One of the effects following optic nerve axon injury is RGC death, which can be seen in histopathological samples from human optic neuropathies (7) and can be studied in greater detail in animal models. For example, in adult rats, 85%-90% of RGCs die by 2 weeks after crushing or cutting the optic nerve (Fig. 2) (8). The more distant the injury from the eye, the less the severity of initial RGC death (8-10), possibly due to the support of optic nerve glial cells (see below, Fig. 1) or persistence of collateral axon branches to other supportive targets (11). The majority of dying RGCs undergo apoptosis, or programmed cell death (8,9,12). After RGC injury, there is an upregulation of proapoptotic proteins (8,13,14); conversely, overexpression of antiapoptotic proteins, such as Bcl-2, results in an increased survival of injured RGCs (15,16). Alternatively, some RGCs undergo necrotic death or secondary degeneration after optic nerve injury but in minimal numbers (17). Depending on the location of the injury, at the cell body or along the axon, activation of distinct RGC death pathways occurs (18).
Axon injury disrupts the connections of RGCs to their target, resulting in a loss of target-derived neurotrophic support. Target-derived signals are retrogradely transported to the cell body and are hypothesized to be required for neuronal survival (19-23). Removal of this support leads to apoptosis, and addition of exogenous neurotrophic factors increases survival and regeneration (24). One of the neurotrophins shown to regulate RGC survival is brain-derived neurotrophic factor (BDNF), expressed in both the retina and the superior colliculus, which is targeted by approximately 100% of RGC axons in the rodent and about 30% of RGC axons in humans. BDNF supports RGC survival in vitro (25,26) and in vivo (27) by binding to its receptor, tropomyosin receptor kinase B (trkB), resulting in activation of downstream effectors, including the Ras-MAPK and PI3K-Akt pathways. The increased survival after axotomy following BDNF application appears to be due to a combination of these 2 pathways (28).
Would trophic factor injection alone be enough to save RGCs? After optic nerve injury, intraocular injection of BDNF neurotrophin 4/5, nerve growth factor, or insulin-like growth factor 1 leads to a temporary increase in the RGC survival (8,13,27,29-33). For example, with application of BDNF or ciliary neurotrophic factor (CNTF), 25% of RGCs are alive at 3 weeks, when nearly all RGCs without treatment would be dead, but by 7 weeks, 95% are dead with or without treatment (27). Sustained overexpression of trophic factors does not solve this problem. For example, transducing other retinal cells, such as Muller glial cells, to overexpress BDNF is neuroprotective for RGCs, but these effects do not persist (29). Neurotrophic factors, such as glial-derived neurotrophic factor (34-36) and CNTF (27,37,38), have also been found to increase RGC survival after injury.
The failure of neurotrophins to support sustained RGC survival may also be due to a decreased ability of RGCs to respond to neurotrophins following optic nerve axon injury (48). After optic nerve injury in animal models, RGCs lose their trophic responsiveness, such that they are unable to respond to neurotrophic factors or activate their downstream intracellular signaling components, even in the presence of BDNF, for example (26,49). This trophic responsiveness can be restored by increasing the number of trkB receptors present on the plasma membrane, either by directly overexpressing them (50) or by enhancing their recruitment to the surface. Surface recruitment can be elicited by elevating RGCs' intracellular cyclic adenosine monophosphate (cAMP) levels by pharmacologic treatment or depolarization (26,49). RGCs exhibit a decrease in cAMP levels after injury, possibly due to decreased electrical activity (49). These findings suggest a therapeutic approach, that is, to increase RGCs' cAMP levels after injury, although cAMP injections alone do not increase survival (51) and may need to be accompanied by neurotrophic factors.
Trophic responsiveness and neuroprotection of RGCs after axon injury can also be enhanced by electrical stimulation (52). RGCs are less electrically active after optic nerve injury (53). Increasing activity through electrical stimulation increases cAMP levels in RGCs (49) and greatly potentiates the neuroprotective effects of neurotrophic factor treatment (54), possibly by increasing the number of neurotrophin receptors on the neuronal surface (26). In the peripheral nervous system (PNS), electrical stimulation after injury results in an accelerated expression of regeneration-associated genes (55,56), suggesting that electrical activity may also positively influence axon growth. Recent studies have shown that transcorneal stimulation after optic nerve crush increases not only the number of surviving RGCs but also the number of axons projecting past the lesion (57,58). This experimental result suggests that electrical stimulation may be used as a therapeutic strategy to increase RGC survival and growth in future studies.
