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A Pausing growth cone
B Developing branch
C Elongating branch
FIGURE 6.6 Axons branch at pause points. A. A growth cone pauses, microtubules splayed. B. The growth
cone moves on but leaves behind it a zone where the cytoskeleton remains somewhat disorganized. C. A
branch forms at this zone. (After Dent and Kalil, 2001)
1997). In these mice, axons that are normally restricted
from innervating skin that expresses Sema3a now
enter these territories. Sema3a is also expressed at
the posterior boundary of the olfactory bulb, where
it seems to act to restrict olfactory axons to the bulb,
preventing them from entering the telencephalon
(Kobayashi et al., 1997). The repulsive molecule
Ephrin-A5, which we will discuss in more detail below
with respect to topography, reaches its highest con-
centration just posterior to the superior colliculus or
tectum, the target of retinal axons, suggesting that this
ligand may also serve as a factor that confines these
axons to the target. Recent studies show that retinal
axons extend freely beyond the posterior border of
the superior colliculus in Ephrin-A5 knockout mice
(Frisen et al., 1998).
This raises the question of whether this type of
mechanism is used to help segregate neural circuits
that carry different kinds of information to different,
but nearby, centers of the brain, thus preventing inap-
propriate targeting. Re-innervation and cross-innerva-
tion experiments show that when the normal targets
of axons have been surgically removed, functional
synapses can indeed be made on the wrong targets.
Similarly, when the brain is injured, the normal targets
of some axons may die and nearby regions may
become denervated. In these cases, axons that origi-
nally innervated the injured areas may sprout new
growth cones to invade denervated but inappropriate
targets. To test how promiscuous axons are, and whom
they will synapse with if given the chance, one can
test a variety of foreign targets with different axonal
populations. For example, to know how determined
retinal ganglion cell axons are to invade a specific
target, one of their normal targets, the visual thalamus,
was left to degenerate by ablating the visual cortex and
a neighboring nonvisual area, the somatosensory thal-
amus, was denervated (Metin and Frost, 1989). In this
case, retinal axons innervated the somatosensory thal-
amus (Figure 6.7). In a similar experiment, retinal gan-
glion cell axons innervated the auditory thalamus (Roe
et al., 1992). The thalamocortical connections have not
been changed and are basically normal in these
animals, giving rise to the weird condition that these
animals process visual information in the somatosen-
sory or auditory cortex, thus perhaps having the con-
scious sensation of feeling or hearing the visual world
(Figure 6.7). Normally, of course, the nuclei of the thal-
amus have modality-specific innervation. The ques-
tion is whether segregation is a result of molecular
barriers that normally separate these brain areas. It is
interesting to note, then, that high levels of Ephrin-A2
and Ephrin-A5 define a distinct border between the
visual and auditory thalamus. If the normal input to
the auditory thalamus is denervated and the visual
thalamus is spared, retinal axons seem happy to
remain in their uninjured normal targets. However,
when this experiment is done in knockout mice that
lack both Ephrin-A2 and Ephrin-A5, there is extensive
rewiring and retinal axons invade and innervate the
deafferented auditory thalamus (Lyckman et al., 2001)
(Figure 6.7). These findings suggest that signals that
induce innervation may compete with barriers, such as
repulsive guidance molecules, that serve to contain
axons within the normal targets.
Border patrol is not the only mechanism for main-
taining appropriate targeting. In cross-innervation
experiments in amphibians, in which extensor motor
nerves are forced to innervate flexor muscles and
flexor motor nerves are forced to innervate extensor
muscles, the animals develop expected inappropriate
motor behaviors after surgery. Interestingly, however,
normal behavior usually recovers after a rather long
period of time. This was first interpreted as the animals
learning to use these muscles in a new way, but
detailed anatomical investigations of these animals
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