genes. New technologies in molecular genetics have 
made it feasible to isolate these genes, and the labo- 
ratory is attempting to clone two such genes: the 
mouse obesity genes ob {obese) and db (diabetes) . 
Each gene, if defective, results in a grossly obese 
state, with affected mice weighing up to three times 
normal. Recent progress has narrowed the search for 
the ob gene to ~ 400-600 base pairs of DNA on 
mouse chromosome 6. Similar efforts have localized 
db to a relatively small region of mouse chromo- 
some 4. The identification of these genes should 
lead to a fuller understanding of the factors that con- 
trol body weight in health and disease. 
The laboratory of Assistant Investigator Paul A. 
Overbeek, Ph.D., M.B.A. (Baylor College of Medi- 
cine) is studying a transgenic family of mice 
(OVE210) with a mutation that causes a reversal of 
the normal left-right polarity of embryonic develop- 
ment. Homozygous mice show a transposition of 
their internal organs, with their stomach, spleen, 
pancreas, and heart all located on the right rather 
than the left side of their body. This condition, situs 
inversus, also occurs occasionally in humans. Since 
the mutation in these mice is linked to transgenic 
DNA, recombinant DNA techniques have been used 
to isolate the adjacent genomic sequences. These 
sequences map to mouse chromosome 4, in a region 
homologous to human chromosome 9. This novel 
situs inversus mutation may allow the first posi- 
tional cloning of a gene that specifies polarity dur- 
ing normal mammalian embryogenesis. 
Mutations that disrupt the development and be- 
havior of nematodes have been analyzed to define 
the "genetic flowcharts" that control normal devel- 
opment and behavior. The laboratory of Associate 
Investigator Paul W. Sternberg, Ph.D. (California In- 
stitute of Technology) has found four genes similar 
to mammalian oncogenes that act in series to control 
the fates of cells during development of the male 
and hermaphrodite reproductive system of the nem- 
atode. Other genes that act antagonistically to this 
set of four genes have been identified. Neurons con- 
trolling various steps in male mating behavior have 
been identified by killing individual cells and ob- 
serving subsequent defects in mating. 
Assistant Investigator Carl S. Thummel, Ph.D. 
(University of Utah) and his colleagues are studying 
the molecular basis of metamorphosis in the fruit fly 
Drosophila melanogaster by isolating and charac- 
terizing regulatory genes induced directly by the ste- 
roid hormone ecdysone. One set of regulatory genes 
is induced by a relatively low ecdysone concentra- 
tion 1-2 days before the onset of metamorphosis. 
The proteins encoded by these genes comprise the 
transcriptional machinery required for the subse- 
quent induction of a second wave of regulatory gene 
activity, with the peak hormone titers that precede 
puparium formation. This second set of genes both 
transduces and amplifies the hormonal signal by co- 
ordinating the induction of large sets of secondary- 
response genes. Further studies of the genetic cir- 
cuitry activated by ecdysone should provide key 
insights into the mechanisms of steroid hormone 
function in higher organisms, as well as provide a 
paradigm for the control of genetic regulatory hier- 
archies during development. 
The laboratory of Investigator Thomas C. Kauf- 
man, Ph.D. (Indiana University) is involved in the 
analysis of the homeotic genes of Drosophila. These 
genes act as developmental switches that direct the 
synthesis of DNA-binding proteins and regulate the 
expression of other genes. Moreover, these control 
genes are present and perform similar functions in 
flies and mice. The group has shown that the spatial 
patterns of expression of these genes are in sepa- 
rately regulated subdomains. This subregulation is 
seen in the portions of the DNA of each gene respon- 
sible for the subdomains, as well as in the identity of 
other genes that regulate each homeotic gene in its 
proper pattern. 
Assistant Investigator Shigeru Sakonju, Ph.D. (Uni- 
versity of Utah) and his colleagues are studying the 
molecular mechanisms by which homeotic genes 
specify identities of body segments in Drosophila. 
The research focuses on three homeotic genes, 
called Ubx, abd-A, and Abd-B, that specify the fate 
of cells in thoracic and abdominal segments, and on 
downstream genes that are regulated by them. The 
laboratory's experiments have shown that the ho- 
meotic proteins use cell-type-specific mechanisms 
to regulate the expression of a downstream gene. 
The work has also revealed that the identities of 
body segments are not determined at the same time 
during embryonic development. Rather, the identi- 
ties of abdominal segments are established prior to 
those of thoracic segments. 
The mechanisms by which the segment polarity 
and homeotic genes of Drosophila control segmen- 
tal differentiation are the focus of the laboratory of 
Assistant Investigator Philip A. Beachy, Ph.D. (Johns 
Hopkins University). His group has isolated and 
characterized at the molecular level the segment po- 
larity gene hedgehog, which encodes a protein tar- 
geted to the secretory pathway. Expression of hedge- 
hog functions in, and is sensitive to, cell-cell 
signaling for the purpose of specifying positional 
identities of cells within segments. Additional prog- 
ress was made in the determination and comparison 
of DNA-binding specificities for homeodomains en- 
coded by several homeotic genes, as a step toward 
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