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fact, it has been known for some time that retinoic acid
can induce the expression of Hox genes when added to
embryonic stem cells. With low concentrations of RA
added to the ES cells, only those Hox genes normally
expressed in the anterior embryo are expressed, while
at progressively higher concentrations of RA, more
posteriorly expressed Hox genes are expressed in the
cell line (Simeone et al., 1991). Targeted deletion of
the RARs produces defects similar to those observed
from pharmacological manipulation of this pathway
(Chambon et al., 1995). Finally, both the Hoxa1 and the
Hoxb1 promoters have RAREs, and these elements are
both necessary and sufficient for the rhombomere-
specific pattern of expression of these genes. These
facts all point to the importance of RA signaling in
hindbrain development, but where does the gradient
of RA come from in normal embryos? Early models of
gradient formation invoked a highly expressing source
of the signal and a declining gradient from the source,
possibly “sharpened” by an active degradation mech-
anism. Evidence from several labs now indicates that
the source of the RA is the mesoderm that lies imme-
diately adjacent to the neural tube. The so-called
paraxial mesoderm contains enzymes that synthesize
the RA, and this then diffuses into the hindbrain
neural tube to activate the pattern of Hox gene expres-
sion. The fact that the nonneural tissue outside the
developing nervous system can have such a critical
impact in its formation reminds us that the nervous
system does not develop in a vacuum, but rather many
important aspects of its development rely on interac-
tions with adjacent nonneural tissues.
Overall, the similarity of body segmentation in
Drosophila and hindbrain rhombomere development in
vertebrates has led to a rapid understanding of both
processes. However, the development of other regions
of the vertebrate nervous system does not rely so
heavily on the same mechanisms. Instead, other types
of transcription factors control the development of the
more anterior regions of the brain. In the next sections
we will review how divisions in these other brain
regions arise.
RA signalling system
acid (RA)
Cytoplasmic retinoic
acid binding protein
RA receptor
Retinoic acid response
element (RARE)
RA in posterior mesoderm at neurula stage
Low RA levels
permit anterior Hox
genes to be expressed
High RA levels
repress anterior Hox
genes and activate
posterior Hox genes
10 -8 M RA
10 -6 M RA
FIGURE 2.8 Retinoic acid signaling is important for the anterior-
posterior pattern of Hox gene expression. RA crosses the cell
membrane to bind a cytoplasmic receptor. The retinoic acid
receptor (RAR) translocates into the nucleus where it can regulate
gene expression through interaction with retinoic acid response
element (RARE). RA levels are about 10 times higher in the poste-
rior region of Xenopus embryos, and RA-treated embryos typically
show defects in the anterior parts of the nervous system. When
embryos are exposed to increasing concentrations of RA, they fail to
develop head structures and the expression of anterior genes is
RA concentration, with RA levels about 10 times
higher in the posterior region of Xenopus embryos.
When Xenopus embryos are treated with RA, they typ-
ically show defects in the anterior parts of the nervous
system. When embryos are exposed to increasing con-
centrations of RA, they fail to develop head structures
(Figure 2.8), and the expression of anterior Hox genes
is inhibited (Durston et al., 1989).
Do the teratogenic effects of RA have anything to do
with the control of regional identity in the CNS? In
The overall organization of the anterior-posterior
axis of the nervous system in vertebrates is coupled
with earlier events in axis determination and neural
induction. As noted in Chapter 1, evidence from
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