Brain Development
surface molecules are implicated in re-
stricting cell intermingling, as dissociated
cells from even-numbered rhombomeres
and those from odd-numbered rhom-
bomeres segregate from each other if
mixed in suspensions. Eph receptor ty-
rosine kinases and their ligands, ephrins,
are good candidates in conferring such dif-
ferential afFnity to cells: Even-numbered
rhombomeres express ephrins, while odd-
numbered rhombomeres express Ephs
(±ig. 7c). This complementary pattern of
Eph/ephrin expression is important be-
cause bidirectional signaling between cells
with receptors and those with ligands
leads to mutual repulsion at the inter-
face. As a result, cell intermixing between
rhombomeres is strictly regulated and
rhombomere boundaries are maintained.
The cadherin cell adhesion molecules
are another set of candidates involved in
cell lineage restrictions between rhom-
bomeres. As I mentioned in Sect. 2.1,
cadherins confer subclass speciFc adhe-
siveness to cells. Within the mouse hind-
brain, cadherin-6 is transiently expressed
in rhombomere-6 under regulation of the
transcription factor Hoxa-1. Additionally,
R-cadherin expression has been reported
in odd-numbered rhombomeres. The sort-
ing activity between cells from even-
numbered rhombomeres and those from
odd-numbered rhombomeres has been
shown to be Ca
dependent. Cadherins
might thus serve a role in restricting cell
movement during mouse hindbrain devel-
opment. Cadherins are linked to the actin
Flaments via catenins and this provides
rigid forces for cells to bind each other with
polarity (±ig. 5a). Eph-ephrin signaling ac-
tivates Rho GTPases and could collapse
actin cytoskeletal elements to alter cell
movements. Cadherins and eph-ephrin
signaling may therefore act cooperatively
to regulate the status of actin cytoskeltons
at the rhombomere boundary region.
Midbrain Specifcation
Although no segmental organization has
been identiFed along the A–P axis in
the midbrain during development, this re-
gion contains many types of neurons with
critical functions. ±or example, the ven-
tral compartment produces dopaminergic
neurons of the substantia nigra to control
the motor functions, while the tectum (or
the superior colliculus) region forms the
precise positioning of neurons along the
A–P axis to process visual information.
Because no
genes are expressed in
the brain anterior to rhombomere2, addi-
tional mechanisms are required to pattern
this region.
At the early neural plate stages of chicken
embryos, the expression borders of several
transcription factors are known to demar-
cate the future midbrain territory. ±or
instance, the anterior limit of the future
midbrain (forebrain/midbrain boundary)
has been shown to correspond to the
Fig. 7
A–P patterning of the developing hindbrain.(a) The genetic cascades involved in
A–P patterning, (b) Genomic organization and expression proFles of mouse
gene clusters are
reminiscent of those of
homeotic genes in
and the bithorax complex, (c) The
metameric units in the hindbrain (r, rhombomeres) delineated by the differential expression of
transcription factors and Eph/ephrins are important to produce distinct sets of neurons along the
A–P axis. Dark and light shading represent high and low levels of gene expression in individual
rhombomeres respectively. Note that the migration pattern of neural crest cells as well as the
formation of the branchial arches (BA) are also affected by the hindbrain organization.
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