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double mutants were made with fasI and several other
putative guidance or growth cone function mutants,
each of which also had no striking phenotype on
its own. One of the double mutants tested showed
pathfinding defects in combination with fasI . This was
the fasI/abl double mutant (Elkins et al., 1990). abl codes
for a tyrosine kinase, which probably functions in a
signal transduction pathway in the growth cone. Since
both genes had to be knocked out to cause axon dis-
orientation, the two genes are probably part of two dis-
tinct molecular pathways, either of which may suffice
for axon guidance. Similarly, in vertebrate tissue
culture, motor axon growth over muscle fibers is not
seriously impaired unless two or more adhesion mol-
ecules are simultaneously disabled (Tomaselli et al.,
1986; Bixby et al., 1987). Axonal growth is such an
important part of building an organism that such fail-
safe molecular mechanisms often operate to help
ensure that the nervous system is properly wired.
Early axon tracts can be thought of as subway lines:
the Orange Line, the Red Line, and the Green Line. As
the pioneer axons grow, they express particular CAMs
on their surfaces, creating a labeled “line” that other
growth cones can follow. Guidance along previously
pioneered tracts by selective adhesion is referred to
as the labeled pathways hypothesis (Goodman et al.,
1983). When a new neuron sends out its axon, the
growth cone is able to choose between specific pioneer
axons because it expresses complementary CAMs. Evi-
dence for labeled lines or pathways comes from the
embryonic grasshopper central nervous system. Here,
for example, the axon of the G-neuron extends across
the posterior commissure along a pathway pioneered
by the Q1- and Q2-neurons (Bastiani et al., 1984; Raper
et al., 1984). Once it has crossed, the growth cone of the
G-neuron pauses for a few hours while its filopodia
seem to explore a number of different longitudinal fas-
cicles in the near vicinity. In the electron microscope,
it can be seen that that filopodia from the G-neuron
growth cone preferentially stick to the P-axons of the
A/P-fascicle. The G-growth cone then joins the A/P
fascicle and follows it anteriorly to the brain. If the P-
axons are ablated before the G-growth cone crosses the
midline, the G-growth cone acts confused upon reach-
ing the other side (Figure 5.23). It does not show a high
affinity for any other longitudinal bundle or even the
A-axons. As a result, it often stalls and does not turn
at all. Thus, the P axons seem to have an important
label on their surface that the G growth cone can
recognize, possibly because of a specific receptor on
the G-cell membrane. Examination of CAM expression
with the electron microscope confirms that specific
CAMS are distributed on the surface of axons in par-
ticular fascicles (Bastiani et al., 1987). In vertebrates,
FIGURE 5.23 An experiment supporting the labeled pathway
hypothesis. A. In a control embryo, the G growth cone, after cross-
ing the midline, fasciculates with P-axons and not A-axons. B. When
the P-neuron is ablated, the G growth cone stalls and does not
fasciculate with the A-axons. (After Raper et al., 1984)
too, there is evidence that some axons use a labeled
pathway mechanism. The tract of the postoptic com-
missure (TPOC), for example, is a pioneering tract for
axons from the pineal. The pineal axons fasciculate
with the TPOC as they turn posteriorly at the bound-
ary between forebrain and midbrain. If the TPOC is
ablated, pineal axons often fail to make the appropri-
ate turn (Chitnis et al., 1992).
Just as you may have to change lines at a subway
stop to reach your final destination, so axons may have
to change pathways. To do so, an axon must change
the CAM on its surface. Such a change in the expres-
sion of particular CAMs has now been seen in a
number of systems at places where axons switch direc-
tions. For example, when axons in the central nervous
system of Drosophila travel on longitudinal tract, they
express FasII, but when they leave the longitudinal
tract and turn onto a horizontal commissure, they stop
expressing FasII and express FasI (Figure 5.24). In
addition to following a scaffold of CAM-expressing
axons, a new axon may also pioneer a new route
during the last leg of its journey and add a new CAM
to help future axons reach the same site. Thus, the
simple scaffold of the first pioneers with a small
number of CAMs becomes increasingly complex as
more axons and more CAMs are added to the network.
Not all CAMs are homophilic. Some are involved
in heterophilic interactions with other CAMs. For
example, the CAM, TAG-1, which is expressed on com-
missural interneurons of the spinal cord, binds to a dif-
ferent CAM, called NrCAM which is expressed on
glial cells in the floorplate (Stoeckli and Landmesser,
1995). Antibodies to NrCAM can be used to perturb
the heterophilic interaction between these two CAMs,
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