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 
Institution 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 organisms, the 
fertihzed egg undergoes many divisions to 
produce a mukicellular body. In the fruit fly Dro- 
sophila melanogaster, the body is made up of 
several fused segments in the head, 3 thoracic 
segments with wings and legs, and 10 abdominal 
segments, each showing unique characteristics. 
This basic pattern of body segments, invariant 
from generation to generation, is dictated by a 
genetic blueprint within the organism's own 
genome. 
The characteristics, or identity, of each body 
segment are determined by the activities of the 
so-called homeotic genes. When these do not 
function properly, a body segment or group of 
segments transforms to take on the characteristics 
of another segment. Thus homeotic genes can be 
thought of as master regulatory switches that trig- 
ger the genetic circuits necessary to form normal 
body patterns. Genes similar to the homeotic 
genes of the fruit fly are found in other organisms, 
including humans. The goal in my laboratory is to 
understand how the homeotic genes accomplish 
their task at the molecular level. 
In Drosophila, three homeotic genes — Ultra- 
bithorax (JJbx), abdominal- A (abd-A), and 
Abdominal-B (Abd-E) — are responsible for de- 
termining the characteristics of two thoracic and 
nine abdominal segments. These genes are lo- 
cated in a chromosomal region called the bitho- 
rax complex (BX-C) . Flies carrying mutations in 
any one of the three BX-C genes show characteris- 
tic transformations of body segments. By observ- 
ing which segments are transformed in these mu- 
tants, we know that Ubx is required in two 
thoracic and eight abdominal segments, abd-A in 
the second through eighth abdominal segments, 
and Abd-B in the fifth through ninth abdominal 
segments. 
To learn what homeotic proteins do in the cell, 
we have focused on the proteins encoded by Ubx 
and abd-A. Many homeotic proteins, including 
these, have been shown to bind DNA in vitro, 
suggesting that they act by binding to transcrip- 
tional signals of other genes to regulate expres- 
sion. Whether this is how they act in living organ- 
isms has not been directly shown. Therefore we 
have chosen to study the regulation of a potential 
target gene of Ubx and abd-A proteins, called An- 
tennapedia (Antp), as a paradigm for the mecha- 
nism of homeotic protein actions. 
We have shown that both Ubx and abd-A pro- 
teins bind to a number of sites on the DNA seg- 
ment that contains the signals necessary for tran- 
scription of the Antp gene. We have further 
shown, by creating mutations in the binding sites 
and assaying their effects, that this binding is es- 
sential for repressing the Antp gene expression in 
the embryo. Our study therefore provides direct 
evidence that homeotic proteins do turn on or oflF 
transcription of their target genes. 
What are the target, or downstream, genes regu- 
lated by homeotic proteins? Little is known about 
potential target genes, even though many are 
thought to exist. To identify such targets, we have 
utilized a method, called the enhancer trap, of 
detecting genes with expression patterns that 
suggest homeotic gene regulation. A number of 
candidates have been isolated, and we are testing 
them for further evidence of being the down- 
stream genes. We have shown that the expression 
of several candidate genes is abnormal in the mu- 
tant embryos that do not produce Ubx protein, 
suggesting that the protein does regulate this 
gene. 
We are also interested in determining how the 
homeotic genes with a relatively small number of 
encoded proteins can specify many unique body 
segments. One answer lies in the fact that these 
genes are expressed in different but overlapping 
sets of segments. For example, of the three ho- 
meotic proteins from the BX-C, only Ubx protein 
is detected in the second and third thoracic seg- 
ments; both Ubx and abd-A proteins are present in 
the second through fourth abdominal segments; 
and all three BX-C proteins are found in the fifth 
through eighth abdominal segments. 
These three combinations would of course de- 
fine only three segment identities if all cells 
within segments were expressing the same combi- 
nation of the homeotic genes. In fact, cells within 
a segment do not express the same combination. 
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