Regeneration of axons in the visual system

Issue title: Axonal Regeneraton and Repair of the central Nervous System

Article type: Research Article

Authors: Berry, Martin | Ahmed, Zubair | Lorber, Barbara | Douglas, Michael | Logan, Ann

Affiliations: Molecular Neuroscience Group, School of Experimental and Clinical Medicine, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

Note: [] Corresponding author: Professor M. Berry, MD, DSc, MRCPath, Molecular Neuroscience Group, 2nd Floor, IBR West, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Tel.: +44 121 414 8856; Fax: +44 121 414 8867; E-mail: [email protected]

Abstract: This review will describe the unique advantages that are offered by the visual system of mammals and other vertebrates for studying the regenerative responses of the central nervous system (CNS) to injury, and recent insights provided by such studies. In the mouse and rat visual system a variety of experimental paradigms promote survival of retinal ganglion cells (RGC) and optic nerve regeneration, probably through stimulation by neurotrophic factors (NTF) either directly, or indirectly through retinal astrocyte/Müller cell intermediary activation. NTF induce disinhibition of axon growth through regulated intramembranous proteolysis of p75^{NTR}, and the inactivation of RhoA and EGFR signalling. The concomitant release of metalloproteinases (MMP) and plasminogen activators from RGC axons, and tissue inhibitors of metalloproteinases from optic nerve glia repress scarring and thereby reduce titres of scar-derived inhibitory ligands expressed in the wound. MMP also degrade myelin-derived inhibitory ligands along regenerating axon trajectories after regulated release from glia at the growing front of regenerating RGC axons. Optic nerve transection induces apoptosis of RGC which is blocked by anti-apoptotic regimes and thus, in combination with blockers of axon-growth inhibitory signalling and promoters of axon growth may be a therapeutic formula for promoting sustained axon regeneration. All these findings in the visual system are translatable to the CNS as a whole and thus strategies that successfully promote visual axon regeneration will be equally effective elsewhere in the CNS. Future developments likely to advance the field of regenerative research include a greater understanding of phylogenetic differences in the response of the CNS to injury, the role of NTF, cAMP, EGFR, glia/neuron interactions in disinhibiting and promoting axon growth, the control of neuron death, and effective drug delivery.

Keywords: Axon regeneration, retinal ganglion cells, neurotrophic factors, axon growth inhibition, optic nerve injury, lens injury, regulated intramembranous proteolysis, axon growth disinhibition

Journal: Restorative Neurology and Neuroscience, vol. 26, no. 2-3, pp. 147-174, 2008