Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice.
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-gamma 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.
Goldshmit
Yona
Y
Center for Neuroscience and School of Physiotherapy, University of Melbourne, Melbourne, Victoria 3010, Australia.
Galea
Mary P
MP
Wise
Graham
G
Bartlett
Perry F
PF
Turnley
Ann M
AM
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001369:Axons / Q000502:physiology*; D001921:Brain / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D005911:Gliosis / Q000235:genetics*; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007794:Lameness, Animal / Q000209:etiology / Q000503:physiopathology; D053605:Leukemia Inhibitory Factor; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009416:Nerve Regeneration / Q000502:physiology*; D016501:Neurites / Q000648:ultrastructure; D010264:Paraplegia / Q000209:etiology / Q000503:physiopathology; D011712:Pyramidal Tracts / Q000473:pathology; D036122:Receptor, EphA4 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020127:Recovery of Function; D012012:Red Nucleus / Q000473:pathology; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D007141:Immunoglobulin Fc Fragments; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D007371:Interferon-gamma; D036122:Receptor, EphA4; D020741:rho GTP-Binding Proteins