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

Abstract

Recovery of neurological function after traumatic injury of the adult mammalian central nervous system is limited by lack of axonal growth. Myelin-derived inhibitors contribute to axonal growth restriction, with ephrinB3 being a developmentally important axonal guidance cue whose expression in mature oligodendrocytes suggests a role in regeneration. Here we explored the in vivo regeneration role of ephrinB3 using mice lacking a functional ephrinB3 gene. We confirm that ephrinB3 accounts for a substantial portion of detergent-resistant myelin-derived inhibition in vitro. To assess in vivo regeneration, we crushed the optic nerve and examined retinal ganglion fibers extending past the crush site. Significantly increased axonal regeneration is detected in ephrinB3 −/− mice. Studies of spinal cord injury in ephrinB3 −/− mice must take into account altered spinal cord development and an abnormal hopping gait before injury. In a near-total thoracic transection model, ephrinB3 −/− mice show greater spasticity than wild-type mice for 2 mo, with slightly greater hindlimb function at later time points, but no evidence for axonal regeneration. After a dorsal hemisection injury, increased corticospinal and raphespinal growth in the caudal spinal cord are detected by 6 wk. This increased axonal growth is accompanied by improved locomotor performance measured in the open field and by kinematic analysis. Thus, ephrinB3 contributes to myelin-derived axonal growth inhibition and limits recovery from adult CNS trauma.

A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke

“…Data from single-cell laser capture, in vitro outgrowth assays, and in vivo blockade and induction of ephrin-A5 signaling in two different stroke models identify ephrin-A5 up-regulation in reactive astrocytes and show that ephrin-A5 inhibits axonal sprouting in cortical networks adjacent to the stroke that mediate motor recovery. A convincing study has described the inhibitory effects of myelin-based ephrin-B3 in spinal cord and optic nerve injury (36); however, the current study identifies ephrin-A5 in growth inhibition in the CNS after injury and assigns the cell type and functional role of this molecule in tissue reorganization and recovery after stroke. Functional recovery after stroke has been associated with axonal sprouting in several different brain connections, including corticocortical, corticospinal, and corticobulbar projections (37).…”

Human NgR-Fc Decoy Protein via Lumbar Intrathecal Bolus Administration Enhances Recovery from Rat Spinal Cord Contusion

“…8,26,27,29,36 The spinal cord 10 mm rostral to and 10 mm caudal to the lesion center was embedded in a glutaraldehyde-polymerized albumin matrix and cut parasagittally in the thickness of 40 lm on a vibratome. Transverse sections (40 lm) were collected from the spinal cord 11-16 mm rostral to and 11-16 mm caudal to the lesion center.…”

“…Image analysis was performed with National Institutes of Health (NIH) image version 1.62, as described previously. 26,27,29,36 For analysis of serotonin innervation, immunoreactive serotonin fibers in the ventral horn of transverse sections caudal to the lesion center were selected by thresholding; then the length of serotonin fiber per area was measured after using the ''skeletonize'' function.…”

Inflammation and Optic Nerve Regeneration

“…Injured RGC terminals express the cognate ligand EphrinB3, which interacts with macrophage EphB3 and stimulates local axonal sprouting (Liu et al, 2006). However, EphrinB3 is also expressed by oligodendrocytes, which inhibit axonal sprouting (Benson et al, 2005), and contributes to the inhibitory effects of myelin (Duffy et al, 2012). Thus, infiltrating macrophages can both promote and inhibit axonal sprouting through EphB3, depending on whether they act on EphrinB3 in axonal terminals or on oligodendrocytes, respectively.…”