Development of the Drosophila Visual System 
in R7 development, we have examined the pat- 
tern of sevenless expression in the developing 
retina and have studied the effects of experimen- 
tally altering this pattern. By transiently express- 
ing the sevenless protein, we have shown that 
there is only a brief period during eye develop- 
ment when the sevenless protein is required for 
t-he formation of the R7 photoreceptor. Our re- 
sults are consistent with the proposal that seven- 
less directly reads positional information re- 
quired to specify the R7 developmental pathway. 
A major current goal is to elucidate the intra- 
cellular signal transduction pathway that is acti- 
vated by stimulation of the sevenless protein. 
That is, how does activation of the sevenless tyro- 
sine kinase instruct a cell to become an R7 pho- 
toreceptor? Defining the biologically relevant 
substrates of tyrosine kinase receptors has been a 
long-standing and difficult problem. We have 
taken a genetic approach toward identifying 
genes whose products act downstream of seven- 
less, including those that might be direct sub- 
strates for the sevenless kinase. 
We have utilized two strategies. First, we have 
looked for other mutations that give the same phe- 
notype as sevenless — transformation of the R7 
cell into a nonneuronal cell type. In this way we 
isolated the seven-in-absentia (sina) gene. 
Function of the sina gene is required only in R7 
for correct R7 cell development. The sina pro- 
tein, which has a potential metal-binding do- 
main, is localized in the nuclei of several omma- 
tidial precursor cells, including R7, and sina 
expression in R7 appears before R7 overtly be- 
gins to differentiate. These data indicate that the 
sina gene product is necessary at a stage in the 
determination of R7 cell fate when R7 receives 
and interprets developmental signals from neigh- 
boring cells and possibly acts by regulating gene 
expression. 
Second, we utilized a crippled sevenless pro- 
tein, whose activity is just barely adequate to 
specify R7 cell development, to establish a highly 
sensitive assay for other components of this signal 
transduction pathway. Using this assay we looked 
for other genes in which a 50 percent reduction 
of the level of their protein products resulted in a 
failure to specify R7 cells. In this way we have 
identified seven genes that appear to encode 
products that act to interpret the signal mediated 
by the sevenless receptor. 
The putative products of two of these seven 
genes have been identified. One encodes a ras 
protein. The ras oncogene is implicated in as 
many as 30 percent of human tumors. The ras 
proteins exist in two different states: an inactive 
GDP-bound state and an active GTP-bound state. 
The active ras protein transmits a signal by inter- 
action with unidentified cellular targets. The 
other locus whose product we have identified en- 
codes a protein that is homologous to the Sac- 
charomyces cerevisiae CDC25 protein, an acti- 
vator of GDP-GTP exchange by ras proteins. 
These results suggest that the stimulation of ras 
protein activity is a key element in the signaling 
by sevenless and that this stimulation may be 
achieved by activating the exchange of GTP for 
bound GDP by the ras protein. The evolutionary 
conservation of the ras signaling pathway sug- 
gests that studies in Drosophila could provide 
clues to the role of ras in oncogenesis and devel- 
opmental abnormalities in humans. 
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