Brain Development
101
plays an essential role in conferring re-
gional identities. Supporting the model,
many anterior homeotic transformations
are found in
Drosophila
embryos lacking
these homeodomain-containing genes.
Intriguing
is
the
fact
that
clusters
similar to the
Drosophila
homeodomain-
containing gene complex (
antenapedia
/
bithorax complex) are found in the genome
of various animals including humans, and
they are named
Hox
gene clusters as the
genome sequences encoding the home-
odomain are called
homeobox
(Fig. 7b).
Notably, the anterior boundaries of
Hox
gene expressions coincide with the rhom-
bomere boundaries, implicating them in
the important role of hindbrain segmen-
tation (Fig. 7c). The functional analyses by
gene targeting in mice (see Sect. 7 for this
methodology) indeed indicate that regional
identities in the hindbrain are controlled
by the differential expression of these
Hox
genes along the A–P axis with gene knock-
out phenotypes just being similar to the
Drosophila
homeotic mutant phenotypes.
Hox
genes have been revealed to be reg-
ulated by early posteriorizing signals such
as Wnt, FGF, and retinoic acid (RA), all of
which are secreted by surrounding tissues
including somites, highlighting the pivotal
role of
Hox
genes in linking the molecular
events that occur between neural induction
and hindbrain segmentation. For example,
Krumlauf and colleagues have found sev-
eral RA responsible elements in the
Hox
gene regulatory regions, where RA and its
receptor complex can directly interact to
control the
Hox
expression, and RA treat-
ment has been shown to affect the Hox
expression
in vivo
. Itasaki et al. have fur-
ther shown that anteriorly grafted somites
have an activity that shifts the expression
boundary of Hox anteriorly. This poste-
riorizing activity of the somites can be
separated with a simple treatment by RA,
indicating that several factors could coop-
eratively regulate the Hox gene expression
in the hindbrain.
One of the critical events that occur
during hindbrain segmentation is com-
partmentalization. If a cell is labeled by
v
i
ta
ldyes(D
iI
)andtracedforafewdays
,
sibling cell migration and/or prolifera-
tion is restricted within each rhombomere
Fig. 6
A–P patterning of the neural tube/plate. (a) Anterior part of the neural/plate becomes
segmented during development, generating brain regions with distinct structure and functions,
(b) Early patterning of the chicken neural plate by the differential expression of transcription factors.
Gene expression boundaries eventually form the anatomically distinguishable territories in the brain.
A/B, alar/basal boundary; di, diencephalon; FMB, forebrain/midbrain boundary; HH, Hamburger
Hamilton stages; me, mesencephalon; MHB, midbrain/hindbrain boundary; mt, metencephalon; my,
myelencephalon; te, telencephalon; ZLI, zona limitans interthalamica. (c) A fate-mapping result of
the mouse neural plate. The area painted by a given color on the right side of neural plate at the
5-somite stage (left) produces the brain region of the same color at E10.5 (right). Faint lines indicate
prospective boundaries of brain regions. Cell lineage restricted compartment boundaries are
indicated by bold dashed lines. Note that several gene expression boundaries demarcated by different
colors on the left side of the neural plate coincide well with prospective boundaries of brain regions:
blue line; Pax6/cadherin-6 expression boundary, red line; Otx1 expression boundary, orange line;
Nkx2.2 expression boundary, purple line; Nkx2.1 expression boundary, and green area; Emx2 mRNA
positive region in the neural plate. A/B; alar/basal boundary, FMB; forebrain/midbrain boundary, me;
mesencephalon, MHB; midbrain/hindbrain boundary, p; prosomeres, POS; preotic sulcus, r;
rhombomeres, ZLI; zona limitans interthalamica. An arrow indicates the anterior most part of the
brain at the embryonic day (E) 10.5. (See color plate p. xxvi).
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