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Unc-5, but it can also be mediated by DCC alone,
depending on the level of intracellular cAMP (Ming et
al., 1997). When cAMP inside the growth cone is high,
Netrin acts like an attractant to spinal and retinal axons,
but when cAMP is experimentally lowered using drugs
that block adenylate-cyclase, then the response to
Netrin by the very same axons is one of avoidance and
repulsion (Figure 5.37). Similarly, many other attrac-
tants can be switched to repellents by pharmacologi-
cally down-modulating cAMP in growth cones. One
hypothesis for how this works is that the signal from the
guidance receptor catalyses cytoskeletal polymerization/
depolymerization reactions. In high cAMP this reaction
favors polymerization, while in low cAMP it favors
depolymerization (Ming et al., 1997; Song et al., 1997).
Although some guidance cues are primarily modulated
in this way by cAMP, others such as NGF and Sema3A
are modulated by cGMP (Song et al., 1998).
How might this modulation happen in vivo?
Earlier, it was noted that the combination of Netrin and
laminin is repulsive to retinal axons and drives them
from the retinal surface into the optic nerve. Laminin
dramatically reduces the cAMP level in these growth
cones, so that when these retinal axons are grown on
high levels of laminin in vitro, the cAMP level in the
growth cones is low and Netrin is repulsive (Hopker
et al., 1999). If the cAMP level is artificially raised, retinal
growth cones on laminin are once again attracted to
Netrin. If the same neurons are grown on low levels
of laminin or fibronectin, cAMP is high in the growth
cone, and Netrin is attractive, but this can be switched
by experimentally lowering cAMP. So it seems that
environmental cues, such as which ECM molecules the
growth cones are most exposed to, can modulate
whether a guidance cue is attractive or repulsive.
As axons grow past intermediate targets, such as
the optic nerve head, they are also getting older and
maturing. This intrinsic aging process may also affect
their internal cAMP levels and thus the way an axon
responds to a guidance cue like Netrin. By the time
retinal axons enter the brain, they are no longer
responsive to Netrin (even if they are grown on low
levels of laminin), and by the time they reach the
tectum Netrin is repulsive. This change in responsive-
ness happens in a stage-dependent way even in iso-
lated retina explants where the axons are not exposed
to the optic pathway (Shewan et al., 2002). Another
way that growth cones can change their sensitivity to
a particular guidance cue is to make or degrade pro-
teins that are critical for responding to the cue, such as
a receptor. Retinal growth cones do not “see” Sema3A
in their pathway until they grow along the optic tract.
At early stages of pathway navigation, retinal axons do
not express Neuropilin, the Sema3A receptor, and so
Sema3A is neither attractive nor repulsive to them.
However, by the time these axons have entered the
optic tract, they express Neuropilin and are repelled by
Sema3A (Campbell et al., 2001).
It was initially thought that all proteins in the
growth cone were made in the cell body and shipped
to the growth cone. It now appears that the growth
cone is full of mRNAs, ribosomes, and other transla-
tional machinery, and can respond to guidance cues
by making new proteins that are involved in growth
and navigation (Campbell and Holt, 2001). Growth
cones also have degradation machinery, including
ubiquinating enzymes and proteosomes (Campbell
and Holt, 2001). Both synthesis and degradation can
be activated in growth cones by guidance cues, and if
either process is experimentally inhibited, a number of
guidance cues become completely ineffective, suggest-
ing that growth cone navigation may depend on
the local manufacture and degradation of proteins.
mRNAs, such as beta-actin mRNA, which code for
FIGURE 5.37 cAMP modulates growth cone turning. A. When internal cAMP is high, the growth cone
of embryonic spinal neurons grows toward a source of Netrin, ejected by a pipette. B. When cAMP is phar-
macologically lowered, the same neurons are repelled by Netrin. (After Ming et al., 1997)
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