

Neuron

Cell

Dev. Biol.

Trends Cell Biol.

Cell

Neuroscience

Exp. Neurol.

Curr. Opin. Neurobiol.

Cell

Cell

Brain Res. Bull.

Neuron

Neuron

Neuron

Exp. Cell Res.

Dev. Biol.

Brain Res. Dev. Brain Res.

Neuron

Neuron

Cell

Trends Neurosci.

Neuron

Dev. Biol.

Curr. Opin. Neurobiol.

Neuron

Neuron

Neuron

Prog. Neuro-Psychopharmacol. Biol. Psychiatry

Cell

Neurosci. Lett.

Exp. Neurol.

Exp. Neurol.

Curr. Opin. Cell Biol.

Exp. Neurol.

Trends Neurosci.

Mech. Dev.

Cadherin–catenin complex: protein interactions and their implications for cadherin function

J. Cell. Biochem.

B-ephrin reverse signaling is required for NMDA-independent long-term potentiation of mossy fibers in the hippocampus

J. Neurosci.

Persistence of graded EphA/Ephrin-A expression in the adult frog visual system

J. Comp. Neurol.

Reactive astrogliosis in the neonatal mouse brain and its modulation by cytokines

J. Neurosci.

NI-35/250/nogo-a: a neurite growth inhibitor restricting structural plasticity and regeneration of nerve fibers in the adult vertebrate CNS

Glia

EphB receptors and ephrin-B ligands regulate spinal sensory connectivity and modulate pain processing

Nat. Neurosci.

Astrocytes and microglial cells incorporate degenerating fibers following entorhinal lesion: a light, confocal, and electron microscopical study using a phagocytosis-dependent labeling technique

Glia

Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation

Mol. Cell. Biol.

Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth

Proc. Natl. Acad. Sci. U. S. A.

Review
Roles of Eph receptors and ephrins in the normal and damaged adult CNS