Drosophila Behavior and Neuromuscular 
Development 
Michael W. Young, Ph.D. — Investigator 
Dr. Young is also Professor of Genetics at the Rockefeller University. He received his B.A. degree in biology 
from the University of Texas, Austin. Staying on to work at the university with Burke Judd, he earned his 
Ph.D degree for genetic and cytological studies o/Drosophila chromosome structure. Dr. Young did 
postdoctoral work in biochemistry at Stanford University Medical School with David Hogness. He moved 
to Rockefeller as a fellow of the Andre and Bella Meyer Foundation. 
A biological clock, composed of a few thou- 
sand cells within the mammalian brain, con- 
trols timing of daily behaviors such as sleep with 
an accuracy of minutes. Chemical and electrical 
rhythms have been detected in these mammalian 
pacemaker tissues. Still, little is known about the 
underlying biochemistry used to calculate time. 
The genes and proteins central to biological 
timing are beginning to be recovered and charac- 
terized in a simpler model organism, the fruit fly 
Drosophila. The best-studied gene in the Dro- 
sophila clock system has been named per {pe- 
riod^. Several mutant forms of the gene have 
been recovered that affect the pace of the insect's 
clock and certain aspects of cell physiology. 
In the per^ mutant, circadian locomotor activ- 
ity rhythms have a long period of 30 rather than 
24 hours. For the mutant per^, daily cycles have a 
shortened, 1 9-hour period. Mutants with no daily 
rhythms are designated per^ . Corresponding 
changes in cycle time are found for a high- 
frequency rhythm — a courtship song produced 
in males by pulses of wing beating: an 80-second 
song (instead of the normal 55 seconds) for per\ 
40 seconds for per^, and song arrhythmicity for 
per^. Also, the mutations change the period of a 
daily oscillation in per transcription, which may 
be important for establishing rhythmic behavior. 
Finally, for at least some tissues, the mutants ap- 
pear to alter conductance of specialized channels 
(gap junctions) between cells. 
The molecular changes associated with the 
mutations have been established. The per^ mu- 
tant cannot express a full-length protein. On the 
other hand, per^ and per^ make per proteins, but 
these are altered by substitution of a single, dif- 
ferent amino acid. Comparable changes in cycle 
time can also be effected by altering the amount 
of per protein the fly produces. For example, mi- 
croinjection of a gene that underproduces the per 
protein 20-fold induces 40-hour daily rhythms. 
From these results it has been suggested that the 
per^ and per^ mutations generate, respectively, 
hyper- and hypoactive proteins. 
In a recent effort to understand how changes in 
protein structure can affect per activity, genes 
carrying new mutations, produced in vitro, were 
reintroduced into the fly by microinjection. It 
was found that mutations changing the structure 
of a certain segment of about 20 amino acids pre- 
dominantly confer short-period (per'-like) rhyth- 
micity. Apparently the mutations identify a re- 
gion of the per protein that regulates the activity 
level in normal flies. 
A variety of experiments have demonstrated 
that the per protein acts in the nervous system to 
control daily and circaminuten rhythms. We have 
become interested in tracking the development 
of the fly's clock in an effort to determine when it 
begins to run, whether it requires signals from 
outside the organism to start, and where the first 
cells expressing per arise and develop. We have 
learned that Drosophila reared in constant envi- 
ronmental conditions spontaneously start their 
clocks only hours after formation of the embryo. 
Evidence of a running clock is first seen after 
completion of the embryonic nervous system and 
just following cessation of high levels of per ex- 
pression in certain neural cells. 
Until recently, only the per locus was known to 
be essential for production of biological rhythms 
in the fruit fly. Genetic screens for rhythm muta- 
tions have led to the discovery of additional, in- 
dispensable genes. Of special interest is a new 
mutation found on the second chromosome {per 
maps to the X chromosome). The new mutation, 
like per^, renders flies arrhythmic, and in molecu- 
lar studies appears to block the circadian rhythm 
in per transcription. Thus the newly recognized 
gene may be required for per to function. 
Development of Skin, Muscle, and Nerve 
In the embryo the nervous system and skin are 
derived from a common set of cells, the ecto- 
derm. Each of these cells must choose a fate, and 
in certain Drosophila mutants the choice goes 
awry. For one set of mutants known as "neuro- 
genic," the capacity to choose skin has been lost 
and only nerve is formed. We believe the mutants 
have lost the ability to form a set of signals that act 
early in development, so we are using the muta- 
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