In addition to the loss of positive signals such as trophic support and electrical activity, there is an increase in negative prodeath signals after optic nerve injury. For example, there is an increase in superoxide levels in RGCs from the mitochondrial electron transport chain; blocking this increase leads to a reduction in RGC death (59). Providing extra neurotrophins cannot block this increase in superoxides (59), suggesting that the cell death pathway for trophic factor withdrawal is separate from that of free radical-induced cell death. Treating RGCs with novel reducing agents to block this rise in superoxides is neuroprotective in RGCs at low doses (60).
These studies suggest that there are multiple strategies for increasing RGC survival after injury, including elevating cAMP, providing multiple exogenous trophic factors, electrically stimulating RGCs to increase their activity, and reducing superoxide levels. It is likely that combinations of these strategies will be required to optimally increase RGC survival and regeneration. Some of the same signals that increase survival also increase the RGC ability to regenerate (48).
After injury anywhere in the adult central nervous system (CNS), the ability of axons to regenerate is actively inhibited by the mature CNS environment and the cellular response to injury (Fig. 3). The response by meningeal cells, microglia, oligodendrocytes, and astrocytes can include migration to the site of injury, proliferation, and changes in cellular morphology and protein expression. The expression and secretion of inhibitory molecules and proteins, and the presence of myelin debris, create an unfavorable environment for axon regeneration in the CNS. These inhibitory phenomena do not occur in the PNS, where axons regenerate after injury. One difference between the CNS and PNS is the makeup of the glial cells. Whereas peripheral nerve Schwann cells are supportive of axon growth due to their secretion of neurotrophins and lack of associated inhibitory factors, optic nerve oligodendrocytes and reactive astrocytes are inhibitory to axon growth, expressing many inhibitory proteins, as has also been demonstrated throughout the brain and spinal cord (61).
Damaged oligodendrocytes degenerate after injury, leaving myelin debris containing inhibitory proteins such as Nogo-A, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (Omgp) at the site of injury. Astrocytes, however, respond to injury by becoming hypertrophic and proliferating, forming a “glial scar” at the optic nerve injury site. Astrocytes release inhibitory extracellular matrix molecules, such as chondroitin sulfate proteoglycans (CSPGs), creating a molecular barrier to regeneration (61). In the spinal cord, treatment with a bacterial enzyme chondroitinase ABC degrades the sulfated glycosaminoglycan side chains and can partially interfere with this inhibition (62). In addition to actively inhibiting axon growth, CSPGs may also mask growth-promoting proteins such as laminin (63) or may change normally growth-attracting proteins like semaphorin 5A into repulsive cues (64). Other semaphorins secreted from infiltrating meningeal cells and expressed by oligodendrocytes and neuroepithelial cells also inhibit axon regeneration (65,66). Some of these inhibitory molecules are used as guidance cues during development and may be reexpressed after injury. For example, semaphorin 3A acts as a repulsive guidance cue during development (67) but is also upregulated after injury, inhibiting axon regeneration (68). The expression of netrin-1 at the optic nerve head, which normally attracts RGC axons to exit the retina and grow into the optic nerve in early development, becomes an inhibitory signal in the later life due to the low levels of cAMP in adult RGCs (69). The complexity with which these inhibitory proteins interact with RGCs needs to be further defined.
Pretreating neurons with neurotrophins prior to exposure to MAG and myelin decreases their ability to inhibit axon growth. Neurotrophin pretreatment increases levels of intracellular cAMP (76), and a developmental decrease in cAMP correlates with a developmental increase in the negative response to MAG/myelin (77). These phenomena identify cAMP as an important modulator of axon growth after injury.
Many of these inhibitory environmental signals converge on a downstream target called Rho, a small GTPase (78). Targeting a convergent downstream signal relieves the need to block each glial-associated inhibitor separately. Rho signaling leads to actin cytoskeleton remodeling (79) and growth cone collapse (80). Experiments inactivating Rho with C3 transferase, which ribosylates Rho proteins, showed increased regeneration of CNS fibers (81-84) when Rho was inactivated soon after injury (85). Multiple injections of this inhibitor after injury also increased RGC survival (85). The combination of Rho inactivation, overexpression of CNTF, cAMP treatment, and peripheral nerve grafting after axotomy enhanced viability as well as increased regeneration of those surviving fibers (86). Recently, collapsin response mediator protein 4b (CRMP4) was identified as interacting with Rho to carry out its inhibitory functions. Knockdown of CRMP4 or blocking of CRMP4 and Rho interaction resulted in attenuation of inhibition from myelin substrates, identifying an even more specific therapeutic target (87). Inhibition of ROCK, a downstream effector of Rho, has also shown promising results in overcoming environmental inhibition and promoting neurite outgrowth both in vitro and in vivo (38,88-93).
