Spinal cord injury (SCI) initiates a cascade of processes that ultimately form a nonpermissive environment for axonal regeneration. Emerging evidence suggests that regenerative failure may be due in part to inhibitory factors expressed by reactive spinal cord glial cells and meningeal fibroblasts, such as the
Eph receptor protein-tyrosine kinases and their corresponding
ligands (
ephrins). Here we sought to assess the role of
ephrin B2, an inhibitory axonal guidance molecule, as an inhibitor of the recovery process following SCI. To determine the extent of
ephrin B2 involvement in axonal regenerative failure, a SCI model was performed on a conditional
ephrin B2 knockout mouse strain (
ephrin B2(-/-)), in which the
ephrin B2 gene was deleted under the GFAP promoter . The expression of
ephrin B2 was significantly decreased in astrocytes of injured and uninjured
ephrin B2(-/-) mice compared to wild-type mice. Notably, in the
ephrin B2(-/-) mice, the deletion of
ephrin B2 reduced
astrogliosis, and accelerated motor function recovery after SCI. Anterograde axonal tracing on a hemisection model of SCI further showed that
ephrin B2(-/-) mice exhibited increased regeneration of injured corticospinal axons and a reduced
glial scar, when compared to littermate controls exposed to similar injury. These results were confirmed by an in vitro neurite outgrowth assay and
ephrin B2 functional blockage, which showed that
ephrin B2 expressed on astrocytes inhibited axonal growth. Combined these findings suggest that
ephrin B2 ligands expressed by reactive astrocytes impede the recovery process following SCI.