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proteins that form the growth cone filopodia, are selec-
tively transported to growth cones (Bassell et al., 1998),
a finding that suggests that the concentration of
cytoskeletal components in the growth cone may be
affected by guidance cues. Another way that local
protein synthesis might be involved in guidance is in
the manufacture of new receptors once growth cones
have reached intermediate targets; this would allow
them to become sensitive to new guidance cues on the
next leg of the journey (Brittis et al., 2002).
Various studies have shown that growth cones
adapt to guidance cues. For example, if a growth cone
bumps into an axon with a repulsive guidance cue (as
mentioned above), it will collapse and retract. When it
regrows, it may run into the same axon again and
repeat the collapse to regrowth cycle. However, after
several such cycles, it has been observed that growth
cones generally become desensitized to the collapse-
inducing factor and are able to grow over repulsive
axons (Kapfhammer et al., 1986). In another study,
axons were tested to see how far they would crawl
along a membrane on which there was an increasing
gradient of the repulsive guidance factor, EphrinA.
Axons were started on a platform of different levels of
EphrinA, and those that started on higher concentra-
tions ended up growing the farthest, suggesting that
they had partially adapted to EphrinA (Rosentreter et
al., 1998). Adaptation can be subdivided into two parts,
desensitization followed by resensitization. Recent
work suggests that desensitization involves the inter-
nalization and degradation of receptors to guidance
factors (Piper et al., 2005), while resensitization
involves making new proteins that counteract this
process (Ming et al., 2002; Piper et al., 2005). Growth
cones can thus adjust the levels of the proteins that are
critical for axon navigation. When this is added to the
ability of growth cones to regulate cyclic nucleotides
that can rapidly mediate a switch between attraction
and repulsion, the picture that emerges of the growth
cone is that of a very autonomous machine capable of
continually redefining itself as it navigates through the
embryonic brain.
growth factors are received by receptors on the surface
of the growth cone. Many such receptors have intra-
cellular domains that have enzymatic activity when
an extracellular ligand is bound and are thus able to
amplify the signal (Strittmatter and Fishman, 1991).
For example, the Robo receptor has one kind of intra-
cellular domain that mediates a repulsive response
to Slit, while the Frazzled receptor (the Drosophila
homolog of DCC) has a different intracellular domain
that mediates attraction to Netrin. The specific action
of these intracellular domains is made clear in experi-
ments where domains are switched, as in Robo-Fraz-
zled fusion proteins (Bashaw and Goodman, 1999),
where the intracellular domain of Frazzled is fused
with the extracellular domain of Robo, the repulsive
Slit receptor, which makes neurons attracted to Slit.
Similarly, neurons expressing Frazzled-Robo fusion
proteins are repelled by netrin.
Receptors that have intracellular tyrosine kinase
(RTKs) or tyrosine phosphatase (RTPs) activity have
been found in abundance on growth cones (Goldberg
and Wu, 1996; Goodman, 1996). An RTK in Drosophila
called derailed is expressed on particular fascicles in the
nervous system, and derailed mutants exhibit striking
pathway errors (Callahan et al., 1995). Derailed
appears to be a receptor for a wingless protein that is
expressed on the posterior commissure and acts as a
repellent to Derailed expressing axons (Yoshikawa et
al., 2003). Some receptors do not possess intracellular
enzymatic domains on their own. However, they may
be able to recruit other RTKs, such as the FGF recep-
tor, to do the work. Thus, there is a CAM binding site
on the FGF receptor, and NCAM binding can stimu-
late phosphorylation of growth cone proteins via FGF
receptor activity (Williams et al., 1994). In addition to
RTKs, some receptors are thought to signal through
cytosolic tyrosine kinases and phosphatases. Among
the nonreceptor tyrosine kinases (NRTK) are src , yes ,
and fyn . Neurons from single-gene mouse knockouts
that have no src are specifically unable to grow on the
CAM, L1, while neurons from single-gene knockout
mice that have no fyn are unable to grow on NCAM
(Beggs et al., 1994). A number of RTPs are found pre-
dominantly in growth cones, such as DLAR, which is
expressed in Drosophila motor axons. Mutants in these
genes can also lead to growth and pathfinding defects
(Desai et al., 1996). It is not precisely known what the
critical targets of each of these phosphorylation and
dephosphorylation reactions are in the growth cone
for any of these pathways, but it is likely that many of
them act on proteins involved in cytoskeletal dynam-
ics. Well known among these are the small GTPases of
the Rho-family (Luo et al., 1997; Dickson, 2001). These
exist in two states: an active GTP bound state and an
SIGNAL TRANSDUCTION
Signal transduction in growth cones is the process
by which guidance cues exert their effects on the
dynamic cytoskeleton. Some aspects of signal trans-
duction such as the activation of kinases, phos-
phatases, cyclic nucleotide levels, and protein turnover
have been mentioned in the above sections. CAMs,
integrins, repulsive factors, attractive factors, and
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