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or away from the brain (Lyuksyutova et al., 2003)
(Figure 5.33). Shh , which as we have seen participates
in patterning the ventral neural tube, also acts as a
guidance cue at the ventral midline of the spinal cord
(Charron et al., 2003) and at the optic chiasm (Trousse
et al., 2001). Conversely, BMPs that pattern the dorsal
spinal cord are repulsive to the growth cones of dorsal
interneurons that grow away from the dorsal midline
(Augsburger et al., 1999).
the repulsive guidance molecule Slit and the mor-
phogen Shh that also acts as a repellent to RGC axons.
Slit and Shh are expressed anterior and posterior to the
chiasm, but not in the chiasm itself (Erskine et al., 2000;
Trousse et al., 2001). Thus, these molecules corral the
RGC axons into the chiasm proper. Zebrafish mutants
called astray do not have a functional Slit receptor in
their RGCs, and in these mutants fewer RGC axons
find the chiasm, and many get lost when they enter the
brain (Fricke et al., 2001; Hutson and Chien, 2002). At
the chiasm itself, there is a high concentration of
another repulsive guidance molecule called EphrinB.
The RGCs from the ventrotemporal part of the mouse
retina express EphB, the receptor for EphrinB, and so
ventrotemporal retinal axons do not cross the chiasm
but remain ipsilateral while the dorsal and nasal
axons, insensitive to EphrinB, cross the chiasm to the
other side of the brain (Nakagawa et al., 2000; Williams
et al., 2003). Once in the optic tract, retinal axons are
influenced by the repulsive guidance cue Sema3A and
the ECM heparan sulfate so that they are guided
toward the tectum (Walz et al., 1997; Campbell et al.,
2001; Irie et al., 2002). At the front of the tectum, the
RGC axons encounter a sudden drop of FGF, which
signals that they have entered the target area (McFar-
lane et al., 1995). In the target area they encounter
orthogonal gradients of EphrinA and EphrinB that
signify tectal coordinates (see Chapter 6). In the frog
embryo, retinal growth cones encounter all these cues
and several others during their journey of no more
than about 800 mm (Figure 5.34).
THE OPTIC PATHWAY
The optic pathway from the retina to the tectum
presents one of the most complete examples of the
various different kinds of guidance cues that are used
in guiding a single axon from its origin to its target
(Dingwell et al., 2000; Johnson and Harris, 2000).
Retinal axons travel centrifugally from a peripheral
location on the retina toward the optic nerve. When
they get to within about 50 mm of the optic nerve head,
they encounter a high concentration of netrin, which
acts as an attractant for RGC axons (Deiner et al., 1997).
At the optic nerve head on the vitreal surface of the
retina is a layer of the ECM molecule laminin. The
combination of laminin and netrin is repulsive rather
than attractive, and so these retinal axons turn away
from the surface of the retina and dive into the optic
nerve where they travel until they enter the brain near
the chiasm (Hopker et al., 1999). Here they encounter
A
B
D
A
A
P
P
V
D
V
D
Floor plate
Floor plate
C
D
A
P
fz3 knockout
Cos cells
expressing
wnt 4
FIGURE 5.33 Local gradients of morphogens can orient axons. A. Commissural interneurons of the spinal
cord, once they cross the ventral midline, grow anteriorly toward the brain, and up the Wnt4 concentration
gradient. B. These axons can be seen well in a filleted preparation grown in culture. The neural tube is sliced
open at the dorsal midline and flattened out. Label is applied to the commissural interneurons. C. Commis-
sural interneurons grow posteriorly if a ball of COS cells expressing Wnt 4 is placed on the posterior side of
such an explant. D. In a fz3 knockout, lacking the Wnt4 receptor, commissural interneurons do not grow
either anteriorly or posteriorly once they cross the midline. (After Lyuksyutova et al., 2003)
 
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