Elsevier

Experimental Neurology

Volume 287, Part 3, January 2017, Pages 365-373
Experimental Neurology

Review Article
Reaching the brain: Advances in optic nerve regeneration

https://doi.org/10.1016/j.expneurol.2015.12.015Get rights and content

Abstract

The optic nerve has been widely used to investigate factors that regulate axon regeneration in the mammalian CNS. Although retinal ganglion cells (RGCs), the projection neurons of the eye, show little capacity to regenerate their axons following optic nerve damage, studies spanning the 20th century showed that some RGCs can regenerate axons through a segment of peripheral nerve grafted to the optic nerve. More recently, some degree of regeneration has been achieved through the optic nerve itself by factors associated with intraocular inflammation (oncomodulin) or by altering levels of particular transcription factors (Klf-4, -9, c-myc), cell-intrinsic suppressors of axon growth (PTEN, SOCS3), receptors to cell-extrinsic inhibitors of axon growth (Nogo receptor, LAR, PTP-σ) or the intracellular signaling pathway activated by these receptors (RhoA). Other regulators of regeneration and cell survival continue to be identified in this system at a rapid pace. Combinatorial treatments that include two or more of these factors enable some retinal ganglion cells to regenerate axons from the eye through the entire length of the optic nerve and across the optic chiasm. In some cases, regenerating axons have been shown to innervate the appropriate central target areas and elicit postsynaptic responses. Many discoveries made in this system have been found to enhance axon regeneration after spinal cord injury. Thus, progress in optic nerve regeneration holds promise not only for visual restoration but also for improving outcome after injury to other parts of the mature CNS.

Section snippets

[Introduction]

The optic nerve is an integral part of the central nervous system (CNS) by virtue of its embryonic origin and cellular composition, and like most CNS pathways in mature mammals, it cannot regenerate if injured. Consequently, victims of traumatic or ischemic nerve injury or degenerative conditions such as glaucoma suffer irreversible losses of vision. Because of its unique accessibility, relatively simple anatomy, and functional importance, the optic nerve has become one of the principal systems

Developmental regulation of intrinsic growth capacity: role of Klf transcription factors

During the initial formation of visual projections, RGCs extend axons rapidly in vivo or when placed in culture (Chen et al., 1995, Goldberg et al., 2002a, So et al., 1981), and can regenerate injured axons in vivo, at least over short distances (Chen et al., 1995). The capacity for rapid axonal growth and regeneration are both lost in the early postnatal period at about the time when RGCs increase dendritic growth in the retina and synaptic inputs expand (Fig. 1A). Cell culture experiments

Axon regeneration in a peripheral nerve and CNS environment

Although mature mammalian RGCs are normally unable to regenerate axons through the optic nerve itself, a modest number of RGCs exhibit robust axon regeneration when given the opportunity to grow through a peripheral nerve graft sutured to the cut end of the optic nerve (Aguayo et al., 1991). If the distal end of the graft is directed into the superior colliculus, regenerating axons form synapses in anatomically appropriate layers (Aguayo et al., 1991). If the peripheral nerve graft is directed

Inflammation and oncomodulin induce optic nerve regeneration

Subsequent experiments showed that intraocular inflammation, induced either by injecting Zymosan into the eye or as a result of lens injury, is sufficient to cause RGCs to regenerate axons through the injured optic nerve (Leon et al., 2000, Yin et al., 2003). This growth is associated with a change in RGCs' intrinsic growth state, as evidenced by a massive upregulation of SPRR1A, GAP-43, and other gene products that are also known to be upregulated during axon regeneration in the peripheral

Other trophic factors

Ciliary neurotrophic factor (CNTF) has also been proposed to mediate the effects of intraocular inflammation on axon regeneration (Muller et al., 2007). However, although CNTF and related chemokines of the cardiotrophin family become elevated in the eye after intraocular inflammation (Kurimoto et al., 2013, Leibinger et al., 2009), many studies report only weak effects of intraocular CNTF on regeneration in vivo (Lingor et al., 2008, Pernet and Di Polo, 2006, Qin et al., 2013, Smith et al., 2009

Cell-intrinsic suppressors of regeneration

As noted above, SOCS3 is upregulated postnatally and suppresses the ability of RGCs to activate the Jak-STAT pathway (Park et al., 2009, Qin et al., 2013, Smith et al., 2009). Another potent suppressor of axon regeneration is PTEN, which inhibits protein translation by repressing the activation of PI3 kinase and downstream signaling via Akt, mTOR, and S6 kinase. Deletion of pten in RGCs activates this pathway and enables a few hundred α-RGCs to undergo considerable axon regeneration (Duan et

Cell-extrinsic inhibitors of optic nerve regeneration

In addition to cell-intrinsic factors that suppress axon regeneration, multiple molecules in the extracellular environment are inhibitory to axon growth. One of the primary suppressors of axon growth in the CNS is the myelin derived from oligodendrocytes. The inhibitory effects of myelin are linked to multiple molecules, including isoforms of the reticulon-like protein Nogo, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein (Schwab, 2002, Yiu and He, 2006). Although these

Relationship between RGC survival and ON regeneration

Although the ability of RGCs to regenerate axons clearly requires that the cells remain viable, the intracellular pathways that regulate axon regeneration and cell survival are at least partially distinct from one another. This is particularly evident when RGCs overexpress pro-survival members of the Bcl family, which strongly enhances RGC survival in cell culture or after optic nerve injury in vivo but does not promote axon regeneration in the absence of additional factors (Chierzi et al., 1999

Reinnervation of central visual areas and restoration of physiological responses

During the course of development, RGC axons are guided to their appropriate destinations by an intricate interaction between attractive or repulsive molecules along their trajectory and cognate receptors expressed on RGCs' growth cones (Feldheim and O'Leary, 2010, Osterhout et al., 2011, Rajagopalan et al., 2004, Schmitt et al., 2006). In fish and amphibia, RGCs regenerate their axons and restore visual functions after optic nerve injury even in the absence of outside interventions, implying

Future prospects

In the past two decades, the optic nerve has gone from being a paradigm of regenerative failure to one of the premier models of regenerative success in the CNS. Nonetheless, a great deal more remains to be learned if we are to restore vision in a clinically meaningful way. Studies to date have enabled only a small percentage of RGCs to regenerate axons to the appropriate target areas, and visual recovery will require that we increase the number of regenerating cells substantially. We do not yet

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