understanding the basis for functional specificity of 
these genes. A gene encoding a novel homeodomain 
also was identified as a target for regulation by the 
homeotic gene of the bithorax complex. 
Genetic analysis of Drosophila has identified 
most of the genes involved in early development. 
Many of these genes contain a homeodomain (HD), 
a DNA-binding motif also present in mammals. The 
laboratory of Associate Investigator Claude Desplan, 
Ph.D. (Rockefeller University) is studying hov^ pro- 
teins with related sequences, such as the HD, per- 
form their specific roles during development. The 
determinants of HD specificity in vivo are being in- 
vestigated. Single-amino acid changes can affect 
both the base pair recognition and the dimerization 
state of HD proteins and therefore affect their func- 
tion during development. Other DNA-binding do- 
mains such as the Paired domain are also found asso- 
ciated with the HD and act in combination or 
independently to broaden the specificity range of 
the developmental protein. Another level of speci- 
ficity is achieved by post-transcriptional control of 
the HD proteins. For example, the activity of the 
Bicoid morphogen, whose concentration gradient is 
required for anterior patterning, is modified by a 
signal transduction pathway at the anterior pole of 
the embryo, leading to its inactivation. The nature of 
these modifications is being investigated both in 
vivo and biochemically. 
Position-effect variegation is a phenomenon seen 
in Drosophila in which a chromosome rearrange- 
ment places a gene in an unaccustomed location, 
leading to its dysfunction. For one particular gene, 
the copy on the normal homologous chromosome 
also becomes dysfunctional. The laboratory of In- 
vestigator Steven Henikoflf, Ph.D. (Fred Hutchinson 
Cancer Research Center) is investigating the genetic 
basis for this effect on the homologue. In other 
work, they are studying a chromosome that is highly 
unstable throughout development, apparently due 
to a chromosomal rearrangement that causes centro- 
mere dysfunction. Methods for detecting distant re- 
lationships between sequences of proteins are also 
under development. 
Assistant Investigator Norbert Perrimon, Ph.D. 
(Harvard Medical School) and his colleagues have 
undertaken a molecular and genetic analysis of two 
signal transduction pathways implicated in cell fate 
determination in the Drosophila embryo. The first 
pathway operates through local activation of the re- 
ceptor tyrosine kinase torso gene. Work has shown 
that the D-ra/serine/threonine kinase, a C5?f nonre- 
ceptor protein-tyrosine phosphatase, and ras-1 are 
required to transduce the torso signal. The second 
pathway under investigation involves the secreted 
protein of the wingless gene, which shows signifi- 
cant homology to the mammalian Wnt-1 protein. 
Among the signal transducers isolated so far are a 
zw3 serine/threonine kinase and a novel dsh pro- 
tein. The long-term goal of the laboratory is to iden- 
tify the components involved in these pathways and 
test their interactions in order to decipher how the 
morphogenetic signals from these systems control 
gene expression in the receiving cells. 
Through enhancer detector screens, two Drosoph- 
ila genes that are expressed in the differentiating 
embryonic peripheral nervous system (PNS) have 
been cloned and sequenced in the laboratory of 7\s- 
sistant Investigator Hugo J. Bellen, D.V.M., Ph.D. 
(Baylor College of Medicine). Both genes are ex- 
pressed in the sensory motor cells and differ- 
entiating PNS. One gene encodes a protein with an 
RNA-binding domain that may regulate RNA process- 
ing of genes required for normal functioning of 
the PNS. The other gene encodes an extracellular 
immunoglobulin-like molecule that is membrane- 
associated and secreted. This gene may play a role in 
the fasciculation of peripheral neurons and forma- 
tion of the neuromuscular junction. Also under in- 
vestigation is a third gene that encodes synaptotag- 
min, a synaptic vesicle protein. Studies on its role in 
the release of neurotransmitters suggest that it is an 
essential gene. 
Research in the laboratory of Assistant Investiga- 
tor Stephen M. Cohen, Ph.D. (Baylor College of Med- 
icine) is concerned with the origin and control of 
limb development during embryogenesis. This 
problem is particularly accessible in the Drosophila 
because of the ease of isolation of mutations that 
disrupt normal developmental processes. These 
studies have led to identification of a key gene that 
controls limb development in the Drosophila em- 
bryo. The Distal-less gene is required to instruct 
embryonic cells to become a part of the prospective 
limb. This gene is expressed in the presumptive 
limb cells and may initiate their developmental pro- 
gram by activating a set of genes specific for limb 
development. It is therefore important for the em- 
bryo to regulate stringently the locations at which 
the gene is activated. The means by which this con- 
trol is effected are being studied. Genes through 
which Distal-less acts are also being explored in 
order to understand the organization of limb devel- 
opment at a molecular level. 
Investigator Michael Rosbash, Ph.D. (Brandeis 
University) and his colleagues work in two different 
areas. They are examining gene expression with an 
emphasis on the mechanisms by which RNA tran- 
scripts are processed in the nucleus before they are 
transported to the cytoplasm for protein synthesis. 
GENETICS 145 
