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FIGURE 2.11 Expression of otx2 reflects the basic division between the rostral brain and the hindbrain
and spinal cord. Otx2 expression at various stages of embryonic development in the chick brain. Otx2 is
expressed in the anterior neural plate (A) and remains expressed in most of the brain throughout develop-
ment (B-E). The arrowhead points to the midbrain-hindbrain boundary. (From Millet et al., 1996)
rior end of the brain to the midbrain/hindbrain border,
while Otx2 has the complementary pattern of expres-
sion, from the midbrain/hindbrain border to the ante-
rior-most part of the brain (Figure 2.11). Direct
evidence that shows these genes are critical for this
fundamental division of the CNS into anterior and
posterior compartments come from mouse gene tar-
geting experiments. Deletion of the Otx2 gene in mice
results in animals without a brain anterior to rhom-
bomere 3 (Figure 2.12; Matsuo et al., 1995; Acampora
et al., 1995). In mice without the Gbx2 gene, the con-
verse result is observed: the mice lack the hindbrain
region (Millet et al., 1999; Wassarman et al., 1997).
These genes are initially induced in this region by
another type of transcription factor, known as Xiro .
One current model is that Xiro activates both Otx2 and
Gbx2 , which then cross-repress one another to create a
sharp border between them (Glavic et al., 2002). This
type of cross repression of transcription factors is a
widely used mechanism for the generation of distinct
boundaries between expression domains in the
embryo. As we shall see in the next section, the mid-
brain/hindbrain boundary becomes an important
organizing center in its own right.
FIGURE 2.12 Otx2 is required for the formation of the mouse
head. A dramatic illustration of the importance of the otx2 gene in
the development of the mouse forebrain and rostral head. If the gene
is deleted using homologous recombination, embryos without either
allele of the gene fail to develop brain regions rostral to rhombomere
3, a condition known as anencephaly. Since many of the bones and
muscles of the head are derived from neural crest, which also fails
to form in these animals, the animals lack most of the head in addi-
tion to the loss of the brain. (From Matsuo et al., 1995)
tures derived from this region, the midbrain/hind-
brain border (or mesencephalon/metencephalon
border) has a special developmental function. Like the
Spemann “organizer” of the gastrulating embryo, the
midbrain/hindbrain border expresses signaling mole-
cules that have an important organizing influence
on the development of the adjacent regions of the
The idea that specific regions of the neural tube act as
organizing centers for patterning adjacent regions was
The division between the metencephalon and the
mesencephalon appears to be a fundamental one. This
boundary is a major neuroanatomical division of the
mature brain as well; the metencephalon gives rise to
the cerebellum, and the mesencephalon gives rise to
the midbrain (superior and inferior colliculi) (Figure
2.13). But in addition to the important neural struc-
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