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The Journal of Neuroscience, February 18, 2004, 24(7):1646-1651; doi:10.1523/JNEUROSCI.5119-03.2004

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Development/Plasticity/Repair
Counteracting the Nogo Receptor Enhances Optic Nerve Regeneration If Retinal Ganglion Cells Are in an Active Growth State

Dietmar Fischer,^1,3 Zhigang He,^2,4,5 and Larry I. Benowitz^1,3,5

Department of ¹Neurosurgery and ²Division of Neuroscience, Children's Hospital Boston, Massachusetts 02115, and Departments of ³Surgery and ⁴Neurology and ⁵Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115

Mature retinal ganglion cells (RGCs), like other CNS neurons, cannot regrow injured axons into a myelin-rich environment. If stimulated by macrophage-derived factors, however, RGCs can regenerate their axons for considerable distances through the distal optic nerve. Using this "sensitized background," we investigated the effects of either increasing the expression or suppressing the activity of the Nogo receptor (NgR). NgR mediates the growth-inhibiting effects of three myelin proteins, Nogo, OMgp (oligodendrocyte-myelin glycoprotein), and MAG (myelin-associated glycoprotein). Transfecting growth-sensitized RGCs with adeno-associated viruses expressing a dominant-negative form of NgR (NgR^DN) increased axon regeneration several-fold; however, when the growth program of RGCs was not activated, NgR^DN expression had no beneficial effects. Overexpression of wild-type NgR blocked almost all regeneration from growth-sensitized RGCs and caused axons proximal to the lesion site to retract. We conclude that gene therapy is an effective approach to enhancing axon regeneration in the CNS and that inactivation of NgR functioning greatly enhances axon regeneration provided the intrinsic growth program of neurons is activated.

Key words: axon; macrophage; myelin; regeneration; retinal ganglion cell; virus; Nogo receptor; gene therapy; CNS; Nogo; MAG; OMgp

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Received Nov 19, 2003; revised December 17, 2003; accepted December 18, 2003.

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