Besides activation of RhoA by these inhibitory environmental signals, there is an increase in intracellular calcium that may be involved in the downstream activation of the epidermal growth factor receptor (EGFR) and protein kinase C (PKC), although whether these 2 are interrelated has yet to be determined. Inhibition of PKC activity by CSPG and myelin-based activation increases regeneration in dorsal column axons (94). Inhibiting EGFR pharmacologically after optic nerve crush blocks myelin and CSPG inhibition on neurite growth and promotes regeneration of RGCs (95), although this EGFR inhibitor may be acting through other mechanisms (96,97). A number of drugs that block the responses of RGCs and other CNS neurons to inhibition are now in clinical trials for spinal cord injury, and identification of further downstream targets of inhibitory signaling will create more specific therapeutic targeting strategies for future studies (98).
Not all the cellular responses to injury or disease are negative or inhibitory. For example, macrophages associated with inflammation can potentially be neuroprotective and induce axon outgrowth (99). Macrophages are recruited with lens injury and elicit an 8-fold increase in RGC survival and a 100-fold increase in regeneration of RGC axons past the site of an optic nerve crush (100-102). Similar macrophage activation can be elicited by injection of zymosan, a yeast cell wall preparation that activates macrophages (101,103,104). How does lens injury create these effects? Macrophages migrating into the retina express oncomodulin, which causes extensive outgrowth of RGCs (with concurrent elevation of cAMP) after optic nerve crush in the adult optic nerve (105). However, activated macrophages and oncomodulin may not be the primary effectors of increased regeneration after injury (106). Combinatorial approaches may further enhance regenerative response, as by using macrophage-derived factors to “sensitize” neurons prior to dominant-negative suppression of the activity of NgR (107) or in combination with Rho inactivation (108).
The immune system has recently been targeted for clinical trials in optic nerve neuropathies and spinal cord injuries. Immunization with a peptide derived from Nogo-A, an inhibitory protein present on myelin, can increase recovery after spinal cord injury (109). In addition, vaccination with copolymer 1 (Cop-1), a synthetic chain of amino acids that cross-reacts with myelin basic protein, could activate the immune system and decrease secondary degeneration of surviving fibers after optic nerve injury. Cop-1 is a drug presently used to treat multiple sclerosis and is not known to create any additional immunogenic effects, making it a good candidate for clinical testing (110). Clinical trials were started for Cop-1 treatment in progressive optic nerve degeneration and started but suspended for transplantation of autologous activated macrophages into the injured spinal cord (111). Further studies to find additional proteins released following lens injury or macrophage activation may reveal potential candidates involved in increasing CNS survival and regeneration.
Bypassing the inhibitory optic nerve environment entirely is the oldest approach. As early as 1911, Tello (112) used peripheral nerve grafts attached to cut optic nerve to demonstrate that RGCs could regenerate a short distance if given a permissive substrate. Such experiments were rejuvenated by Aguayo et al (113) in the 1980s, using sciatic nerve transplants to connect the retina to the superior colliculus. Although the majority of RGCs died as a result of the optic nerve injury, replacement of a portion of the injured optic nerve with a piece of peripheral nerve enabled about 20% of the surviving RGCs to regrow long axons back to their targets. This process took approximately 2 months (114-116).
The less inhibitory environment of the peripheral nerve, as well as the trophic environment secreted by Schwann cells, creates a very permissive substrate for growth. In addition, the peripheral nerve graft may act to change the role of cells already present in the injured optic nerve. Whereas astrocytes typically respond to CNS injury by hypertrophy, proliferation, expression of inhibitory proteins such as CSPGs, and creation of a glial scar in peripheral nerve grafts, astrocytes were found to encircle axonal bundles and act in conjunction with the Schwann cells of the peripheral nerve to guide those axons, which regenerated through the peripheral graft, ultimately changing the environmental response at the injury site (117).
In addition to peripheral nerve grafts, other substrates have been grafted in experiments to increase RGC outgrowth and regeneration. Transplanted perinatal optic nerves (118), RGC target tissue from fetal brain (119-122), cell transplants (123-125), various bridge matrices containing Schwann cells (126-130), exogenously delivered neurotrophic factors (131-134), olfactory ensheathing cells (135,136), and peripheral nerve transplants into the vitreous (137,138) have shown varied results. The graft and transplantation studies have shown that, at a minimum, some CNS neurons can regenerate to their targets. It is now important to determine if these techniques can be translated into therapeutic treatments for patients.
