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N. Holder et al.
8.2 Eph/Ephrin Signalling Functions in Axon Guidance
in the Peripheral and Central Nervous System
A vital aspect of the neuronal differentiation process is the production of
an axon which grows and seeks a specific synaptic partner. It is evident
from work on the retinotectal system (see below) that Eph signalling is
involved in guiding axon growth. Initial evidence for such a role in the
formation of centrally and peripherally projecting axon tracts arose from
studies of the EphB2 receptor (Pasquale et al. 1992). EphB2 is expressed in a number of domains in the chick and mouse brain, including
the retina. It has been shown that EphB2 in the chick retina is highly
phosphorylated, particularly during the phase when interneuronal contacts are established (Pasquale et al. 1994). To further implicate EphB2
function in the formation of appropriate neuronal contacts, this receptor
has been immunolocalised to the surface of growth cones of spinal
motor neuron and oculomotor neuron axons from the onset of their
growth towards their respective targets (Henkemeyer et al. 1994). Furthermore, functional studies using a different receptor, EphA5, and a
ligand by which it is activated, ephrin-A5, showed directly that Eph
receptor signalling is involved in axon fasciculation (Winslow et al.
1995). In these experiments fasciculation ofaxons from cortical neurons
growing on astrocytes was inhibited by soluble forms of both the receptor and the ligand which are assumed to act in a dominant-negative
manner. The strongest evidence to date implicating EphB2 in axon
outgrowth in the embryo comes from targeted mutation studies in the
mouse (Henkemeyer et al. 1996). An embryo homozygous for loss of
EphB2 function lacks part of the anterior commissure. However, as the
neurons projecting axons across the anterior commissure do not express
EphB2, the authors suggest that the phenotype may reflect loss of
signalling through the ligand to which it normally binds. Loss of commissural axons is more dramatic in mice null for both EphB2 and EphB3
(Orioli et al. 1996). In such animals the anterior commissure and the
corpus callosum are affected as well as the forming palate, an area of the
embryo in which both receptors are normally expressed. It was further
observed that at least one eNS axon bundle running in the anterior-posterior direction, the habenular-interpeduncle tract, was partially defasciculated in the double mutants, although the projection to its target, the
ventral midbrain, appeared normal.
N. Holder et al.
8.2 Eph/Ephrin Signalling Functions in Axon Guidance
in the Peripheral and Central Nervous System
A vital aspect of the neuronal differentiation process is the production of
an axon which grows and seeks a specific synaptic partner. It is evident
from work on the retinotectal system (see below) that Eph signalling is
involved in guiding axon growth. Initial evidence for such a role in the
formation of centrally and peripherally projecting axon tracts arose from
studies of the EphB2 receptor (Pasquale et al. 1992). EphB2 is expressed in a number of domains in the chick and mouse brain, including
the retina. It has been shown that EphB2 in the chick retina is highly
phosphorylated, particularly during the phase when interneuronal contacts are established (Pasquale et al. 1994). To further implicate EphB2
function in the formation of appropriate neuronal contacts, this receptor
has been immunolocalised to the surface of growth cones of spinal
motor neuron and oculomotor neuron axons from the onset of their
growth towards their respective targets (Henkemeyer et al. 1994). Furthermore, functional studies using a different receptor, EphA5, and a
ligand by which it is activated, ephrin-A5, showed directly that Eph
receptor signalling is involved in axon fasciculation (Winslow et al.
1995). In these experiments fasciculation ofaxons from cortical neurons
growing on astrocytes was inhibited by soluble forms of both the receptor and the ligand which are assumed to act in a dominant-negative
manner. The strongest evidence to date implicating EphB2 in axon
outgrowth in the embryo comes from targeted mutation studies in the
mouse (Henkemeyer et al. 1996). An embryo homozygous for loss of
EphB2 function lacks part of the anterior commissure. However, as the
neurons projecting axons across the anterior commissure do not express
EphB2, the authors suggest that the phenotype may reflect loss of
signalling through the ligand to which it normally binds. Loss of commissural axons is more dramatic in mice null for both EphB2 and EphB3
(Orioli et al. 1996). In such animals the anterior commissure and the
corpus callosum are affected as well as the forming palate, an area of the
embryo in which both receptors are normally expressed. It was further
observed that at least one eNS axon bundle running in the anterior-posterior direction, the habenular-interpeduncle tract, was partially defasciculated in the double mutants, although the projection to its target, the
ventral midbrain, appeared normal.