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A B
FIGURE 5.34 Local cues for retinal ganglion cells. A. A photograph of a single retinal ganglion cell
growing toward the tectum. The cell has been filled with a dye for visualization. B. Various guidance cues
that the growth cone of the RGC uses to orient toward its target in the tectum are artificially colored in,
although in close correspondence to the known distribution of these guidance cues. (Courtesy of Christine
Holt)
THE MIDLINE
form of Robo which an axon expresses determines
where it forms its longitudinal fascicle (Rajagopalan
et al., 2000; Simpson et al., 2000). Later axons use a
combination of this Robo code, plus the expression
of a particular homophilic CAM or fasiclin to join their
appropriate fascicle.
Vertebrate commissural interneurons also only
cross the midline once. But here a different mechanism
is at play. Instead of gaining sensitivity to a midline
repellent, they lose sensitivity to the midline attractant,
Netrin. Whole pathway preparations were placed into
culture to show that once these axons had crossed
the midline, they no longer responded to a source of
netrin, and that if they were exposed to a source of
netrin before they reached the midline, they were no
longer attracted to the midline (Shirasaki et al., 1998).
In addition, Slit at the vertebrate midline activates the
Robo receptor on these axons. Once activated, the
intracellular domain of the Robo receptor binds to
the intracellular domain of the DCC receptor and
blocks Netrin signaling, and so once these axons have
crossed the midline they only sense the repellent
activity of Slit and not the attractive activity of Netrin
(Stein and Tessier-Lavigne, 2001).
A very interesting problem in axonal guidance is
that commissural axons generally only cross the
midline once; they do not return. This seems a bit odd
if the midline has solely an attractive function. This
point is brought home in a Drosophila mutant round-
about ( robo ). Commissural axons in robo mutants cross
the midline and then recross it at the next commissure.
They do this over and over, sometimes going in circles
(Figure 5.35). Robo is the receptor for a midline repel-
lent Slit, and slit mutants show a similar phenotype.
Interestingly, there is another class of mutant in
Drosophila called commissureless that has the opposite
phenotype (Seeger et al., 1993; Tear et al., 1993). In
these mutants, commissural neurons are unable to
cross the midline and remain ipsilateral (Figure 5.35).
Only axons that cross the midline express commissure-
less ; those that do not, never cross the midline. At
the midline, it appears that Comm binds Robo and
removes it from the growth cone surface into internal
vesicles so that the axons are not repelled by Slit
(Keleman et al., 2002; Myat et al., 2002). Once they
cross the midline, Comm protein levels are reduced
and Robo returns to the surface so the axons do not
recross.
In Drosophila , there are actually three different Robo
genes, and each one has a different affinity for Slit. The
Robo with the highest affinity is expressed on longitu-
dinal fascicles that are farthest away from the ventral
midline, the source of Slit, while the Robo with the
lowest sensitivity to Slit is expressed on axons that
grow right next to the midline. Thus, the particular
ATTRACTION AND REPULSION:
DES ENSITIZATION AND ADAPTATI ON
The responses of growth cones to the same cues
may change as axons progress toward their final des-
tinations. We have just seen examples of this at the
ventral midline, which can be considered an interme-
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