In nearly all the experiments described above, only a small percentage of RGCs have regenerated and typically very slowly, even when some of the inhibitory signals have been neutralized. Could it be that the adult neurons have lost their capacity to regrow axons? In spinal cord injury studies in cats, the neonatal nervous system retains its ability to regenerate, but this ability is lost as the animals develop (139). This finding was confirmed in rats whose spinal cords were injured at birth or in adulthood, demonstrating that the neonatal CNS retains the ability to regenerate, whereas the adult CNS does not (140). Is this simply because the adult glia turned on their expression of inhibitory molecules? This question has been addressed by using “heterochronic cultures,” in which tissues from younger and older animals are cocultured. For example, embryonic retinal explants can extend axons into embryonic or adult brain explants, but adult retinal explants cannot extend axons into either, suggesting that the problem is with the retina or RGCs (141). Similarly, coculturing mature postnatal explants with young environmentally permissive explants have demonstrated a differential effect of tissue age on regenerative ability in hippocampal (142), cerebellar (143,144), and hindbrain tissues (145). Such studies have suggested that intrinsic changes within the neurons themselves limit their regenerative ability.
Pure RGC cultures were finally used to demonstrate definitively that RGCs turn off their intrinsic capacity for rapid axon growth during early development. To remove all influence of any potential extrinsic inhibitory environment, RGCs from embryonic or postnatal ages were purified away from all other cell types, allowing the study of their intrinsic axon growth capacity. Whether cultured in a strongly trophic environment or even transplanted back in vivo, purified embryonic RGCs extended their axons up to 10-fold faster than postnatal or adult RGCs (Fig. 4) (146). Altering the extrinsic environment did not change this fundamental observation, pointing to intrinsic limitations in RGC axon growth ability. Additionally, it was found that this developmental decrease can be initiated by a membrane-associated signal on presynaptic amacrine cells (Fig. 1) (146). These findings confirm the in vivo and in situ experiments, suggesting that a developmental program in RGCs is involved in their inability to regenerate.
One method of increasing intrinsic axon growth ability may be to alter the expression of specific genes that are upregulated or downregulated during development or after injury or in disease. For example, overexpression of Bcl-2, an antiapoptotic gene whose expression is decreased developmentally, increases RGC survival and slightly increases the regenerative capacity of RGCs in tissue explants (147). In vivo, Bcl-2 overexpression increases regeneration of RGC axons after injury in early postnatal rodents but not in later postnatal rodents, even when the negative influence of astrocytes is minimized (148). Using lithium to induce Bcl-2 expression and removing astrocytes at the injury site by means of an astrocyte toxin resulted in an increase in optic nerve regenerations but did not increase RGC survival (149). Bcl-2 may yet be a promising target to increase RGC survival and possibly regeneration in vivo despite these mixed results.
The levels of cAMP within neurons also appear to be developmentally regulated such that embryonic neurons have high cAMP levels that drop sharply postnatally and remain low throughout adulthood (77). The response of these neurons to MAG/myelin is also dependent on the neuron's stage of development and the neuron's intrinsic level of cAMP, as described previously (77). Embryonic axons, possessing endogenously high cAMP levels, are promoted by MAG/myelin, and this effect requires the activation of the transcription factor cAMP response element-binding protein (CREB) (150). CREB's upregulation of arginase I (Arg I), an enzyme that synthesizes polyamines, may be a part of the molecular pathway involved in overcoming myelin inhibitors (150-152). The expression profile of Arg I parallels that of cAMP levels during development, and its overexpression is sufficient to block the switch from promotion to inhibition by MAG/myelin (150,151). Therefore, the change in cAMP levels and downstream effectors during development is a switch that allows neurons to respond differently to extrinsic inhibitory environments (77,151).
Other developmentally regulated signaling pathways could be important in axon regeneration. For example, the activation of the MAP kinase pathway was recently found to be important in the regeneration of motor neurons in Caenorhabditis elegans (153). The Dlk-1/MKK-4/PMK-3 MAP kinase pathway was found to be required for axon regeneration and also for normal growth cone formation and morphology. This pathway was not necessary during development, suggesting that there are specific signaling pathways activated during regeneration that are separate from those activated during development (153). Dlk has also been shown to be important for the degeneration of severed axons, a necessary component in successful regenerative systems, clearing the way for regeneration following injury (154). Thus, the effect of Dlk seen in regeneration could be due, at least in part, to its effect on degeneration.
Another signaling pathway that is developmentally regulated centers on the mammalian target of rapamycin (mTOR) protein. Deleting the phosphatase and tensin homolog protein or the tuberous sclerosis complex 1, both of which normally inhibit mTOR, leads to a dramatic increase in the number of regenerating axons after optic nerve injury, as well as to an increase in RGC survival (155).
