Cell-Cell Interactions Determine Cell Fate in the 
Drosophila Retina 
S. Lawrence Zipursky, Ph.D. — Associate Investigator 
Dr. Zipursky is also Associate Professor of Biological Chemistry at the University of California School of 
Medicine, Los Angeles. He received his Ph.D. degree from Albert Einstein College of Medicine, where he 
studied mechanisms ofDNA replication in bacteria in the laboratory of ferard Hurwitz. He moved to the 
California Institute of Technology to pursue postdoctoral studies in Drosophila neurogenetics with 
Seymour Benzer. He has been on the faculty of UCLA for seven years. 
WE are interested in two questions in devel- 
opmental biology. First, How are specific 
cell fates established through cell-cell interac- 
tions? And second, What are the mechanisms un- 
derlying the specificity of neuronal connectivity? 
To address these issues, we have focused our stud- 
ies on the development of the Drosophila visual 
system. I will briefly describe progress we have 
made in understanding the cellular and molecu- 
lar mechanisms underlying the specification of a 
unique cell fate in the developing retina. This 
work is supported in part by a grant from the Na- 
tional Institutes of Health. We are using similar 
genetic and molecular approaches toward under- 
standing how different classes of photoreceptor 
neurons identify their unique postsynaptic tar- 
gets in the developing brain. 
Development of the Drosophila Retina 
The Drosophila retina has a near-crystalline 
structure of some 800 identical units called om- 
matidia. Each ommatidium contains a group of 
cells organized in a stereotyped fashion, with 
eight photoreceptor neurons, designated R1-R8, 
forming its core, surrounded by accessory cells 
that produce screening pigments and the lens. 
Genetic studies in the 1970s established that 
there were no strict cell lineage relationships be- 
tween the cells in the fly's eye. Observations have 
supported the view that the developmental mech- 
anisms regulating the acquisition of cell identity 
are dependent not on a cell's ancestry but rather 
on its interactions with other developing cells. 
The R cells are the first to develop within the 
ommatidial unit. Their stereotyped and sequen- 
tial pattern of diff'erentiation suggested to early 
workers that cell fates were established as a con- 
sequence of a cascade of inductive interactions. 
Cell fates were proposed to be a result of unique 
inductive cues provided by differentiating neigh- 
boring cells. The first cell to differentiate is R8, 
followed by the cells surrounding it. The last cell 
to differentiate is R7. It contacts the differentiat- 
ing R8, Rl, and R6 cells as well as a number of 
other unpatterned and undifferentiated cells. It 
was proposed that the unique R7 cell fate was 
induced by specific signals requiring direct cell 
contacts between the R7 precursor and the Rl, 
R6, and R8 cells. 
An Inductive Event Specifying 
R7 Development 
The first step toward a molecular description 
of the developmental mechanisms regulating R7 
development was the discovery of the sevenless 
{sev) mutation. In flies carrying this mutation, 
the R7 cell fails to assume its normal fate and 
becomes a nonneuronal lens-secreting cone cell. 
The sev gene was shown to encode a receptor 
tyrosine kinase, which is expressed in the R7 pre- 
cursor cell and many other cells of the develop- 
ing eye. The molecular structure of the sev pro- 
tein, its expression pattern, and its genetic 
requirement in the R7 precursor cell led to the 
proposal that it is a receptor for an inductive cue 
specifying an R7 cell fate. 
Several years ago we identified a mutation in 
another gene, bride of sevenless (boss), which 
resulted in a phenotype identical to sev. Genetic 
studies indicated that boss is required in R8, not 
for its own development but for that of the R7 
cell. This raised the intriguing notion that the 
boss protein is an inductive ligand to which the 
sev receptor binds. Molecular analysis of the boss 
protein revealed that it is an integral membrane 
protein with a large extracellular domain, multi- 
ple transmembrane segments, and a short cyto- 
plasmic tail. Using antibodies, we showed that 
boss is specifically expressed in the R8 neuron. 
Three observations argue that the boss protein 
is a ligand for the sev receptor. First, mixtures of 
sev and boss-expressing tissue culture cells bind 
specifically to one another. Second, membranes 
containing the boss protein rapidly and specifi- 
cally activate the sev tyrosine kinase activity. And 
finally, boss was shown to be transferred from the 
surface of the R8 cell to an organelle in R7 re- 
ferred to as a multivesicular body. This internal- 
ization is strictly dependent upon the presence of 
the sev protein on the surface of the R7 cell. 
Earlier workers had demonstrated that the sev 
471 
