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through their interactions with the Pbx and Meis
homeodomain proteins. Moens and her colleagues
(Waskiewisz et al., 2002) have taken advantage of this
interaction to ask what the hindbrain would look
like without any functional Hox code. By eliminating
the Pbx genes from the hindbrain of the zebrafish
with a combination of genetic mutation and antisense
oligonucleotide gene inactivation, they have found
that the “ground state” or default condition of the
hindbrain is rhombomere number 1. Embryos lacking
both Pbx genes that are normally expressed in the
hindbrain during rhombomere formation lose rhom-
bomeres 2-6, and instead these segments are trans-
formed into one long rhombomere 1 (Figure 2.7).
The remarkable conservation of Hox gene function-
ing in defining segmental identity in both Drosophila
embryos and vertebrate hindbrain prompts the ques-
tion whether similar mechanisms upstream of Hox
gene expression are also conserved. As discussed
above, a developmental cascade of genes—the gap
genes, the pair-rule genes, and the segment polarity
genes—parcel up the domains of the fly embryo into
smaller and smaller regions, each of which has a
unique Homeobox expression pattern. Does a similar
mechanism act in the vertebrate brain to control the
expression of the Hox genes? Although the final
answers are not yet known, there are several key
observations that indicate vertebrates may use some-
what different mechanisms to define the pattern of
Hox expression.
One of the first signaling molecules to be implicated
as a regulator of Hox expression was a derivative of
vitamin A, retinoic acid (RA). This molecule is a
powerful teratogen; that is, it causes birth defects.
Retinoic acid is a common treatment for acne, and
since its introduction in 1982, approximately one thou-
sand malformed children have been born. The most
significant defects involve craniofacial and brain
abnormalities. The way in which RA works is as
follows: RA crosses the cell membrane to bind a cyto-
plasmic receptor (Figure 2.8). The complex of RA and
the retinoic acid receptor (RAR) moves into the
nucleus, where it can regulate gene expression through
interaction with a specific sequence in the promoters
of target genes (the retinoic acid response element, or
RARE). In the normal embryo, there is a gradient of
wt
MZizr; pbx2MO
A
B
C
D
r3 r4 r5
MHB
E
F
FIGURE 2.7 What would the hindbrain look like without Hox genes? By eliminating the pbx genes from
the hindbrain of the zebrafish with a combination of genetic mutation and antisense oligonucleotide gene
inactivation, Moens and colleagues found that the “ground state” or default condition of the hindbrain is
rhombomere number 1. To the right is a drawing of the fish for orientation, with the hindbrain highlighted
in red. A, C, and E show the wild-type embryo, and panels B, D, F show the mutant embryo hindbrain. In
embryos lacking both pbx genes all segments are transformed into one long rhombomere 1, and both the spe-
cific gene expression seen in rhombomeres 3, 4, and 5 (D) and the diversity of neurons that form in the hind-
brain (E) are lost in the mutant. (Modified from Waskiewicz et al., 2002)
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