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expresses more receptor and thus should be more sen-
sitive to Ephrin-A, and another that is normally sen-
sitive. The results are that the two populations of
ganglion cells from the same eye form separate shifted
maps in the tectum, leading to a kind of double vision
(Brown et al., 2000) (Figure 6.13). The RGCs that
express higher levels of Eph-A map more rostrally
than those that express normal levels. This finding
clearly favors a model in which retinal growth cones,
by the levels of Eph-A they express, read the levels of
Ephrin-A in the tectum to establish a graded map.
The data described above, however, does not fully
explain the problem of topographic mapping across the
anterior to the posterior axis of the tectum. Since Ephrin-
As are noted as axon repellents, one of the key questions
that remains is why any axons bother to go to the poste-
rior tectum, especially as all axons express at least some
Eph-As and should prefer to map to the anterior tectum.
Is there a counterbalancing attractive mechanism? One
idea in this regard is that the tectum is a source of a
limited supply of neurotrophin, for which retinal axons
compete (Wilkinson, 2000). The nasal axons that have
the least Eph-A find the competition less fierce in the
posterior tectum, which is why they map there. This
idea may explain the otherwise puzzling observation
that removal of the Ephrin-As from the tectum not only
causes a posterior shift for temporal axons, but also
causes an anterior shift for nasal axons, as if the two
populations were competing. There is, however, another,
though not mutually exclusive, explanation that has to
do with the finding that Ephrins are not always repul-
sive. A systematic in vitro analysis shows that Ephrin-
A2, while capable of inhibiting the growth of temporal
axons at high concentrations, actually promotes the
growth of these axons at low concentrations (Hansen et
al., 2004) (Figure 6.14). Moreover, the transition from
growth inhibition to growth promotion varies across the
retina according to how much Eph-A is expressed in
RGCs; so nasal axons with low levels of Eph-As may
actually be attracted to the posterior tectum.
The possibility that Ephrins are involved in attrac-
tive as well as repulsive signaling is much clearer in the
other axis of retinotectal map formation, in which axons
from the dorsal retina map to the lateral tectum while
axons from the ventral retina map to the medial tectum.
Eph-B receptors have been found in a ventral (high) to
dorsal (low) gradient in the retina, whereas Ephrin-B
ligands are found in a medial (high) to lateral (low) gra-
dient in the tectum (Braisted et al., 1997; Holash et al.,
1997) (Figure 6.15). Interestingly, Ephrin-Bs are also
expressed in the retina, in a dorsal (high) to ventral
(low) gradient, whereas Eph-Bs are expressed in the
tectum in a lateral (high) to dorsal (low) gradient. These
expression patterns suggest that attraction rather than
Te mporal Injection
Nasal Injection
Te c tum
Wild type
Te c tum
EphrinA2, EphrinA5
double knockout
Te c tum
EphA3 expressed
under control of
FIGURE 6.13 Topographic mapping in Ephrin-A2 and Ephrin-
A5 double knockouts and with mosaic Eph-A3 misexpression.
A. Label is injected into the temporal (left) or nasal (right) retinas.
B. The result in the normal mice is a projection to the anterior (left)
or posterior (right) colliculus. C. In the Ephrin-A2, Ephrin-A5 double
knockouts, termination zones are all over the AP extent of the col-
liculus for both nasal and temporal injections. D. Two separate over-
lapping maps form from the RGCs that express Brn3c and thus extra
Eph-A3 and those that express the normal amount of Eph-A3. (After
Brown et al., 2000; Feldheim et al., 2000)
the receptors to the Ephrins, corroborates these find-
ings (Feldheim et al., 2004). If Eph-A3 is knocked out
in temporal axons in the chick, they project more pos-
teriorly than they normally would within the tectum.
A gene disruption of mouse Eph-A5 receptors caused
similar map abnormalities. A very interesting experi-
ment with Eph-A receptors involves gene targeting to
elevate Eph-A receptor expression in just one subset of
retinal ganglion cell in the mouse, while leaving the
neighboring ganglion cells to express normal levels of
Eph-A. The effect of this manipulation is to produce
two intermingled ganglion cell populations, one that
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