Accumulation of the inhibitory receptor EphA4 may prevent regeneration of corticospinal tract axons following lesion

Fabes, Jez; Anderson, Patrick N.; Yáñez‐Muñoz, Rafael J.; Thrasher, Adrian J.; Brennan, Caroline H.; Bolsover, Stephen R.

doi:10.1111/j.1460-9568.2006.04704.x

Cited by 74 publications

(73 citation statements)

References 43 publications

(66 reference statements)

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“…in addition, the up-regulation of EphA4 in injured axons leads to the retraction of corticospinal axons and inhibition of axon regeneration in the weeks after a spinal lesion [56] . Notably, a study by Turnley's team showed that astrocytic gliosis and glial scars are greatly reduced in EphA4-deficient mice after a lateral spinal cord hemisection [57] .…”

Section: Eph/ephrinsmentioning

confidence: 99%

The glial scar in spinal cord injury and repair

2013

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Glial scarring following severe tissue damage and inflammation after spinal cord injury (SCi) is due to an extreme, uncontrolled form of reactive astrogliosis that typically occurs around the injury site. The scarring process includes the misalignment of activated astrocytes and the deposition of inhibitory chondroitin sulfate proteoglycans. Here, we first discuss recent developments in the molecular and cellular features of glial scar formation, with special focus on the potential cellular origin of scar-forming cells and the molecular mechanisms underlying glial scar formation after SCi. Second, we discuss the role of glial scar formation in the regulation of axonal regeneration and the cascades of neuro-inflammation. Last, we summarize the physical and pharmacological approaches targeting the modulation of glial scarring to better understand the role of glial scar formation in the repair of SCi.Keywords: glial scar; spinal cord injury; axonal regeneration; astrocyte activation; reactive astrogliosis; neuroinflammation IntroductionSpinal cord injury (SCi) is a common and devastating central nervous system (CNS) insult that results in disruption of cord microstructure and is followed by limited neuronal regeneration and insufficient functional recovery in adult mammals. After severe SCi, and in response to changes in the local microenvironment, astrocytes, the most abundant glial cells in the CNS, transform into reactive astrocytes and undergo dramatic morphological changes [1] as well as massive variations in gene expression [2] . Reactive astrocytes, the major component of glial scars, along with other cells in the spinal cord and blood-borne cells leaking from the damaged blood-spinal cord barrier, participate in the process of scar formation [3] .From the historical perspective, a glial scar is recognized as an impediment to the regeneration of axons in the cord because of the irregular rearrangement of hypertrophic astrocytic processes, as well as major components of the axonal inhibitory extracellular matrix (ECM), including chondroitin sulfate proteoglycans (CSPGs) that are secreted by the reactive astrocytes [4] . Currently, increasing evidence is advancing our knowledge of the mechanism of the formation of glial scars after a lesion and the roles of glial scars in the regulation of neuro-inflammation and repair processes [5,6] .This article reviews the following: (1) the molecular and cellular properties of glial scar formation following SCi;(2) the roles of glial scar formation in axonal regeneration and neuro-inflammation; and (3) the current status of scarmodulating therapeutic strategies for spinal cord repair after injury. Molecular and Cellular Properties of Glial Scars Characterization of Glial ScarsTraumatic damage of the spinal cord can result in seallike scar tissue in the lesion zone, which is filled with dense cellular components and a connective matrix. Generally, the scar tissue is classified into two parts, fibrotic and glial. 422The fibrotic scar, primarily composed of invading fibrobl...

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Section: Eph/ephrinsmentioning

confidence: 99%

The glial scar in spinal cord injury and repair

2013

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“…In both of these scenarios, the loss of positive guidance cues and/or gain of negative cues correlated with failed regeneration. Eph/ephrin signaling has recently been correlated with failure of cortical spinal axon regeneration (Fabes et al 2006). EprhinB2, an EphA4 receptor ligand, is normally expressed flanking the corticospinal tract in adults.…”

Section: Developmental Guidance Cues Associated With Failed Regenerationmentioning

confidence: 99%

Molecular/genetic manipulation of extrinsic axon guidance factors for CNS repair and regeneration

Curinga

Smith

2008

Experimental Neurology

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During development, guidance molecules play a key role in the formation of complex circuits required for neural functions. With the cessation of development, this exuberant growth process slows and stabilizes, and inhibitory molecules expressed by glia prevent initial attempts for axonal regeneration. In this review, we discuss the expression patterns and relative contribution of several guidance molecules on the regenerative process. Injury to the immature CNS or species capable of regenerating exhibit a complete or partial recapitulation of their developmental guidance patterns; whereas, similar injuries to adult mammals results in altered expression that acts to further hinder regeneration. Manipulations of guidance molecules after injury have been used to control detrimental effects of axon sprouting and target regenerating axons within the spinal cord.

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“…2) [61,62]. EphrinB3 is expressed in oligodendrocytes of the adult spinal cord [63], while ephrinB2 increases in astrocytes following SCI [11,57]. Increased recovery of plantar stepping was observed in these studies; however, the developmental effects of ephrinB3 knockout on intraspinal circuitry and gait [53,54], as well as the potential for contralateral sprouting of intact corticospinal axons after unilateral injury in ephrinB2 conditional knockout mice, may be a confound to interpretation of functional recovery data.…”

Section: Ephrinsmentioning

confidence: 62%

“…EphA4 is expressed in adult corticospinal motor neurons and accumulates in injured axon tips [56,57]. Knocking out EphA4 has been proposed to promote axon regeneration in a unilateral hemisection model; however, the potential effect of spared axons in that study cannot be discounted [58].…”

Section: Ephrinsmentioning

confidence: 86%

Axon Guidance Molecules and Neural Circuit Remodeling After Spinal Cord Injury

Hollis

2016

Neurotherapeutics

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…once the development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. Santiago Ramón y CajalCajal's neurotropic theory postulates that the complexity of the nervous system arises from the collaboration of neurotropic signals from neuronal and non-neuronal cells and that once development has ended, a paucity of neurotropic signals means that the pathways of the central nervous system are Bfixed, ended, immutable^. While the capacity for regeneration and plasticity of the central nervous system may not be quite as paltry as Cajal proposed, regeneration is severely limited in scope as there is no spontaneous regeneration of long-distance projections in mammals and therefore limited opportunity for functional recovery following spinal cord injury. It is not a far stretch from Cajal to hypothesize that reappropriation of the neurotropic programs of development may be an appropriate strategy for reconstitution of injured circuits. It has become clear, however, that a significant number of the molecular cues governing circuit development become re-active after injury and many assume roles that paradoxically obstruct the functional re-wiring of severed neural connections. Therefore, the problem to address is how individual neural circuits respond to specific molecular cues following injury, and what strategies will be necessary for instigating functional repair or remodeling of the injured spinal cord.

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Accumulation of the inhibitory receptor EphA4 may prevent regeneration of corticospinal tract axons following lesion

Cited by 74 publications

References 43 publications

The glial scar in spinal cord injury and repair

The glial scar in spinal cord injury and repair

Molecular/genetic manipulation of extrinsic axon guidance factors for CNS repair and regeneration

Axon Guidance Molecules and Neural Circuit Remodeling After Spinal Cord Injury

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