Eph Receptors and Ephrins Are Key Regulators of Morphogenesis 133
subsequent differentiation of neurons (Lumsden and Krumlauf 1996). In
both regions of the embryo the segments develop clear boundaries at
which the cells undergo distinctive behaviours involving cell shape
changes. In the hindbrain, segmentation occurs within a defined region
of the neural plate, whereas in the paraxial mesoderm segmentation is a
dynamic process linked to the growth of the body axis at the posterior
end. Eph receptors and ephrins are expressed in both hindbrain neural
plate and paraxial mesoderm, and functional analysis of receptor signalling in zebrafish and in Xenopus indicates that such signalling is crucial
for normal development of segment boundaries in both regions of the
embryo (Fig. 2).
The vertebrate hindbrain consists of seven or eight rhombomeres,
which become apparent during neurulation stages, once gastrulation is
completed. Boundaries develop gradually and in a predictable sequence.
The boundaries are evident because cells within the boundary zone have
specific flattened shapes and they are organised in straight lines at right
angles to the body axis (Heyman et al. 1994; Moens et al. 1998). These
edges are barriers to cell movement and are extremes for expression of
genes concerned with patterning the hindbrain (Lumsden and Krumlauf
1996). Eph receptors and ephrins are expressed in specific rhombomeres
in such a way that receptors and ligands interact at the future boundaries.
For example, in Xenopus, EphA4 is expressed in rhombomeres 3 and 5
(Nieto et al. 1992; Gale et al. 1996; Xu et al. 1995) and ephrin-B2 is
expressed in rhombomeres 2, 4 and 6 (Smith et al. 1997). The fields of
cells in these alternating rhombomeres interact only at the future
boundaries between the rhombomeres. This interpretation is consistent
with grafting experiments in the chick embryo in which it has been
shown that interfaces between odd- and even-numbered rhombomeres
are necessary for boundary formation to occur (Guthrie and Lumsden
1991). Interfering with Eph receptor/ephrin signalling following the
injection of RNA encoding a dominant-negative form of EphA4 led to
abnormal rhombomere boundary formation. In such experimental embryos rhombomeres have abnormal shapes and sizes with misplaced
boundaries (Xu et al. 1995). The mechanism of EphA4 function in the
developing hindbrain remains unclear although an analysis of the formation of boundaries in mouse and chick hindbrains shows that the
process is gradual, suggesting that Eph signalling is important for the
control of local cell movement (Irving et al. 1996).
subsequent differentiation of neurons (Lumsden and Krumlauf 1996). In
both regions of the embryo the segments develop clear boundaries at
which the cells undergo distinctive behaviours involving cell shape
changes. In the hindbrain, segmentation occurs within a defined region
of the neural plate, whereas in the paraxial mesoderm segmentation is a
dynamic process linked to the growth of the body axis at the posterior
end. Eph receptors and ephrins are expressed in both hindbrain neural
plate and paraxial mesoderm, and functional analysis of receptor signalling in zebrafish and in Xenopus indicates that such signalling is crucial
for normal development of segment boundaries in both regions of the
embryo (Fig. 2).
The vertebrate hindbrain consists of seven or eight rhombomeres,
which become apparent during neurulation stages, once gastrulation is
completed. Boundaries develop gradually and in a predictable sequence.
The boundaries are evident because cells within the boundary zone have
specific flattened shapes and they are organised in straight lines at right
angles to the body axis (Heyman et al. 1994; Moens et al. 1998). These
edges are barriers to cell movement and are extremes for expression of
genes concerned with patterning the hindbrain (Lumsden and Krumlauf
1996). Eph receptors and ephrins are expressed in specific rhombomeres
in such a way that receptors and ligands interact at the future boundaries.
For example, in Xenopus, EphA4 is expressed in rhombomeres 3 and 5
(Nieto et al. 1992; Gale et al. 1996; Xu et al. 1995) and ephrin-B2 is
expressed in rhombomeres 2, 4 and 6 (Smith et al. 1997). The fields of
cells in these alternating rhombomeres interact only at the future
boundaries between the rhombomeres. This interpretation is consistent
with grafting experiments in the chick embryo in which it has been
shown that interfaces between odd- and even-numbered rhombomeres
are necessary for boundary formation to occur (Guthrie and Lumsden
1991). Interfering with Eph receptor/ephrin signalling following the
injection of RNA encoding a dominant-negative form of EphA4 led to
abnormal rhombomere boundary formation. In such experimental embryos rhombomeres have abnormal shapes and sizes with misplaced
boundaries (Xu et al. 1995). The mechanism of EphA4 function in the
developing hindbrain remains unclear although an analysis of the formation of boundaries in mouse and chick hindbrains shows that the
process is gradual, suggesting that Eph signalling is important for the
control of local cell movement (Irving et al. 1996).