Axon Regeneration

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In the adult mammalian CNS, axons fail to regenerate following injury (Ramony Cajal, 1928; Aguayo et al., 1990). Axons that are cut find it difficult or impossible to cross the lesion site, and many neuronal cells whose axons are cut die as the result of the injury. This means that injuries that break axons in the spinal cord of an adult human can lead to permanent paraplegia or quadriplegia. Work on axonal regeneration is therefore of intense medical interest. The inability of adult central axons to regenerate is in stark contrast to the situation in the peripheral nervous system where regeneration is possible and the situation in lower vertebrates such as fish and amphibia. In these animals, for example, retinal ganglion cells are fully capable of regeneration (Piatt, 1955), and severing the optic nerve in a salamander, an insult that would lead to permanent blindness in an adult human, is followed by the regrowth of these axons and the restoration of vision. The failure of regeneration in the adult mammalian nervous system is also in contrast to the ability of the developing nervous system to send out long axons, and the capacity of central axons to regenerate is lost during the early stages of mammalian development (Kalil and Reh, 1982). It is as though there were a connection between evolution and development in the ability of axons to regenerate central axons. Perhaps the key to central regeneration is to find a way of making the damaged tissue act more like it did during the time when it was developing.

For both intrinsic and extrinsic reasons central neurons are incapable of regeneration. Let us look at the extrinsic factors first, because more work has been done on this aspect of the problem. Several lines of evidence point to the importance of extrinsic factors. For instance, the axons that are able to regenerate following a pyramidal tract lesion in neonatal hamsters or cats grow around the lesion site and are not able to penetrate the injury site (Bregman and Goldberger, 1983). Thus, there is thought to be something inhibitory at the lesion site. The importance of extracellular cues in vivo is clearly illustrated by the ability of peripheral nerve grafts to support central axonal regrowth (Richardson et al., 1980; David and Aguayo, 1981; Aguayo et al., 1990). In a set of classic studies, it was shown that while transected central axons were unable to grow within the CNS, they could grow for many centimeters through a sheath of nonneuronal cells that ordinarily provide insulation to motor axons in the periphery (Figure 5.38). Indeed, while embryonic and peripheral thoracic S spinal cord

sciatic nerve sheath anterograde-labeled axons thoracic S spinal cord sciatic nerve sheath anterograde-labeled axons

retrograde-labeled neurons

FIGURE 5.38 Central neurons in spinal tracts do not regrow long axons after they are transected, but if they are allowed to innervate a sheath of peripheral nerve, they can regrow over substantial distances. (After David and Aguayo, 1981)

retrograde-labeled neurons

FIGURE 5.38 Central neurons in spinal tracts do not regrow long axons after they are transected, but if they are allowed to innervate a sheath of peripheral nerve, they can regrow over substantial distances. (After David and Aguayo, 1981)

glial cells support neurite outgrowth, adult astrocytes and oligodendrocytes appear to inhibit neurite outgrowth. When a central nerve bundle is injured in a mammal, the axons are usually unable to regrow across the wound and thereby reestablish connections they had lost. Part of the problem, it appears, is the invasion of the wound site with various glia, which produce repulsive cues that the axons cannot navigate around. By X-irradiating mouse spinal cords during neonatal development, it was possible to create mice that are deficient in glial cells. In these animals, spinal axons regenerated past a transection point, a behavior that they never display in normal animals (Schwab and Bartholdi, 1996).

To find the molecular components involved in inhibiting central regeneration, the system was brought into culture where it was found that CNS neurons stop, and sometimes collapse, when they touch oligodendrocytes. Liposomes from these cells and preparations of myelin were used to identify an inhibitory factor that causes CNS growth cones to collapse. A monoclonal antibody to this factor, which is now called Nogo, was then made and tested in culture for its ability to block the collapsing activity. In the presence of antibody, axons grew over oligo-dendrocytes without stopping or collapsing. The antibody was then tested in vivo, using mice with partially severed spinal cords. In the presence of Nogo antibodies, many more axons were able to regenerate beyond the crush than in control animals, and there was considerable functional recovery suggesting that Nogo is a critical component of the failure of spinal regeneration (Schnell and Schwab, 1990; Bregman et al., 1995), although there has been some debate as to whether knocking out Nogo in mice leads to enhanced regeneration. The Nogo receptor was identified and found to be a receptor for other myelin-derived inhibitory factors such as Myelin Associate Glycoprotein (MAG), indicating that this receptor may provide an insight into where the signals that inhibit regeneration converge (Fournier et al., 2001).

Astrocytes often accumulate around CNS wounds, forming complex scars. These cells produce an extracellular matrix that is inhibitory to axon regeneration, and one of the key components of this inhibitory material may be chondroitin sulfate glycosaminoglycan chains found on many proteoglycans in the astroglial scar (Asher et al., 2001). Even when plated on the growth-promoting ECM component, laminin, spinal neurons stop growing when they confront a stripe of chondroitin sulfate. In culture, the inhibitory component can be digested away with chondroitinase, rendering the matrix more permissive to axon growth and regeneration. To see if chondroitinase could be used to treat models of CNS injury in vivo, rats whose spinal cords had been transected, were treated locally with the enzyme. Such treatment restored synap-tic activity below the lesion after electrical stimulation of corticospinal neurons and promoted functional recovery of locomotor activity (Bradbury et al., 2002).

It is clear that progress is being made on the extrinsic factors that inhibit axon regeneration, but there is still the problem that older central axons simply do not regenerate very well even when the conditions are good. Adult axons can grow for a short distance (<500 mm) in many central locations (Liu and Chambers, 1958; Raisman and Field, 1973). The growth of very young neurons does not appear to be so restricted in an adult nervous system. Human neuroblasts are able to form long axon pathways when transplanted into excitotoxin-lesioned adult rat striatum (Wictorin et al., 1990). Similarly, mouse embryonic retinal ganglion cells are able to grow long distances within the rostral midbrain of neonatal rats and selectively innervate some normal targets (Radel et al., 1990). Indeed, myelin inhibits regeneration from old but not young neurons. What do these young axons have that older axons do not? It was found that the levels of cAMP in young growth cones are much higher than in older axons (Cai et al., 2001). By increasing the cAMP levels, one can turn old neurons into neurons that behave more like young ones in terms of their regenerative potential (Qiu et al., 2002). Moreover, the recovery from spinal injury in neonatal rats is markedly reduced by lowering cAMP levels.

Another key intrinsic difference between old and young axons may have to do with protein synthesis. Young growth cones are full of protein synthetic machinery, but the axons of older neurons do with less of such machinery. There appears to be a good correlation between the ability of a growth cone to make new proteins and its ability to regenerate in vitro. The challenge now will be to find ways to crank up the protein synthetic machinery in the growth cones of damaged CNS neurons to see if this can aid recovery. When considering all these data, it seems that full recovery after an injury may require a strategy for dealing with both intrinsic and extrinsic factors.

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