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Stage 10
Adult brain
Midbrain (tectum or colliculus)
Stage 10
FIGURE 2.13 A signaling center at the midbrain-hindbrain (mesencephalon-metencephalon) boundary
organizes this region of the brain. A. During normal development, the region of the midbrain-hindbrain
junction expresses the homeodomain transcription factor engrailed (red), and this region of the neural tube
contains the progenitors of the midbrain (tectum) and the cerebellum. B. To determine whether these parts
of the neural tube were restricted in their potential at this time in development, Alvarado-Mallart et al.
transplanted a small piece of the quail metencephalon (red) to the forebrain of a similarly staged chick
embryo. Cerebellum still developed from the metencephalon transplants, but in addition, the transplanted
tissue had induced a new mesencephalon to develop from the adjacent forebrain neural tube
first put on a firm molecular basis through studies of the
midbrain/hindbrain border. In a series of experiments
designed to test the state of commitment of this part of
the neural tube, Alvarado-Mallart and colleagues trans-
planted small pieces of the neuroepithelium from the
midbrain/hindbrain border of chick embryos to simi-
larly staged quail embryos (Alvarado-Mallart, 1993).
Grafting between these two species allows the investi-
gator to follow the fate of the transplanted cells.
Although the chick and quail cells behave similarly and
integrate well together in the tissues, molecular and
histological markers can be used to tell them apart
after histological processing. When the presumptive
metencephalon region was transplanted from a quail to
the metencephalon of a chick embryo, the transplanted
cells developed as cerebellum. When cells from the
mesencephalon were transplanted to a corresponding
region of the chick embryo, the cells developed into
midbrain structures, like the optic tectum (or superior
colliculus). However, when cells from the meten-
cephalon were transplanted to the forebrain, not only
did cerebellum still develop from the metencephalon
transplants (Figure 2.13) but, surprisingly, the trans-
planted tissue “induced” a new mesencephalon to
develop in the forebrain. In other words, the small piece
of hindbrain neural tube was able to re-pattern the more
anterior regions of the neural tube to adopt more poste-
rior identities. This experiment is reminiscent of the
organizer transplant of Spemann, in that a small region
of specialized tissue is able to re-pattern the surround-
ing neuroepithelium when transplanted.
Several important signaling molecules have been
localized to this region and are now known to play a key
role in these patterning activities, including wnt1,
engrailed (en1), and FGF 8 . A member of the wnt gene
family, wnt1 , is expressed in this region (Figure 2.15),
and when this gene is deleted in mice, the animals lose
most of the midbrain and cerebellum (McMahon and
Bradley, 1990). One of the earliest observed defects in
these animals is the loss of expression of a transcription
factor, engrailed-1 (or en1 ), which is normally expressed
in the region of the mesencephalon-metencephalon
boundary. The expression of en1 in this region has also
been shown to be critical for normal development of
midbrain and hindbrain structures. Mice homozygous
for a targeted deletion in the en1 gene are missing most
of the cerebellum and the midbrain similar to the
wnt1 -deficient mice (Wurst et al., 1994). en1 and wnt1
were first identified in Drosophila segmentation
mutants; when either of these genes is defective in flies,
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