Genetic Dissection of a Signal Transduction 
Pathway in Drosophila melanogaster 
Norbert Perrimon, Ph.D. — Assistant Investigator 
Dr. Perrimon is also Assistant Professor of Genetics at Harvard Medical School. Of French nationality, he 
tvas educated at the University of Paris VI, where he majored in biochemistry. His thesis, with Madeleine 
Gans as advisor, was on Drosophila genetics. He moved to Case Western Reserve University as a 
postdoctoral research fellow with Anthony Mahowald. He became a Lucille P. Markey Scholar in 
Biomedical Sciences while in Cleveland. He then assumed his present position at Harvard Medical School. 
INTERCELLULAR communication is a major 
player in the establishment of developmental 
patterns. For example, in the early Drosophila 
embryo, determination of cell fates at the termini 
requires the normal activities of genes from two 
different cell types, the maternal follicle cells 
and the oocyte. The current model is that the 
transmembrane tyrosine kinase receptor encoded 
by the gene torso is locally activated at the egg 
termini by cues emanating from the follicle cells. 
This localized activation of torso is believed to 
trigger a phosphorylation cascade in the egg 
which ultimately controls the expression of the 
transcription factors tailless and huckebein. 
Knocking out this signaling pathway has detri- 
mental effects on embryonic development. Since 
cell fates at both termini are perturbed, the re- 
sulting embryos lack most head and all tail 
structures. 
Our laboratory has focused on identifying the 
genetic components involved in transduction of 
the signal from torso, the membrane-bound tyro- 
sine kinase, to the nucleus. Thus far we have 
characterized two genes, 1(1 )pole hole and 
l( 1 )corkscrew, that are involved in this process. 
Genetic epistasis experiments have demonstrated 
that both these genes act downstream of the torso 
protein activity. Furthermore, l( l)corkscrew 
acts by up-regulating the activity of 1(1 )pole 
hole. 
We previously showed that the l( 1 Jpole hole 
gene product is the homologue of the mamma- 
lian Raf- 1 proto-oncogene and encodes a serine/ 
threonine kinase. Recently we discovered that 
l( 1 ) corkscrew encodes a protein-tyrosine phos- 
phatase similar to the mammalian PTPIC protein. 
Identification of the l( 1 )pole hole and 1(1 Jcork- 
screw gene products has strengthened the 
current model that torso signaling involves a 
phosphorylation cascade, since both genes en- 
code proteins that have the ability to affect 
the level of phosphorylation of intracellular 
components. 
To identify additional molecules involved in 
torso signaling, we have taken a genetic ap- 
proach. Screens for second-site suppressors and 
enhancers of l( 1 Jpole hole and l( 1 Jcorkscrew 
mutations have successfully identified a number 
of loci involved in the torso signaling pathway. 
Future work will involve a detailed characteriza- 
tion of these suppressors. 
In addition to the genetic approach described 
above, we are utilizing a biochemical screen to 
identify and characterize other components of 
this signal transduction pathway. Involved is the 
cloning of genes encoding proteins that bind di- 
rectly to activated receptor tyrosine kinase. In 
this way we are isolating proteins that respond 
directly to the ^or50-encoded receptor. 
Establishment of cell fate at the termini of the 
embryo provides a unique genetic system to dis- 
sect the cascade by which activation of a receptor 
tyrosine kinase controls the expression of tran- 
scription factors. A combination of classical ge- 
netics and molecular and biochemical tech- 
niques will allow characterization of the 
components involved in the various steps of re- 
ceptor tyrosine kinase signaling. 
In addition, the homology between torso and 
the mammalian gene for platelet-derived growth 
factor (PDGF), between l( 1 Jpole hole and the 
mammalian Raf l proto-oncogene, and between 
l( 1 Jcorkscrew and the human PTPIC enzyme 
suggests that biochemically this signal transduc- 
tion pathway may have been conserved in evolu- 
tion between organisms as diverse as Drosophila 
and humans. Thus characterization of this path- 
way in Drosophila may help elucidate the func- 
tions of the homologous mammalian proteins. 
525 
