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Wild type fly
fas II -/-
Contact repulsion
Contact adhesion
Source of
long range
Source of
long range
Contact repulsion
Fasciclin II
axons and
growth cones
FIGURE 5.20 Short-range (or contact) and long-range attractant
and repellents guide an axon. This axon is pushed from the left and
pulled from the right by long-range cues, while hemmed in along
a narrow pathway by contact adhesive and repulsive cues. (After
Tessier-Lavigne and Goodman, 1996)
FIGURE 5.21 Ahomophilic mutant in flies. A. In normal
Drosophila embryos, DMP2, MP1, vMP2, and pCC axons fasciculate
in a longitudinal bundle in which all axons express fasII. B. In a fasII
mutant, these axons do not fasciculate normally. (After Grenningloh
et al., 1991)
Contact repulsion: when growth cones bump into cells
with repulsive membrane molecules, they may col-
lapse or turn away and grow in a different direction;
(3) Long-range attraction: growth cones may exhibit
positive chemotaxis behavior to certain diffusible mol-
ecules originating at distant sources and so grow
toward these chemoattractants; and (4) Long-range
repulsion: growth cones may exhibit negative chemo-
taxis to diffusible molecules and so orient away from
the sources of such factors. In the following sections,
we will introduce many of the specific guidance cues
that work according to these basic mechanisms. In
many systems, it has become clear that growth cones
respond to a combination of these cues, and the molec-
ular directional signaling can become quite complex.
other cell and vice versa, causing the two cells to
adhere to each other. To test whether a particular CAM
is homophilic, nonadherent cells are transfected
with the CAM and assayed with respect to whether
they then form aggregates. During outgrowth, axons
expressing the same CAMs often fasciculate with one
another. Thus, single pioneer axons may use a specific
CAM to guide the follower axons that express the
same CAM, and these axons can attract the fascicula-
tion of still later axons of the same type. In this way,
pioneer axons can become the founders for large
axonal tracts within the CNS.
Monoclonal antibodies raised against axonal mem-
branes have been used to search for cell adhesion
molecules that are expressed on particular fascicles of
fibers during neural pathway formation. Several mol-
ecules were discovered in this manner. Some CAMs
show a particularly restricted expression and result in
very specific defects in axon growth. For example, a
Drosophila CAM, called fasciclinII (FasII), is expressed
on a subset of longitudinal tracts or fascicles in the
CNS (Bastiani et al., 1987). In FasII mutants, axons that
normally express this gene defasciculate, and the lon-
gitudinal tracts in which they run become disorgan-
ized (Grenningloh et al., 1991) (Figure 5.21). When
FasII is transgenically misexpressed on CNS neurons
that would not normally express FasII, their axons
tend to join together abnormally. Another CAM in
Drosophila , called IrreC, is expressed in the optic lobes,
and IrreC mutants show specific miswiring of the optic
pathway (Ramos et al., 1993). The vertebrate homolog
of IrreC has been implicated in the formation of
Growth cones, in addition to using ECM, make
contact with the membranes of other cells and axons.
In this, they are supported by a set of cell adhesion
molecules (CAMs) (Walsh and Doherty, 1997). There
are a host of such molecules, and they come in several
classes (Figure 5.19). The most prominent class is the
IgG superfamily. Members of this class have extracel-
lular repeat domains similar to those found in anti-
bodies, reflecting perhaps an ancient adhesive function
for the IgG superfamily. Another class is the calcium-
dependent cadherins. One property that many CAMs
share is their ability to bind homophilically.
Homophilic binding means that proteins of the same
type bind to each other. Thus, if two cells express the
same homophilic CAM on their surfaces, the CAM on
the one cell will act as receptor for the CAM on the
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