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The Journal of Neuroscience, March 22, 2006, 26(12):3087-3101; doi:10.1523/JNEUROSCI.4797-05.2006

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Development/Plasticity/Repair
EphB3: An Endogenous Mediator of Adult Axonal Plasticity and Regrowth after CNS Injury

Xiao Liu, Elizabeth Hawkes, Tatsuto Ishimaru, Tony Tran, and David W. Sretavan

Program in Neuroscience, Departments of Ophthalmology and Physiology, University of California at San Francisco, San Francisco, California 94143

Correspondence should be addressed to Dr. David W. Sretavan, K107, Box 0730, Beckman Vision Sciences Building, University of California at San Francisco, 10 Kirkham Street, San Francisco, CA 94143. Email: sretavand{at}vision.ucsf.edu

Endogenous mechanisms underlying the remodeling of neuronal circuitry after mammalian CNS injury or disease remain primarily unknown. Here, we investigated axonal plasticity after optic nerve injury and found that macrophages recruited into the injury site and adult retinal ganglion cell (RGC) axons, which undergo injury-induced sprouting and terminal remodeling, were linked by their respective expression of a ligand and receptor pair active in axon guidance. Recruited macrophages specifically upregulated mRNA encoding the guidance molecule EphB3 and expressed EphB proteins capable of binding Ephrin B molecules in vivo and in vitro. Injured adult RGC axons in turn expressed EphrinB3, a known receptor for EphB3, and RGC axons bound recombinant EphB3 protein injected into the optic nerve. In vitro, EphB3 supported adult RGC axon outgrowth, and axons turned toward a source of this guidance molecule. In vivo, both reduction of EphB3 function in adult heterozygous animals and loss of function in homozygous animals greatly decreased RGC axon re-extension or sprouting after optic nerve injury. Comparisons of axon re-extension in EphB3 null and wild-type littermates showed that this loss of axonal plasticity was not attributable to a difference in intrinsic axon growth potential. Rather, the results indicated an essential role for local optic nerve-derived EphB3 in regulating adult RGC axon plasticity after optic nerve injury. Of note, the loss of EphB3 did not affect the ability of injured RGC axons to elaborate complex terminal branching, suggesting that additional EphB3-independent mechanisms governed adult axon branching triggered by CNS damage.

Key words: Eph; Ephrin; regeneration; sprouting; optic nerve; trauma; guidance molecule; macrophage; visual system; retinal ganglion cell

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Received March 22, 2005; revised Jan. 25, 2006; accepted Jan. 27, 2006.

Correspondence should be addressed to Dr. David W. Sretavan, K107, Box 0730, Beckman Vision Sciences Building, University of California at San Francisco, 10 Kirkham Street, San Francisco, CA 94143. Email: sretavand{at}vision.ucsf.edu

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