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need for guidance cues, and we have seen a variety of
cues attached to the extracellular matrix and cell sur-
faces, and as diffusive gradients of guidance molecules.
Some of these factors promote growth and adhesion,
and others inhibit growth and adhesion. We suggested
that these various signals had to be integrated and com-
municated to the motor, and we have seen a variety of
intracellular agents in the growth cone that can be regu-
lated in response to external cues and communicated to
the active cytoskeleton. We are, however, still a long
way from understanding how axons grow to their
targets. The molecules mentioned in this chapter are
used only in some neurons, and it is fair to say that for
even the best studied neurons, we understand only
small parts of their navigation, but not their entire
route. Many more guidance factors are known but are
not mentioned in this chapter, and many others remain
to be discovered. Our insights into how these cues reg-
ulate growth and guidance are still in their infancy but
it is possible that these insights will bring us closer to
understanding how to rejuvenate adult neurons so that
they can regenerate.
BOX 1
AXON REGENERATION
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 restora-
tion 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 con-
nection 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 some-
thing inhibitory at the lesion site. The importance of extra-
cellular 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 cen-
timeters through a sheath of nonneuronal cells that ordi-
narily provide insulation to motor axons in the periphery
(Figure 5.38). Indeed, while embryonic and peripheral
anterograde-labeled
axons
medulla
HRP
thoracic
spinal
cord
~25 weeks
sciatic nerve
sheath
retrograde-labeled
neurons
leg
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 sub-
stantial distances. (After David and Aguayo, 1981)
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