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Spemann and others demonstrated that there may be
separate “head” and “tail” organizers. This fact sug-
gests that the very early inductive signals for neural
development also influence the A-P axis. In a now
classic experiment, Nieuwkoop (see Chapter 1) trans-
planted small pieces of ectodermal tissue from one
embryo into a host at various positions along the ante-
rior-posterior axis. In all cases, the transplanted cells
developed anterior neural structures. However, when
the cells were transplanted in the caudal neural plate,
posterior structures, such as spinal cord, also devel-
oped. Therefore, he concluded that the initial signal
provided by the organizer is to cause ectodermal cells
to develop anterior characteristics, known as the “acti-
vator,” while a second signal is required to transform
a portion of this neural tissue into hindbrain and spinal
cord, known as the “transformer.”
Several more recent lines of evidence are con-
sistent with the activator-transformer hypothesis. For
example, the neural inducers that have been identified
(e.g., noggin, chordin, follistatin) produce primarily
anterior brain structures when added to animal caps
(see Chapter 1). Also, as described in Chapter 1, tar-
geted deletion of putative neural inducers, such as the
noggin/chordin double knockout mouse, results in
headless mice. At the present time, three molecular
pathways have been implicated as contributing to the
“transformer” activity. As described above, retinoic
acid treatment can posteriorize embryos and is almost
certainly responsible for the patterning of the hind-
brain Hox gene expression. Other groups have found
that there is an endogenous AP gradient of wnt/beta-
catenin activity in the embryo, with the highest levels in
the posterior of the embryo (Kiecker and Niehrs, 2001).
Several lines of evidence support the hypothesis that
development of head structures and brain neural tissue
requires the inhibition of not only the BMP signaling
pathway, but also the inhibition of the wnt pathway
(Glinka et al. (1997); Figure 2.9). When dominant-
negative wnt8 was injected into Xenopus embryos along
with the truncated BMP receptor, complete ectopic
axes, including head structures, were formed. In
addition, several inhibitors of the wnt pathway are
expressed in the organizer region. One of the first
factors specifically implicated in head induction was
called cerberus, after the three-headed dog that guards
the gates of Hades in Greek mythology. Injection of
cerberus into Xenopus embryos causes ectopic head for-
mation without the formation of trunk neural tissue
(Baumeester et al., 1996). A second wnt inhibitor,
known as frzB , is a member of a family of proteins that
are similar to the receptors for the wnt proteins, known
as frizzleds. The frzB proteins work by binding to the
wnt proteins and preventing them from binding to their
tBR + dnXwnt-8
tBR + dkk-1
tBR + mouse dkk-1
anti 14 Ab
anti 15 Ab
FIGURE 2.9 Heads vs. Tails: the role of Wnt signaling.
Antagonism of Wnt signaling is important for head induction in
frog embryos. A,B. Injection of four-cell embryo with both the trun-
cated BMP receptor (tBR) and a dominant-negative form of wnt8
(dnXwnt8) causes frog tadpoles to develop a second head. B shows
a section through such a tadpole revealing both the primary and sec-
ondary brains. C,D. Expression of dkk-1 in late gastrulae (stage 12)
Xenopus embryos. In situ hybridization of embryo whole-mount (C)
and section (D). Embryos are shown with animal side up, blastopore
down. Arrows point to corresponding domains in C and D. The
endomesoderm (em) is stained in a wing-shaped pattern, and most
posterior expression is in two longitudinal stripes adjacent to the
chordamesoderm (cm). E,F. Injection of either Xenopus or mouse
Dkk-1 into the blastomeres of a four-cell-stage frog embryo causes
an extra head to develop as long as the truncated BMP (tBR) recep-
tor is co-injected. G-J. Dkk-1 is required for head formation. Stage 9
embryos were injected with antibody (Ab) into the blastocoel and
allowed to develop for three days. G,H. Embryos injected with a
control (anti-14) antibody show no abnormalities. An anterior view
is shown on the right. I,J. Embryos injected with anti- dkk1 (anti-15)
antibody show microcephaly and cyclopia. An anterior view is
shown on the right. Note that trunk and tail are unaffected. (Modi-
fied from Glinka et al., 1997; Glinka et al., 1998)
signaling receptor. Injection of extra frzB into Xenopus
embryos also causes them to form heads larger than
normal. A third wnt inhibitor was isolated by a func-
tional screen similar to that described for noggin (see
above); in this case, Niehrs and colleagues injected the
truncated BMP receptor (tBMPR) along with pools
from a cDNA library and looked for genes that would
cause complete secondary axes, including heads, only
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