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The Journal of Neuroscience, November 10, 2004, 24(45):10064-10073; doi:10.1523/JNEUROSCI.2981-04.2004
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Development/Plasticity/Repair
Axonal Regeneration and Lack of Astrocytic Gliosis in EphA4-Deficient Mice
Yona Goldshmit,1,2 Mary P. Galea,1,2 * Graham Wise,3 Perry F. Bartlett,4,5 * andAnn M. Turnley1 * 1Center for Neuroscience and 2School of Physiotherapy, University of Melbourne, Melbourne, Victoria 3010, Australia, 3School of Biomedical Sciences and 4The Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia, and 5Development and Neurobiology Group, Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville, Victoria 3050, Australia
Spinal cord injury usually results in permanent paralysis because of lack of regrowth of damaged neurons. Here we demonstrate that adult mice lacking EphA4 (-/-), 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. EphA4-/- 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 EphA4-/- spinal cords. EphA4-/- 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 EphA4-/- 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.
Key words: spinal cord injury; astrocytic gliosis; anterograde; retrograde; neurite outgrowth; cytokine
Received July 21, 2004; revised September 27, 2004; accepted September 27, 2004.
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