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can also form homodimers. The E(spl) proteins may
directly interfere with achaete scute -mediated transcrip-
tion, and in addition these proteins bind to nearby sites
on the promoter and recruit additional repressor pro-
teins, such as groucho. As might be expected by their
function as transcriptional repressors, the E(spl) pro-
teins are expressed in the cells surrounding the delami-
nating neuro-blast, and they act to prevent cells from
adopting the neural fate.
E(spl) proteins can be added to the mechanism of
Notch/Delta lateral inhibition in the following way
(Figure 1.30; Bailey and Posokony, 1995). As described
above, Notch activation by Delta causes SuH trans-
location to the nucleus. Specific sequences in the pro-
moters of E(spl) genes bind the SuH protein, resulting
in the expression of E(spl) in these cells. The E(spl) pro-
teins, along with groucho, bind to the E-boxes in the
achaete-scute gene promoter and repress transcription.
Therefore, the amount of achaete-scute protein in the
cells with active Notch declines, and the cell loses its
potential to delaminate as a neuroblast. In addition, since
Delta expression is activated by achaete-scute proteins,
the reduction in the expression of achaete-scute protein
in the cells with activated Notch also results in a reduc-
tion of Delta expression in the same cells. Thus, the Notch/
Delta pathway provides a positive feedback pathway
for neuroblast formation and a molecular mechanism
for lateral inhibitory interactions among cells.
Virtually all of the molecules described in the segre-
gation of neuroblasts in Drosophila have vertebrate
homologs that are required for similar roles in the ver-
tebrate. However, it is important to note that the
Notch/Delta signaling pathway is one of the funda-
mental mechanisms by which neighboring cells become
different in metazoans. Throughout development,
there are numerous examples of cells with a common
lineage differentiating into different cell types. It is
likely that Notch/Delta signaling functions in most, if
not all, of these cases of symmetry-breaking.
structure as the Drosophila achaete scute genes and can
act as transcriptional activators as heterodimers with
vertebrate daughterless homologs, E12 and E47. These
correlative data have all supported a role for achaete
scute -like genes in the vertebrate that may be analo-
gous to that in the Drosophila . In addition, similar genes
have been identified in C. elegans and even Cnidarians ,
and so this seems to be a very ancient system for the
segregation of neuroblasts from the epidermis.
As in Drosophila , the proneural bHLH genes are
both necessary and sufficient for nervous system
formation in vertebrates. There are over 20 bHLH
transcription factors expressed in the developing
CNS of vertebrate embryos. Some of these proteins are
expressed throughout the developing brain and spinal
cord, like Neurogenin and NeuroD1 . However, others
in this family are expressed specifically in particular
regions of the nervous system. Ath5, a homolog of the
Drosophila atonal gene, is expressed specifically in the
developing retina, for example. To determine whether
genes of this class have proneural activity in verte-
brates, the genes can be experimentally overexpressed
in developing Xenopus embryos. Overexpression of
NeuroD1 in this assay causes cells in the ectoderm on
the flank of the embryo to develop as neurons instead
of epidermis (Lee et al., 1995) (Figure 1.31). Deletion of
any single bHLH gene from the mouse using knockout
technology has often not produced a clear answer
as to their requirement during development; how-
ever, it is thought that this is due to a considerable
redundancy and overlap in their expression. In this
case, Ath5 provides a good example. Ath5 is normally
expressed only in the retina, the sensory region of the
eye, and it is only expressed during the time when the
precursor cells of the eye are developing into a specific
class of neurons, the retinal ganglion cells. Deletion of
Ath5 from mice by homologous recombination causes
the specific loss of nearly all the retinal ganglion cells
(Brown et al., 1998). Thus, we can see that in this case
the proneural gene is required not for the initial stages
of neural tube formation, but rather for neurons
to form from the progenitor cells. Although this is
somewhat different from the analogous process in
Drosophila, the conservation of homologous genes in
the earliest stages of neural development suggests that
some aspects of the developmental decision to form
neurons via proneural bHLH genes are conserved
between vertebrates and invertebrates.
What about the system of lateral inhibition, Notch
and Delta? Here the vertebrate nervous system
appears to be somewhat different from the fly. Instead
of a single Notch receptor, vertebrates have at least
four Notch genes, three of which are expressed in parts
NOTCH, DELTA, AND ACHAETE
SCUTE GENES IN VERTEBRATES
Vertebrate homologs of the achaete scute genes have
been identified in several species. The first of these to
be discovered was named Mash1, for a chaete s cute
h omolog-1 (Johnson et al., 1990). In fact, vertebrates
have many more members of this family than do
Drosophila . These genes are expressed in the develop-
ing nervous system in distinct subsets of neural pro-
genitor cells. These genes have the same bHLH
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