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to one another was first proposed by Geoffry Saint-
Hillaire from comparative anatomical studies, and this
appears to be confirmed by these recent molecular
studies (Figure 1.22). Second, the antagonistic mecha-
nism between sog and dpp in the fly also led to the
hypothesis that the various neural inducers might
work through a common mechanism, the antagonism
of BMP4 signaling. The following three key experi-
ments all indicate that this is indeed the case. First,
BMP4 will inhibit neural differentiation of animal caps
treated with chordin, noggin. or follistatin. Second,
BMP4 will also inhibit neural differentiation of disso-
ciated animal cap cells. Third, antisense BMP4 RNA
causes neural differentiation of animal caps without
addition of any of the neural inducers. The dominant-
negative activin receptor induction of neural tissue can
also be understood in this context, since the activin
receptor is related to the BMP4 receptor, and addi-
tional experiments have shown that the expression
of the truncated receptor also blocks endogenous
BMP4 signaling (Wilson and Hemmati-Brivanlou,
1995).
Do all three of these neural inducers act equiva-
lently to inhibit BMP4 signaling? Biochemical studies
have demonstrated that chordin blocks BMP4-receptor
interactions by directly binding to the BMP4 with
high affinity. Noggin also appears to bind BMP4
with an even greater affinity, while follistatin can
bind the related molecules BMP7 and activin. There-
fore, it is likely that at least these three neural
inducers act by blocking the endogenous epider-
malizing BMP4, thereby allowing neural differentia-
tion of the neurogenic ectoderm (Piccolo et al., 1996)
(Figure 1.23).
The studies described in Xenopus embryos have pro-
vided evidence that these factors are capable of induc-
ing neural tissue, but it is more difficult technically to
determine whether these factors are required for
neural induction in Xenopus. To study the requirement
for BMP inhibition in neural induction, several labs
have examined animals that have mutations in one or
more of the putative neural inducer genes. Zebrafish
with mutations in the chordin gene have reductions in
both neural tissue and in other dorsal tissues (Schulte-
Merkerr et al., 1997). In mice, targeted deletions have
been made in the genes for follistatin, noggin, and
chordin. Although deletion of any one of these genes
has only minor effects on neural induction, elimination
of both noggin and chordin has major effects on neural
development. Figure 1.24 shows the nearly headless
phenotype of these animals. The cerebral hemispheres
of the brain are almost completely absent. Neverthe-
less, some neural tissue forms in these animals. Thus,
while antagonism of the BMP signal via secreted BMP
Drosophila
Frog
dpp
BMP4
chordin
Ectoderm
Mesoderm
Notochord
Sog
Neural plate
delaminating
neuroblasts
FIGURE 1.22 Vertebrates and invertebrates use similar mole-
cules to pattern the dorsal-ventral axis. The Drosophila embryo in
cross section resembles an inverted Xenopus embryo. As described
in Figure 1.6, the neurogenic region is in the ventral-lateral
Drosophila embryo, whereas in the vertebrate embryo, the neural
plate arises from the dorsal side. In the Drosophila , a BMP-like mol-
ecule, dpp, inhibits neural differentiation in the ectoderm, and in the
vertebrate embryo, the related molecules, BMP2 and BMP4, sup-
press neural development. In Drosophila , sog (short gastrula) pro-
motes neural development by inhibiting the dpp signaling in the
ectoderm in this region, while in the Xenopus , a related molecule,
chordin (chd), is one of the neural inducers released from the invo-
luting mesodermal cells and in an analogous way inhibits BMP sig-
naling, allowing neural development in these ectodermal cells.
mutants the neurogenic region expands at the expense
of the epidermis, and ectopic expression of dpp causes
a reduction in neural tissue. These Drosophila studies
motivated studies of the distribution of the BMPs at
early stages of Xenopus development, and a similar
pattern has emerged. BMP4 is expressed throughout
most of the gastrula, but at reduced levels in the organ-
izer and neurogenic animal cap. As expected, recom-
binant BMP4 can suppress neural induction by
chordin, the vertebrate homolog of Sog.
The studies of sog/chordin and dpp/BMP4 lead
to two conclusions. First, it appears that the dorsal-
ventral axis of the developing embryo uses similar
mechanisms in both the fly and the vertebrate.
However, as discussed in the previous section, the
neural tissue in the vertebrate is derived from the
dorsal side of the animal, while the neurogenic region
of the fly is on the ventral side (DeRobertis and Sasai,
1996; Holley et al., 1995). The idea that the vertebrate
and arthropod body plans were inverted with respect
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