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different neuronal cell types respond to ephrins. Collectively ephrins play
important roles in setting up the topology of nerve connections between the
retina and the brain, between the various layers of the cortex, and also appear
to be critical in preventing some midline crossing events during corticospinal
tract formation (Kullander and Klein, 2002; Wilkinson, 2001). The
predominant model system has been the projection of retinal ganglion cells
(RGCs) from the retina through the optic chiasm to the tectum in the
developing embryo (Drescher et al., 1997; Flanagan and Vanderhaeghen,
1998).
Ephrins were initially isolated as repulsive axon guidance molecules
expressed in the tectum, which cause collapse of RGC growth cones in vitro
(Drescher et al., 1995; Nakamoto et al., 1996; Monschau et al., 1997; see
Figure 4.2A). Ephrin molecules are also repulsive to RGC axons in vivo, since
disruption of tectal ephrin-A molecules causes RGC axons to overshoot their
target positions (Frisen et al., 1998; Feldheim et al., 2000). Taken together
with expression studies, this strongly suggests a function for ephrins as
contact-cues that might repel axons.
In the embryonic tectum ephrins-A5 and -A2 are expressed in an increasing
anterior-to-posterior gradient. Temporal RGC growth cones express high
levels of receptor (particularly EphA3) and stop at positions in the anterior
tectum, where they experience su
cient repulsive signals from these cells to
trigger contact-repulsion. Nasal axons, expressing lower levels of EphA
receptors, are able to navigate further into the posterior tectum before they
reach the position expressing appropriate levels of ephrin ligand to trigger
contact-repulsion (Drescher et al., 1995; Monschau et al., 1997; Cheng et al.,
1995).
Eph receptor/ephrin mediated control of cell segregation
Segment-restricted expression of Eph receptors and ephrins in the developing
hindbrain prevents intermingling of sub-populations of neural epithelial cells,
promoting the formation of sharp rhombomeric compartment-boundaries
(Xu et al., 1999). The mutual contact repulsion of Eph receptor/ephrin
expressing cells causes them to sort into separate domains. It has been
demonstrated that bi-directional signalling is necessary for the restriction of
cell intermingling (Mellitzer et al., 1999). Likewise, fibroblast-like cells of the
pre-somitic mesoderm in a number of vertebrate species express alternating
stripes of Eph receptors and ephrins that may block cell intermingling (Durbin
et al., 1998).
Developmental patterning of the vasculature is also critically dependent on
interactions between Eph receptors and ephrins. Transgenic mice which are
null for ephrin-B2 or EphB4 (the cognate receptor for ephrin-B2 in endothelial
