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in their promoters, and thus are potentially regulated
by Homeobox genes. In fact, any change in the mor-
phology of a particular segment is likely to require the
coordinated activation and suppression of numerous
genes. For example, it has been estimated that between
85 and 170 genes are likely regulated by the Ubx gene
(Gerhart and Kirschner, 1997). In addition, the Home-
obox genes interact with other transcription factors to
enhance their DNA-binding specificity.
Another striking feature of the Homeobox genes is
their remarkable degree of conservation throughout
the phyla. Organized Homeobox clusters similar to
those found in Drosophila have been identified in
nearly all the major classes of animals, including
Cnidarians, nematodes, arthropods, annelids, and
chordates. Figure 2.5 shows the relationship between
the Drosophila Homeobox genes and those of the mouse.
There have been two duplications of the ancestral Hox
clusters to produce the A, B, C, and D clusters in the
mammal. In addition, there have also been many
duplications of individual members of the cluster on
each chromosome, to produce up to 13 members. In
mammalian embryos, the Hox genes are expressed in
specific domains. As in Drosophila , the Hox gene posi-
tion on the chromosome is correlated with its expres-
sion along the anterior-posterior axis. By aligning the
mammalian Hox genes with their Drosophila counter-
parts, it is possible to infer the organization of the Hox
clusters in the common ancestor between the phyla
(Figure 2.5). In mice and other vertebrates, Hox genes
in the same relative positions on each of the four chro-
mosomes, and similar to one another in sequence,
form paralogous groups. For example, Hoxa4, Hoxb4,
Hoxc4, and Hoxd4 make up the number 4 paralogous
development, the hindbrain undergoes a pattern of
“segment formation” that bears some resemblance to
that which occurs in the fly embryo. In the develop-
ing hindbrain, the segments are called rhombomeres
(Figure 2.6). The rhombomeres give rise to a segmentally
repeated pattern of differentiation of neurons, some of
which interconnect with one another within the hind-
brain (the reticular neurons) and some of which project
axons into the cranial nerves (Lumsden and Keynes,
1989). Each rhombomere gives rise to a unique set of
motoneurons that control different muscles in the head.
For example, progenitor cells in rhombomeres 2 and 3
make the trigeminal motor neurons that innervate the
jaw, while progenitor cells in rhombomeres 4 and 5
produce the motor neurons that control the muscles of
facial expression (cranial nerve VII) and the neurons
that control eye muscles (abducens nerve, VI), respec-
tively. Rhombomeres 6 and 7 make the neurons of the
glossopharyngeal nerve, which controls swallowing.
Without differences in these segments, animals would
not have differential control of smiling, chewing, swal-
lowing or looking down. Clearly, rhombomere identity
is important for our quality of life.
How do these segments become different from one
another? The pattern of expression of the paralogous
groups of Hox genes coincides with the rhombomere
boundaries (Figure 2.6), and in fact the expression of
these genes precedes the formation of obvious mor-
phological rhombomeric boundaries. Members of
paralogous groups 1-4 are expressed in the rhom-
bomeres in a nested, partly overlapping pattern.
Group 4 genes are expressed up to the anterior bound-
ary of the seventh rhombomere, group 3 genes are
expressed up to and including rhombomere 5, while
group 2 genes are expressed in rhombomeres 2-5.
These patterns are comparable in all vertebrates. As
discussed below, loss of a single Hox gene in mice
usually does not produce the sort of dramatic pheno-
types seen in Drosophila . This is probably because of
overlapping patterns of Hox gene expression from the
members of the four paralogous groups. When two or
more members of a paralogous group are deleted, say
Hoxa4 and Hoxb4 , then the severity of the deficits
increases. The deficits that are observed are consistent
with the Hox genes acting much as they do in arthro-
pods. That is, they control the relative identity of a
region of the body.
As noted above, studies of Hox genes in neural
development have concentrated on the hindbrain.
Several studies have either deleted specific Hox genes
or misexpressed them in other regions of the CNS and
examined the effect on hindbrain development. Only
a few examples will be given. Elimination of the Hoxa1
gene from mice results in animals with defects in the
The function of the Hox genes in controlling the
regional identity of the vertebrate nervous system has
been most clearly investigated in the hindbrain. The
vertebrate hindbrain provides the innervation for the
muscles of the head through a set of cranial nerves. Like
the spinal nerves that innervate the rest of the body,
some of the cranial nerves contain axons from motor
neurons located in the hindbrain, as well as sensory
axons from neurons in the dorsal root ganglia. However,
we will primarily be concerned with the motor neurons
for the time being. The cranial nerves of an embryo are
shown in Figure 2.6. As noted above, during embryonic
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