Axonal Regeneration and Lack of Astrocytic Gliosis in EphA4-Deficient Mice

Abstract

Spinal cord injury usually results in permanent paralysis because of lack of regrowth of damaged neurons. Here we demonstrate that adult mice lacking EphA4 (Ϫ/Ϫ), a molecule essential for correct guidance of spinal cord axons during development, exhibit axonal regeneration and functional recovery after spinal cord hemisection. Anterograde and retrograde tracing showed that axons from multiple pathways, including corticospinal and rubrospinal tracts, crossed the lesion site. EphA4Ϫ/Ϫ mice recovered stride length, the ability to walk on and climb a grid, and the ability to grasp with the affected hindpaw within 1-3 months of injury. EphA4 expression was upregulated on astrocytes at the lesion site in wild-type mice, whereas astrocytic gliosis and the glial scar were greatly reduced in lesioned EphA4Ϫ/Ϫ spinal cords. EphA4Ϫ/Ϫ astrocytes failed to respond to the inflammatory cytokines, interferon-␥ or leukemia inhibitory factor, in vitro. Neurons grown on wild-type astrocytes extended shorter neurites than on EphA4Ϫ/Ϫ astrocytes, but longer neurites when the astrocyte EphA4 was blocked by monomeric EphrinA5-Fc. Thus, EphA4 regulates two important features of spinal cord injury, axonal inhibition, and astrocytic gliosis.

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

“…Members of this family are up-regulated following CNS injury (18,19). EphA4 has been implicated in the response to injury both as an astrocyte and as a neuronally expressed protein, but its functional role in recovery from neuronal injury is not clear (20)(21)(22)(23). Macrophage EphB3 has also been implicated in adult axon regeneration (24).…”

One-year clinical study of NeuroRegen scaffold implantation following scar resection in complete chronic spinal cord injury patients

“…Many studies have modulated the gliotic scarring response by enzymatic digestion, antibody blocking, or clonal deletion of specific glial scar molecules to promote axon regeneration and functional SCI recovery (Bradbury et al, 2002;Goldshmit et al, 2004;Shearer et al, 2003). Although these biochemical approaches show promise, the therapeutic effects are relatively limited because of the multiple molecule candidates and complicated scar microenvironment.…”

White matter inhibitors in CNS axon regeneration failure

“…Moreover, in vitro neurite outgrowth studies demonstrated that a significant part of myelin inhibition is mediated by Ephrin-B3, which remarkably equals to the inhibitory activity of Nogo, MAG, and OMgp combined -at least for the postnatal cortical neurons tested (Benson et al, 2005). Interestingly, an independent group reported robust axonal regeneration and improved functional recovery in mice lacking EphA4, the receptor for Ephrin-B3 during CST development (Goldshmit et al, 2004). Furthermore, several potential mechanisms for improved axon regeneration and functional recovery were suggested, including a loss of EphA4-mediated axon growth inhibition, reduced astrogliosis and altered vascular remodeling (Goldshmit et al, 2004;Goldshmit et al, 2006).…”

“…Interestingly, an independent group reported robust axonal regeneration and improved functional recovery in mice lacking EphA4, the receptor for Ephrin-B3 during CST development (Goldshmit et al, 2004). Furthermore, several potential mechanisms for improved axon regeneration and functional recovery were suggested, including a loss of EphA4-mediated axon growth inhibition, reduced astrogliosis and altered vascular remodeling (Goldshmit et al, 2004;Goldshmit et al, 2006). Taken together, these studies illustrated a new role for developmentally critical axon guidance molecules in axon growth inhibition and other important aspects of CNS injury and repair.…”