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repulsion is the overriding mechanism at work in this
dimension. Here Eph-B expressing axons of the ventral
retina are attracted to Ephrin-Bs in the medial tectum,
and Ephrin-B expressing RGC axons of the dorsal retina
are attracted to Eph-B expressing cells in the lateral
tectum via backwards signaling from the receptor to the
ligand. In Xenopus , the prevention of all Ephrin-B/Eph-
B interactions causes dorsal axons to project medially
rather than laterally (Mann et al., 2002a). This effect
seems to depend on Ephrin-B function in the axons
because the same phenotype occurs if retinal axons
express a dominant negative form of Ephrin-B that
lacks an intracellular domain. Thus, reverse signaling
seems to attract Ephrin-B expressing dorsal retinal
axons to Eph-B-expressing cells in the lateral tectum
(Figure 6.15). But then why does the ventral retina
project to the medial tectum? When the Eph-B2 and
Eph-B3 receptors are knocked out, there is an ectopic
projection to the lateral tectum and the phenotype is
even stronger, if the Eph-B receptors are replaced with
receptors that are unable to signal (Hindges et al., 2002).
This result suggests that forward signaling through the
intracellular domain of the receptor is critical for
ventral axons to map to the medial tectum (Figure 6.15).
These studies on Ephrin-As and Ephrin-Bs and their
receptors strongly verify Sperry's chemospecifity ideas
for retinotectal mapping by providing the molecular
identities of at least some cytochemical tags of the kind
that he proposed. The next question is whether the Ephs
and Ephrins are involved in setting up topographic pro-
jections in other regions of the nervous system. Cer-
tainly, the fact that there are many of these ligands and
receptors is consistent with such a possibility, as are the
histological findings that the CNS is painted with a rich
pattern of these ligands and receptors often in recipro-
cal graded arrangements of A-type ligands with A-type
receptors and B-type ligands with B-type receptors
(Zhang et al., 1996). Work in a number of systems has
now established that this is the case. For example, there
is evidence that Ephrin/Eph signaling is used in estab-
lishing the visuotopic projection from the retina to the
visual thalamus (Feldheim et al., 1998), the somatotopic
map of the body surface on the primary somatosensory
area of the cortex (Vanderhaeghen et al., 2000), and the
tonotopic projection from the cochlea onto the nucleus
magnocellularis in the hindbrain (Person et al., 2004).
correct topographic location in tectum (Harris et al.,
1983; Stuermer and Raymond, 1989), but in the chick
and the mouse, axons overshoot their termination
points and subsequently make interstitial branches at
the correct topographic position behind the growth
cone (Nakamura and O'Leary, 1989; Simon and
O'Leary, 1990, 1992) (Figure 6.16). This is a process of
map refinement. The branches that form along the
shaft of RGC do so with good topographic specificity,
which is enhanced through the preferential arboriza-
tion of appropriately positioned branches and elimi-
nation of ectopic branches, thus further refining the
topography. Topographic refinement may occur
throughout life. Consider the case of a goldfish. It
hatches as a tiny 1 mg animal and over the course of
its life may attain a weight of 1 kg or more. It has
increased in volume a millionfold. As the animal
grows, the retina grows in proportion by adding cells
circumferentially at the rim or margin. The tectum
grows as well but mostly at the caudal end. In order
for the retinotectal map to remain evenly distributed,
the retinal axons must continually retract anterior
branches and send out new branches more posteriorly
in the tectum (Gaze et al., 1979). For example, axons
from the center of a large adult retina are from the
oldest retinal ganglion cells that were born when the
fish was just a small larva (Figure 6.17). These axons
used to project to the center of the larval tectum whose
cells remain at the anterior pole of the tectum as new
tectal cells are added caudally, but now they project to
cells in the middle of the large adult tectum, perhaps
a millimeter or so away (Easter and Stuermer, 1984).
These axons have continued to switch their preferred
targets to more posterior cells throughout their life-
times. A similar type of shifting reorganization of con-
nections is evident when half of the retina or half of
the tectum of a fish is ablated. When half the retina is
ablated, the projection of the remaining half of the
retina expands to cover the entire tectum. When half
the tectum is removed, the retina's projection com-
presses to cover the remaining half (Schmidt and
Easter, 1978; Schmidt and Coen, 1995). This sort of reg-
ulation is also observed in neonatal hamsters with a
partially deleted superior colliculus (Figure 6.17). This
form of topographic expansion or compression, like
the natural shift that is a consequence of the asym-
metric growth of the tectum, does not depend on the
activity patterns in retinal fibers. The regulation can
occur in the dark or even in the continuous presence
of tetrodotoxin (TTX) which blocks action potentials
(Meyer and Wolcott, 1987).
These shifting connections are part of larger devel-
opmental phenomenon whereby, once a topographic
map is roughly established, it is adjusted, modified,
SHIFTING AND FINE TUNING
OF CONNECTIONS
Branching can be topographic. In the frog and the
fish, retinal axons make branched terminals in the
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