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when co-injected with the tBMPR. They identified a
gene that was particularly effective in inducing head
structures, dickkopf, for the German word meaning
big-head or stubborn (Glinka et al., 1998). These three
wnt inhibitors are reminiscent of the BMP inhibitors
described above, in that they are expressed in the
organizer region during the time when the inductive
interactions are taking place, and they all have head-
inducing activity, particularly when combined with a
BMP inhibitor (Figure 2.9).
The evidence that there are indeed several putative
wnt inhibitors in the organizer is good support for the
model that a co-inhibition of wnt and BMP signals
leads to induction of the anterior neural structures,
that is, the brain. In fact, the cerberus protein can
inhibit both the wnt and BMP pathways. Additional
support for the model has recently been obtained from
studies of mice in which the mouse homolog to dick-
kopf, dkk1 , has been deleted via homologous recombi-
nation. The mice lacking dkk1 alone are similar to the
compound noggin/chordin knockout mice described
above: they lack head and brain structures anterior to
the hindbrain (Mukhopadhyay et al., 2001; Figure
2.10). Synergy between the BMP antagonist, noggin,
and the wnt antagonist, dkk1 , can be seen by produc-
ing mice with a single allele of each of these genes.
Although the loss of a single allele of either of these
genes has no discernible effect on mice, the loss of a
single allele of both of these genes causes severe head
and brain defects, similar to those animals that have
lost both alleles of the dkk1 gene. Similarly, knocking
out the wnt inhibitor dkk1 leads to a headless embryo,
and in the zebrafish mutant masterblind —where there
is a loss of axin, a component of wnt inhibitory signal-
ing pathway—no forebrain develops. Taken together,
the studies in mice show that the wnt and BMP antag-
onists work together to bring about the correct induc-
tion and pattern of the nervous system.
The third class of molecules that has been proposed
as a “transformer” is FGF. FGFs are able to act as
neural inducers and in addition are able to induce
posterior gene expression in animal caps that have
undergone “neural induction” using a BMP antago-
nist. Although the specific FGF necessary for the
endogenous transforming activity is not known,
several members of this family are expressed in early
development. Although the relative contributions of
FGF , wnt , and RA signaling pathways for A-P axis
specification in the brain are not clear, work by Kudoh
et al. (2003) indicates that these factors may all con-
verge on a common pathway. Both FGF and wnt
signals suppress expression of cyp26, an enzyme
involved in retinoic acid metabolism. Without this
enzyme, the levels of RA rise in the anterior of the
embryo, which could lead to posteriorization.
How do these signals—FGF, RA, and wnt —direct
the development of the different brain regions? As
noted above, the Hox genes are critical in the develop-
ment of rhombomere identity; however, two other
homeodomain transcription factors— Otx2 and Gbx2
are necessary for a more fundamental division of the
brain, the division between the hindbrain and the
forebrain (Joyner et al., 2000). At late gastrula/early
neural plate stages in the frog, one can already see
these genes expressed in domains adjacent to one
another: Gbx2 -expressing cells extend from the poste-
FIGURE 2.10 Dkk1 and noggin cooperate in head induction. Mice in which one allele for the genes for
both Dkk1 and Nog have been deleted have severe head defects. Frontal ( A,B ) and lateral ( A ¢, B ¢) views of
wild-type ( A , A ¢) and mutant ( B,B ¢), newborn animals. Lateral view of skeletal preparations from wild-type
( A ≤) and severe mutant ( B ≤) newborn heads reveal loss of maxillar (mx), mandibular (mn), and other bones
anterior to the parietal bone (p). (Modified from del Barco Barrantes et al., 2003)
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