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the potential to form neuroblasts. Under normal
circumstances, only a single cell from each cluster will
delaminate as a neuroblast. The cell that delaminates
to form the neuroblast continues to express the achaete
scute proneural genes, while all of the other cells in the
proneural cluster downregulate their expression of
achaete scute (Figure 1.25).
In experiments designed to determine whether
interactions among the cells were necessary for sin-
gling out one of the cells of the proneural cluster for
delamination as the neuroblast, Taghert et al. (1984)
used a laser microbeam to destroy the developing neu-
roblast at various times during its delamination
(Figure 1.28). They found that ablation of the delami-
nating neuroblast with a laser microbeam causes one
of the other cells in the cluster to take its place and
delaminate. These results led to the idea that the
expression of achaete scute genes, and hence neuroblast
potential, is regulated by a system of lateral inhibition.
The cell that begins to delaminate maintains its achaete
scute expression and suppresses proneural gene activ-
ity function in the other cells of the cluster. The other
cells then remain as epidermal cells, while the achaete
scute -expressing cell delaminates as the neuroblast.
The mechanisms by which the cell that ultimately
develops as the neuroblast is singled out from the
original cluster have been the subject of intensive inves-
tigation. Studies of this process have uncovered a
unique signaling pathway, which may underlie lateral
inhibitory processes in many regions of the embryo.
Molecules that act prominently in this process are the
Notch receptor and one of its ligands, Delta. Notch is a
large transmembrane protein characterized by an extra-
cellular portion with a large number of repetitive
domains, known as EGF-repeats because of their simi-
larity to the cysteine-bonded tertiary structure of the
mitogen epidermal growth factor, EGF. However,
despite this apparent structural similarity to an
extended peptide mitogen, Notch has no apparent mito-
genic activity, but rather acts to bind two ligands with
somewhat similar structures, Delta and Serrate (Fehon
et al., 1990). These proteins are expressed not only in the
nervous system, but also in many other areas of the
embryo where lateral inhibitory interactions define
tissue boundaries. In fact, Notch and Delta, and the
additional ligand, Serrate, were named for their effects
on wing development, where lateral inhibition is also
mediated by these molecules and is necessary for the
proper development of wing morphology.
The Notch/Delta pathway is critical for singling out
the neuroblast from the proneural cluster, and the fate
of the cells in the neurogenic region depends on their
level of Notch activity. Low Notch receptor activity in
one of these cells causes it to become a neuroblast,
while high activity results in the cell adopting an epi-
dermal fate. In Notch null mutants, nearly all of the
cells in the neurogenic region become neuroblasts; as
a result, the Notch null embryos have defects in the
epidermis (Figure 1.26). A similar phenotype occurs in
Delta null mutants. Because of the phenotypes the
mutant animals show, the Notch and Delta genes have
been termed neurogenic . Of course, activation of this
system actually has the opposite effect and suppresses
neuroblast formation.
One model for how the Notch/Delta signaling
pathway mediates the lateral inhibitory interactions
among the cells of the proneural cluster is shown in
Figure 1.29. Central to this model is the idea that
achaete scute transcription factors the drive expression
of Delta . Initially, all of the achaete scute -expressing
cells also express an equal amount of Notch and
Delta (Hartly et al., 1987). If, by a stochastic process,
the central cell in the proneural cluster expresses
more achaete scute than the others, this cell will then
concomitantly express a higher level of Delta than the
other cells of the cluster. When the Delta in the central
cell activates Notch on the neighboring cells, it sup-
presses their achaete scute expression and further
downregulates their Delta expression, preventing
them from differentiating as neuroblasts. In this way,
only a single neuroblast develops from the proneural
cluster at a particular location in the fly.
How does Notch activation lead to the suppression
of achaete scute in a neighboring cell? In the past few
years a considerable amount of effort has gone into
working out the signal transduction cascade for the
Notch/Delta signaling system, and so a reasonable
answer can now be given to this question. The identi-
fication of the downstream signaling components of
Kill neuroblast
ectodermal cell
New neuroblast
FIGURE 1.28 Ablation of the delaminating neuroblast with a
laser microbeam directed to the ventral neurogenic region of the fly
embryo causes a neighboring ectodermal cell to take its place. This
experiment shows that the neuroblast inhibits neighboring cells
from adopting the same fate via the mechanism of lateral inhibition.
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