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frazzled , shows similar defects in commissural guid-
ance (Kolodziej et al., 1996). These results suggest a
strongly conserved function of netrins and netrin
receptors in chemoattraction toward the ventral
Although guidance to a distant target through the
target's release of a diffusible cue would appear to be
a reasonable way to guide axons to their targets, it
seems that this solution is used rather rarely in the
nervous system, and target tissues do not generally
put out long range attractants. Rather, as we shall see,
axons tend to use a number of intermediate targets and
several distinct local cues on the way to their destina-
tions. The early neuroepithelium is like a patchwork
quilt of various guidance cues that act as attractants
and repellents and operate in context with particular
ECM molecules and CAMs. This rich, detailed molec-
ular array covers the entire developing brain. Axons
read the terrain and respond appropriately. Consistent
with this analogy are the results of various embryonic
perturbations. If the tectum is removed, retinal axons
grow toward the missing tissue, suggesting that optic
axons use these local cues rather than a diffusible
attractant from the tectum as they grow along the optic
tract (Taylor, 1990). If a small piece of the optic tract
neuroepithelium is rotated 90° before the axons enter
it, then they become misoriented when they enter the
rotated transplant (Harris, 1989) (Figure 5.32) and
correct their course of growth when they exit. These
results confirm that the neuroepithelium contains local
information to which growing axons respond and that
they are not simply following gradients of attractants
released by their targets.
As a growth cone migrates through the embryonic
nervous system, it encounters new molecular cues
every 10 to 50 mms or so. How does such a molecularly
complex terrain get established in the neuroepithe-
lium? It appears that the early molecular events that
pattern the embryo play a role in setting up the
domains of these guidance cues. The homeobox genes
that provide segmental identity (see Chapter 1) also
direct the expression of various axon guidance cues,
and pioneer axons are often found at the boundaries
of brain territories that express different homeobox posi-
tional markers. Moreover, axonal tracts in embryonic
brains exhibit unusual patterns when the expression
of homeobox genes is perturbed (Wilson et al., 1997).
Sometimes the molecules that are involved in the
initial patterning of the nervous system are also used
as cues in pathfinding. We learned in Chapter 2, for
example, that Wnts are expressed in caudal high to
rostral low gradient during gastrulation. The same
Wnt gradient appears to be involved in giving cues to
spinal axons about whether they are traveling toward
Te ctum
Axons still
grow towards
missing tectum
FIGURE 5.32 Retinal axons follow local guidance cues in the
neuroepithelium. A. When the tectum is removed, the axons still
grow correctly to the tectum, indicating that the tectum is not the
source of a diffusible attractant. B. A piece of neuroepithelium in
front of the retinal axons is rotated 90° (top). When the retinal axons
enter the rotated piece, they are deflected in the direction of the rota-
tion, but they correct their trajectories when they exit the rotated
piece, showing that these axons pay attention to localized cues
within the epithelium. (After Harris, 1989, and Taylor, 1990)
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