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molecules, temporal axons no longer showed such a
preference (Walter et al., 1987a; 1990). This suggests
that the relevant activity is a membrane-linked protein
that is repulsive to temporal axons, and to which nasal
axons are rather insensitive. By examining the choices
that temporal axons make between membranes
extracted from successive rostrocaudal sixths of the
tectum, it became clear that this inhibitory activity is
graded across the tectum, highest at the caudal pole
and lowest at the rostral pole. Two repulsive factors,
now called Ephrin-A5 and Ephrin-A2, were then iden-
tified as the inhibitory molecules involved by the
Bonhoffer and Flanagan laboratories (Cheng et al.,
1995; Drescher et al., 1995). Ephrins, of which several
are now known, come in two subfamilies, a GPI-linked
or A-type, and a transmembrane or B-type. Their recep-
tors, known as Ephs, also divide into two A- and B-type
families. The Ephrin-As generally activate Eph-As,
while the Ephrin-Bs generally activate Eph-Bs
(Flanagan and Vanderhaeghen, 1998). Both Ephrin-A5
and Ephrin-A2 are expressed in a posterior (high) to
anterior (low) gradient in the tectum (Figure 6.12). The
retina, as expected, shows a gradient of Eph-As, the
receptors for these ligands. Temporal axons that have
high levels of Eph-A avoid the posterior pole of the
tectum that has the highest level of the Ephrin-A
ligands. When Ephrin-A2 is misexpressed by transfec-
tion across the entire tectum in chick embryos, tempo-
ral axons find it difficult even to enter the tectum. When
membrane stripes are made from the transfected ante-
rior tectal cells, temporal axons will not grow on them.
These results predict that when the Ephrins are
knocked out, there will be mapping errors. In mutant
mice, in which Ephrin-A5 is knocked out, temporal
axons map more posteriorly (Frisen et al., 1998), but
the mapping phenotype is even more striking in
double knockouts of both Ephrin-A2 and Ephrin-A5
(Figure 6.13). In these mice, the anteroposterior order
is largely, though not totally, lost. Temporal axons ter-
minate all over the tectum and freely invade the pos-
terior poles (Feldheim et al., 2000). The fact that there
is still some order left in this projection suggests that
there may be as yet other undiscovered chemospeci-
fity factors that are involved. Knocking out Eph-As,
Rostral to caudal gradient of tectal Ephrin
gradient is highest in
posterior half of the
Te mporal
Te c tum
Te c tum
FIGURE 6.12 Nasotemporal to anteroposterior retinotopic guidance system. A. There is a gradi-
ent of Ephrins in the tectum, high in the posterior pole and low in the anterior pole. B. A retinal gan-
glion cell in the temporal retina expresses active receptors for these tectal Ephrins and avoids the
posterior tectum. C and D. Show the opposing gradients of active Eph-A receptor expressed in the
retina and the gradients of A-type Ephrins in the tectum. This system can at least partially account for
topographic mapping in this axis. E. The Ephrin-A gradient is shown in the tectum of a chick that uses
a soluble Eph-A receptor fused to alkaline phosphatase to reveal the distribution of the Ephrin-A
ligands in the tectum. (After Cheng et al., 1995; Drescher et al., 1995)
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