In the cerebellar granule neurons (another type of CNS neuron), the ubiquitin ligase Cdh1-anaphase promoting complex (Cdh1-APC) and its downstream targets have been identified as important players in the intrinsic regenerative ability of CNS neurons. Cdh1-APC was first identified to be a cell cycle ubiquitin ligase; however, a new role for this complex has been discovered in regulating axonal growth, in particular for axon growth inhibition (156-160). Cdh1-APC targets the inhibitor of differentiation 2 (Id2) for degradation, releasing a basic helix-loop-helix transcription factor (E47) to upregulate genes involved in axon growth inhibition, including NgR (157). Cdh1 also targets the transcription factor SnoN, whose degradation results in reduced axonal growth (158). These results suggest that the loss of intrinsic axon growth ability could be induced by critical transcriptional changes. It is not known, however, if these pathways function similarly in RGCs.
Our lab has recently found that a family of transcription factors, called Krüppel-like factors (KLFs), may affect axon growth ability during development and regeneration. There are 17 members of the KLF family; 15 are expressed in RGCs, and many of these are developmentally regulated (161). For example, the expression of KLF4 and KLF9 increases during postnatal development. When overexpressed in RGCs, these KLFs decrease neurite growth significantly. Using a gene knockout of KLF4 in RGCs, we have found that removal of KLF4 increases neurite growth of RGCs in vitro, and more importantly, increases axon regeneration after optic nerve injury. Taken together, these results suggest that the KLF family of transcription factors may be involved in the loss of intrinsic axon growth ability seen during development in RGCs.
The presence of such a large number of signaling pathways, proteins, and transcription factors suggests that not one single target will be adequate to increase optic nerve regeneration. Coaxing RGC axons through an injured or degenerating optic nerve may take a multifactorial approach, addressing RGC survival, glial inhibitors, and RGCs' intrinsic capacity for rapid axon regeneration.
Work on regeneration is in too early a stage to permit predictions on what will happen “postregeneration.” However, much is known about developmental mapping from which assumptions can be drawn. For example, during embryonic development, RGC axons are attracted to the optic nerve head by glial cells expressing netrin-1 (162). Half of these axons are guided by ephrin B2 ligands to remain ipsilateral at the optic chiasm (163) and are funneled within the optic nerve by semaphorin 5A, expressed by neuroepithelial cells (164), and Slit (165-167). To keep spatial orientation intact, RGC axons must topographically map onto the superior colliculus, their target in the midbrain. This mapping occurs through gradients of ephrin ligands, which create the specificity of the visual map, allowing RGCs to communicate their positional relevance (168).
Experiments have shown that after deafferentation of the superior colliculus (the major target for RGCs in rodents), there is reexpression of some of the same guidance cues, creating a crude topographic map (169-172). After optic nerve injury, ephrin A2 expression in the superior colliculus is upregulated (173-175). If RGC survival is enhanced, RGCs express the appropriate Eph A5 receptors in a gradient that mimics development (176). Other developmental guidance molecules such as ephrin B1, however, are only minimally expressed in the adult and deafferented superior colliculus (175). In experiments in which a small percentage of regenerating axons were able to reach their target through peripheral nerve grafts, functional synapses were identified at the target tissue (177-183), although the axonal arbors made by these neurons were much smaller than normal (184). The fibers that reinnervated the superior colliculus created a rough topographic map, suggesting that developmental cues may be reexpressed in the target tissue to allow for appropriate mapping (172). Additional grafting studies connecting a severed optic nerve with the pretectum (important for pupillary reflexes) revealed a restoration of a functional pupillary reflex after 2-4 months (182,185,186), supporting the notion that regenerating axons can functionally reinnervate their target tissues. Taken together, these findings suggest that if RGCs can be promoted to regenerate, there are some developmental cues available to guide axons back to their targets and possibly re-create topographic maps of visual space.
Promoting optic nerve regeneration may seem an insurmountable task. Research in the field of CNS regeneration suggests that we must simultaneously address RGC death after optic nerve injury, the inhibitory glial environment, and changes in the RGCs' intrinsic potential for axon regeneration. We must ultimately think about how regenerating axons may innervate their targets in the brain. With a number of these approaches entering into human clinical trials in the optic nerve or the spinal cord, and with many new technologies and strategies, we are getting closer to offering real hope to those with optic nerve disease.
The authors are especially indebted to Mary Jo Adams-Kocovski for graphic design (Fig. 1), to Ying Hu for use of images (Figs. 2 and 3) and to Timothy Boyce for assistance in preparing figures.
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