Molecular Genetics of Development in Drosophila 
Shigeru Sakonju, Ph.D. — Assistant Investigator 
Dr. Sakonju is also Assistant Professor of Human Genetics at the University of Utah School of Medicine. He 
received a B.A. degree from Columbia Union College and a Ph.D. degree in biology from the Johns Hopkins 
University, having developed his doctoral thesis in the Department of Embryology at the Carnegie Institu- 
tion of Washington, Baltimore, with Donald Brown. He was a Helen Hay Whitney Postdoctoral Fellow 
with E. B. Lewis at the California Institute of Technology and at Stanford University with David Hogness. 
DURING the development of higher organ- 
isms, a fertilized egg undergoes many divi- 
sions to produce a multicellular body with char- 
acteristic segments. The basic pattern of the body 
is invariant from generation to generation and is 
dictated by a genetic blueprint within the organ- 
ism's own genome. My group is interested in 
learning about the genetic blueprint of the fruit 
fly Drosophila melanogaster. 
The fruit fly's body is made up of several fused 
segments in the head, three thoracic segments 
with wings and legs, and ten abdominal seg- 
ments. The unique characteristics of each seg- 
ment are determined by the activities of the genes 
called homeotic. When these genes malfunction, 
a body segment or group of segments transforms 
to take on characteristics of another segment. For 
example, some mutations in the homeotic gene 
Ultrabithorax cause the transformation of a non- 
winged segment into one with wings, leading to a 
four-winged instead of the normal two-winged 
fly. Thus homeotic genes can be thought of as 
master regulators that trigger the genetic circuits 
necessary for the normal body pattern. Our goal is 
to understand how the homeotic genes accom- 
plish this task at the molecular level. 
Three homeotic genes — Ultrabithorax {Ubx), 
abdominal- A (abd-A), and Abdominal-B (Abd- 
E) — are responsible for determining the charac- 
teristics of two thoracic and eight abdominal seg- 
ments. They are located in a chromosomal region 
called the bithorax complex (BX-C) . Flies carry- 
ing mutations in any one of these BX-C genes 
clearly show characteristic transformations. By 
noting which segments are transformed in these 
mutants, we can infer that Ubx is active in two 
thoracic and eight abdominal segments, abd-A in 
the second-through-eighth abdominal segments, 
and Ahd-B in the fifth-through-ninth abdominal 
segments. 
To learn about what the homeotic gene prod- 
ucts do, we have focused our studies on abd-A 
and Abd-B. Since each of the abdominal segments 
shows unique characteristics, it seemed possible 
that these genes encode multiple protein prod- 
ucts that are each responsible for determining the 
identity of a particular segment. Contrary to this 
expectation, we have found that abd-A and Abd- 
B encode one and two proteins, respectively. 
Each of these proteins contains a stretch of almost 
identical amino acid sequence, known as the ho- 
meodomain. This sequence is found in the pro- 
teins from many organisms, including humans. 
As has been shown for other homeodomain- 
containing proteins, we have demonstrated that 
abd-A and Abd-B proteins bind to DNA. Further- 
more, we have shown that the abd-A protein can 
repress the transcription of other genes in cul- 
tured Drosophila cells. It seems, therefore, that 
the abd-A and Abd-B proteins accomplish their 
tasks by regulating the transcription of other 
genes, which in turn contribute to unique char- 
acteristics of each segment. 
We are now extending our work to demon- 
strate that the homeotic proteins regulate the 
transcription process in developing embryos as 
well as in tissue culture cells. For this purpose we 
are studying the interaction of abd-A with a tran- 
scription start site, or promoter, for another ho- 
meotic gene, Antennapedia (Antp). Genetic evi- 
dence suggests that Antp expression in wild-type 
embryos is suppressed in the first abdominal seg- 
ment by Ubx and in the second-through-seventh 
abdominal segments by abd-A. From the genetic 
evidence, however, it is not known if this sup- 
pression is direct or indirect. We have now 
shown that purified Ubx and abd-A proteins bind 
to a number of sites near the promoter of the Antp 
gene. 
To test if these in vitro binding sites are indeed 
utilized for repression of Antp in embryos, we 
have mutagenized each binding site, rendering it 
incapable of binding the homeotic proteins. 
These altered DNA sequences are being intro- 
duced into the genome of the fly to see if the 
normally observed repression of Antp by Ubx or 
abd-A protein is abolished. If so, this would pro- 
vide the first conclusive evidence that homeotic 
proteins act as transcriptional regulators in devel- 
oping embryos. 
We are also interested in knowing how the ho- 
meotic genes, with a relatively small number of 
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