Healthcare and Medicine Reference
In-Depth Information
Proneural
cluster
Notch
ICD
nucleus
CSL
A SC
Delta
Neural
genes
A SC
Delta
Delta
Notch
ICD
nucleus
Neuroblast
CSL
HES
ICD
H ES
Neural
genes
HE S
FIGURE 1.29 Just prior to the delamination of a neuroblast, a
group of cells in the ectoderm express the proneural genes, achaete
and scute (light red); this group is the proneural cluster. Shortly after,
one of the cells near the center expresses a higher level of the
proneural genes and through a process of lateral inhibition begins
to block proneural gene expression in the cells around it. Finally,
only this one cell is left expressing the proneural genes, and it delam-
inates to form the neuroblast (red).
Delta
FIGURE 1.30 The lateral inhibitory mechanism involves the
neurogenic proteins, Notch and Delta. A cell expresses achaete scute
genes (ASC), and Notch is inactive (top). The ASC activates its own
transcription to maintain its expression and also acts as a transcrip-
tion factor to activate the expression of downstream neural-specific
genes and the Notch ligand Delta. This cell would then become a
neuroblast. However, if a neighboring cell expresses more Delta and
thus activates the Notch pathway in the cell (bottom),
the activated Notch leads to a proteolytic release of the intracellular
part of the Notch molecule. The piece of Notch that has been
chopped off is known as the ICD (for intracellular domain). The
Notch ICD interacts with another molecule, Suppressor of Hairless
(SuH, also known as CSL), and together they diffuse to the nucleus
and act as transcription factors to turn on the expression of another
gene, called Hairy or Enhancer of Split (or more simply HES). The
HES proteins are repressors of ASC gene transcription, and so
they block further neural differentiation and reduce the levels of
Delta expression. Thus, this cell is suppressed from the neural fate
because of Notch activation by a neighboring cell that expressed
more Delta.
the Notch pathway took advantage of other Drosophila
mutants, as well as biochemical analysis of the homol-
ogous pathway in vertebrates. As described above,
Notch is a transmembrane protein, with many EGF-
repeats in the extracellular domain and a distinct intra-
cellular domain, which contains a repeating motif
known as cdc10/ankyrin repeats. The cdc10/ankyrin
repeats in the intracellular domain of Notch are criti-
cal for the signal transduction via this system. Muta-
tions in Notch that delete the cdc10/ankyrin repeats
in the intracellular domain affect Notch signaling.
Moreover, another neurogenic protein in Drosophila,
Suppressor of hairless (SuH), has been shown to
specifically bind to the cdc10/ankyrin repeats of Notch
(Fortini and Artavanis-Tsakonis, 1994). A current
hypothesis for how signal transduction works in this
system is as follows (Figure 1.30). When Notch is not
bound to Delta, SuH is tethered to the cytoplasm,
bound to the cdc10/ankyrin repeats of Notch. The acti-
vation of Notch by binding to Delta causes SuH to be
released from Notch. SuH can then be translocated to
the nucleus where it acts as a transcriptional activator
at genes with the specific DNA sequence GTGGAA in
their promoters.
The genes activated by SuH should suppress
neuroblast formation, since Notch activation in the epi-
dermal cells prevents them from delamination. This
expectation has been confirmed by the demonstration
that SuH directly regulates the transcription of another
class of bHLH proteins, the enhancer of split complex
(E(spl)) of genes. The E(spl) genes code for proteins that
are similar to the proneural bHLH proteins of the achaete
scute class, but instead of acting as transcriptional acti-
vators, they are strong repressors of transcription. There
are seven E(spl) genes in Drosophila, and their expres-
sion patterns overlap considerably, so they are thought
to be at least partly redundant. The proteins coded by
these genes form heterodimers with the achaete scute
proteins through their dimerization domains, but they
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Search Pocayo ::




Custom Search