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factors is linked to the normal differentiation of the
respective cells in which it is expressed, as revealed by
the fact that a particular cell type fails to develop in an
eye disc that lacks the corresponding gene.
Shortly following its own determination, R8 puts
out signals that activate two different signaling path-
ways, the Notch pathway and the Ras pathway
(Freeman, 1997; Brennan and Moses, 2000). The Notch
pathway, as we know, is activated by Delta. The Ras
pathway is a highly conserved biochemical cascade of
cytoplasmic kinases (Ras, Raf, MPK), which in this case
are activated by the epidermal growth factor receptor
(EGFR). R8 emits an EGF-like molecule, Spitz (Spi) that
activates this receptor. Activation of these signaling
cascades spreads concentrically from R8 to R2, R3, R4,
and R5 and then the remainder of the ommatidial cells.
The precise, temporally regulated activation of the
EGFR and Notch signaling pathways assigns distinct
phenotypes to the cells that join the ommatidial
clusters.
The determination of the R7 cell deserves special
mention in view of the pivotal role it has played in
opening up the molecular-genetic study of signaling
pathways. One of the first mutant screens in the field of
cell determination took advantage of the fact that only
R7 is sensitive to UV light. Thus, mutagenizing flies
and screening for offspring that are blind to UV light
yielded a fly line that lacked the R7 cell in every omma-
tidium and was therefore aptly called sevenless ( sev )
(Harris et al., 1976), (Figure 4.10). Lack of the receptor
causes the cell that would normally become R7 to
develop as a cone cell instead. In several followup
screens, many signaling molecules in the Ras pathway
activated by the Sev receptor were identified (Rubin,
1991; Hafen et al., 1994) (Figure 4.11). Among them
were the Drosophila homologs of Ras, Raf, MEK,
MAPK, and Gap1, parts of the ras signaling pathway,
as well as new genes in the signaling pathway such as
Son of sevenless ( Sos ) and Daughter of sevenless ( Dos ). This
pathway regulates the activity of transcription factors
yan and pointed (pnt) that also were identified in such
screens, and these factors control the expression of
genes involved in the differentiation of R7. One of the
most satisfying discoveries from the screens for the sev-
enless phenotype was the signal called Bride of seven-
less (Boss), which binds to Sev. Boss is expressed
specifically in R8 cells, so when any cell expressing Sev
touches R8, the Ras signaling pathway fires in this cell
and it becomes R7 (Reinke and Zipursky, 1988). These
experiments provide an impressive demonstration of
the power of genetic screens.
R8
boss
sev
Pi
Ksr
Ras 1
Ras 1
P
P
Hsp83
Raf
GTP
GTP
SOS
P
GDP
P
P
SH2
SH3
Ser/Thr
MEK
A
B
SH1
P
Thr
P
Tyr
R7
MAPK
Nuclear membrane
P
sina
Thr
Tyr P
MAPK
P
P
P
P
P
Yan
Pnt P2
ON
ETS
Target Gene Expression
R7 fate
FIGURE 4.11 Components of the sevenless transduction
pathway, include the seven transmembrane signaling molecule
bride of sevenless (boss) which is expressed by R8, the sevenless
receptor molecule (sev), and a number of downstream components
of the signaling cascade such as daughter of sevenless and (Dos) and
son of sevenless (Sos) and various members of the Ras Raf pathway
ending in the activation of the yan and pointed genes. (Courtesy of
E. Hafen)
FIGURE 4.10 Photoreceptors in the eye of normal flies (A) and
sevenless mutants (B). The red images show light that is piped up
through the clusters of receptors in each facet. The inserts are elec-
tron micrographs through a single facet and show cross sections of
the photoreceptor array. Notice that the seventh central photorecep-
tor is missing in each facet of the mutant eye.
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