rhythms, both biochemical and molecular genetic 
approaches are being used to study mutants of Dro- 
sophila melanogaster that manifest aberrant or de- 
fective rhythms. A major emphasis continues to be 
on analyzing the function of the period gene {per) 
and the role it plays in the generation or mainte- 
nance of circadian rhythms. Mutations in per give 
rise to flies that have fast rhythms, slow rhythms, or 
essentially no rhythms. Recent work from the Ros- 
bash laboratory suggests that the gene product func- 
tions to modulate transcription and that this func- 
tion is important for the running of the circadian 
clock. 
The per product is a nuclear protein and has ho- 
mology with several known or suspected transcrip- 
tion factors from mammals and from Drosophila. It 
also negatively modulates its own transcription, a 
feedback loop that is likely to play an important role 
in circadian clock function. In vitro and in vivo 
experiments indicate that the per protein undergoes 
homotypic interactions and suggest that it under- 
goes heterotypic interactions as well. 
The per gene product contains no known DNA- 
binding region, and all indications are that it does 
not bind DNA. As a consequence, the current work- 
ing hypothesis is that these putative heterotypic in- 
teractions serve to inhibit one or more bona fide 
transcription factors, including one that acts on its 
own gene. This would generate the negative feed- 
back loop described above and would also affect 
clock output functions important for the manifesta- 
tion of rhythm phenotypes. 
Current work is designed to identify the partners 
with which the per protein undergoes these pro- 
posed heterotypic interactions. These and other ex- 
periments should deepen understanding of the 
gene's function as well as the regulatory loops im- 
portant for this ubiquitous timing system. 
The second rhythm project is designed to uncover 
new Drosophila genes that affect circadian pheno- 
types. Currently under investigation are several 
genes that were uncovered in a recent genetic 
screen for novel mutants that affect circadian 
rhythms. These are being characterized for their ef- 
fects on central oscillator function as well as on the 
phenotypic outputs commonly measured as circa- 
dian rhythm indicators. The two genes of most inter- 
est at present are likely to act downstream of the 
central circadian pacemaker. Although the mutant 
flies are behaviorally arrhythmic, the circadian 
oscillations of pefs mRNA levels occur normally. 
The laboratory continues to pursue genetic screens 
to identify additional rhythm-related genes. (This 
project was supported by a grant from the National 
Institutes of Health.) 
Dr. Rosbash is also Professor of Biology at 
Brandeis University, Waltham, and Adjunct Pro- 
fessor of Molecular Biology at Massachusetts Gen- 
eral Hospital, Boston. 
Articles 
Hardin, P.E., Hall, J.C., and Rosbash, M. 1992. Be- 
havioral and molecular analyses suggest that cir- 
cadian output is disrupted by disconnected mu- 
tants in D. melanogaster. EMBO / 1 1 :l-6. 
Liu, X., Zweibel, L.J., Hinton, D., Benzer, S., Hall, 
J.C., and Rosbash, M. 1992. The period gene en- 
codes a predominantly nuclear protein in adult 
Drosophila. f Neurosci 1 2:2735-2744. 
Rutila, J.E., Edery, I., Hall, J.C., and Rosbash, M. 
1992. The analysis of new short-period circadian 
rhythm mutants suggests features of D. melano- 
gaster period gene function. / Neurogenet 
8:101-113. 
MOLECULAR ANALYSIS OF DEVELOPMENT IN DROSOPHILA MELANOGASTER 
SfflGERu Sakonju, Ph.D., Assistant Investigator 
Drosophila melanogaster is a metameric organ- 
ism showing unique segmental characteristics. 
These segmental identities are determined by regula- 
tory functions of homeotic genes during develop- 
ment. Research in Dr. Sakonju's laboratory is fo- 
cused on understanding, at the molecular level, 
how these key regulatory genes direct cells to take 
on appropriate developmental pathways. 
Transcriptional Regulation by Homeotic 
Proteins UBX and ABD-A 
Homeotic proteins bind to specific DNA se- 
quences and regulate transcription of target pro- 
moters in vitro and in cultured cells. However, lit- 
tle is known about mechanisms of transcriptional 
regulation by homeotic gene products during devel- 
opment. Dr. Sakonju and his colleagues have ana- 
GENETICS 255 
