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Wild type
beat-1a mutant
Enter, branch
and do
not leave
beat-1a, beat-1c
double mutant
beat receptor
Find topographic
FIGURE 6.2 Defasciculation is regulated by Beat proteins.
A. Two motor axons growing off the intersegmental nerve (ISN) are
shown, one that branches off the nerve in the region of its target.
B. In a beat-1a mutant, the motor axon at right does not defascicu-
late. C. The beat-1a mutant phenotype is rescued in a beat-1c mutant
background. D. Model where the axons are fasciculated, integral
membrane beat-1c protein binds the beat receptor. Where the axons
defasciculate, soluble beat-1a binds the receptor, breaking the adhe-
sion. (After Vactor et al., 1993; Fambrough and Goodman, 1996;
Pipes et al., 2001)
Find layer
Connect with
target cells
branes. In the previous chapter, we looked at the role
of polysialic acid (PSA) in decreasing the adhesivity of
N-CAM in the nerve plexus, where defasciculation
was necessary to get different motor neurons sorted
into the correct mixed nerves. The relative PSA levels
of L1 and N-CAM are also important in balancing
axon-axon versus axon-muscle adhesion during
target innervation (Landmesser et al., 1990). If PSA
is removed, the result is increased axon fascicula-
tion, reduced nerve branching, and reduced target
It seems likely that the targets themselves contribute
to the defasciculation of the axons that will innervate
them. In Drosophila mutants lacking mesoderm, the
main motor nerves form, but motor axons fail to defas-
ciculate from these bundles. Experiments by Landgraf
et al. (1999) have shown that founder myoblasts are
the source of defasciculation cue(s) and that a single
founder myoblast can trigger the defasciculation of an
entire nerve branch. This suggests that the separate
targets, through the release of possibly different defas-
ciculation factors at different locations, lead to the
patterned branching of nerves.
FIGURE 6.1 Conceptual stages of targeting. From top to bottom,
an axon defasciculates in the region of the target. It enters the target
and begins to branch, and is prevented from exiting by a repulsive
border. The axon responds to a topographic gradient that promotes
branching at the correct location. It then selects a particular layer and
finally homes in on particular target cells. (After Holt and Harris,
2001). Interestingly, beaten path embryos are rescued by
reducing the levels of cell adhesion molecules, like
Beat-1c, and thus it is the balance between these pro-
and anti-adhesive functions that regulates whether
particular axons will take the appropriate exits or stay
on the main road (Figure 6.2). Other factors may also
serve to alter the balance, including repulsive guidance
factors such as Semaphorin-1a, which can also cause
axons to branch off the main pathways (Yu et al., 2000).
Branching patterns of nerves are mediated by defas-
ciculation in vertebrates too. One way to reduce
fasciculation is to secrete an anti-adhesive factor, like
Beat-1a. Another is to post-translationally modify
adhesion molecules before putting them into the mem-
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