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the animals have defects in segmentation. Moreover, in
Drosophila the homologous gene for wnt1 , wingless , is
required for maintaining the expression of the
Drosophila engrailed gene at the segment boundaries.
Thus, the midbrain-hindbrain boundary is another
example where the same basic mechanisms as those
used in segmentation in Drosophila create differences
and boundaries in the brain. In addition to the wnt and
engrailed patterning system, the midbrain-hindbrain
junction also expresses another key signaling molecule,
FGF8, a receptor tyrosine kinase ligand. FGF8 is
necessary for both setting up this boundary and main-
taining it, since mice deficient in fgf8 show defects in
cerebellar and midbrain development similar to the
Wnt1 and En1 knockout animals (e.g., Meyers et al.,
1998). fgf8, En1 , and wnt1 seem to be in an intercon-
nected network, since deleting any one of them affects
the expression of the other two. fgf8 's role in patterning
the tissue around the mes-met boundary was demon-
strated in a remarkable experiment; Crossley et al.
(1996) placed a bead coated with fgf8 protein onto a
more anterior region of the neural tube and found that
this molecule was sufficient to induce the repatterning
of these anterior tissues into midbrain and hindbrain
structures (Figure 2.14) (Crossley et al., 1996). Thus, the
fgf8 produced by midbrain/hindbrain acts like an
“organizer” for the midbrain and hindbrain.
The model of how the midbrain-hindbrain signal-
ing center arises described above can thus be extended
as follows (Figure 2.16). Xiro activates both Otx2 and
Gbx2 in this region of the developing CNS. Gbx2 and
Otx2 cross inhibit one another, and it is at this point of
inhibition that fgf8 is expressed (Glavic et al., 2002).
The interaction between Otx2 and Gbx2 maintains fgf8
expression, and fgf8 induces engrailed in those cells that
express both Xiro and Otx2 . Through these cross-
regulatory loops between cells, the border is initially
set up and maintained through development (Rhinn
and Brand, 2001). The FGF8 produced by this region
then goes on to regulate growth of the progenitor cells
in this region to ultimately produce the brain struc-
tures of the midbrain and hindbrain, including the
cerebellum and the superior colliculus.
The unique signaling characteristics of the mid-
brain-hindbrain boundary suggest that such localized
organizing centers may be a basic mechanism of brain
patterning. There is evidence that other key organiz-
ing regions may exist between the dorsal and ventral
thalamus and at the anterior pole of the neural tube.
Moreover, as development proceeds and the brain
expands, new organizers and signaling centers appear
to pattern the newly expanded regions. It may be that
the appearance of new signaling centers coincides
with the expansion of the neuroepithelium past the
+ FGF8
Te l
Te l
Te l
Te l
FIGURE 2.14 FGF8 is a critical signal for the “organizer” activity of the mes-met boundary tissue.
(A) Crossley et al. placed a bead (shown in arrow) of FGF8 onto the telencephalon of the chick embryo and
found that this caused a new mes-met boundary to form with a mirror duplicated midbrain (B), similar to
the transplant experiment of Alvarado-Mallart. (C) Shows the control animal. (Modified from Martinez et al.,
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