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Te c t u m
Te c t u m
FIGURE 5.12 Actin filaments are necessary to guide growth cones. A. In the grasshopper limb, the Ti1
growth cones are hairy with active filopodia (top). If the growth cones are treated with the actin-depoly-
merizing agent, cytochalasin, the axon fails to navigate (bottom). B. In the vertebrate visual system, axons
enter the brain from the optic nerve and grow toward the tectum by growing dorsally and turning posteri-
orly (top). When these axons are treated with cytochalasin, the axons fail to make the appropriate posterior
turn, and most axons miss the tectum (bottom). (After Bentley and Toroian-Raymond, 1986; Chien et al., 1993)
where unpolymerized tubulin is fashioned into micro-
tubules and stabilized. Microtubules run straight and
parallel inside of the axon, but when they enter the
base of the growth cone, they splay out and bend like
soft spokes and sometimes appear as broken frag-
ments (Figure 5.10). Like the actin filaments in the
filopodia, the microtubules of the axons have a “plus”
end where polymerization takes place, and this is posi-
tioned at the growing tip. The fact that axons treated
with cytochalasin B continue to grow, albeit slowly, is
probably due to the distal growth of microtubules, as
depolymerization of microtubules inhibits axon elon-
gation completely (Marsh and Letourneau, 1984). The
control of microtubule assembly is partially controlled
by post-translational modifications that affect their
stability. A carboxyl terminal tyrosine is added to a-
tubulin by the enzyme, tubulin tyrosine ligase, inside
of the growth cone. The tyrosinated form of tubulin is
quite dynamic and sensitive to depolymerizing agents.
In contrast, tubulin loses the tyrosine group and
becomes acetylated instead when it enters the axon,
making axonal microtubules more stable (Brown et al.,
1992). Dynamic microtubules in the growth cones can
rapidly polymerize and extend transiently into the
P-zone. Dynamic microtubules can also go through
catastrophes, that is, rapid disassembly. This dynamic
instability of the tyrosinated microtubules is critical
for normal growth cone motility. If the dynamics
are altered with a reagent like taxol which stabilizes
microtubules growth cones advance more slowly
and become incapable of turning (Williamson et al.,
Experiments on the local microtubule dynamics
show that microtubules may be involved in growth
cone turning in a similar way to actin (Figure 5.14).
Thus, if the microtubule stabilizing agent taxol is deliv-
ered on one side of a growth cone, the growth cone will
turn in that direction, while if a depolymerizing agent
such as nocodazole is delivered to one side, the growth
cone will turn the other way (Buck and Zheng, 2002).
The similarity of the results with actin and microtubule
destabilizers means that each of these cytoskeletal ele-
ments may be able to work independently to produce
turning or that actin and microtubules interact in ways
that are critical for proper growth cone navigation. The
actin fibers at the periphery may restrict the dynamic
microtubules from invading peripheral domains. It is
thought that the myosin-driven retrograde flow of actin
at the leading edges bends and breaks the dynamic
microtubules and thus keeps many of them from suc-
cessfully invading the P-domain. But dynamic micro-
tubules continue to polymerize and probe the P-domain,
as though they were trying to get a foothold. There is
evidence that those microtubules that do successfully
invade the peripheral domain become associated with
actin bundles in a filopodium (Zhou and Cohan, 2004).
Such interactions then lead to the stabilization of the
both the microtubules and the actin bundles.
The keys to making the growth cone cytoskeleton
dynamic in this way are the numerous proteins that are
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