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 post- 
doctoral 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. 
OF the billions of cells composing the mam- 
malian brain, a few thousand, located in the 
hypothalamus, function together to form a biolog- 
ical clock. This clock can control the timing of 
daily behaviors such as sleep and wakefulness 
with an accuracy of minutes. Although chemical 
and electrical rhythms have been detected in 
these mammalian neural pacemakers, little is 
known about the underlying biochemistry used 
by these cells to compute time. 
In a simpler model organism, the fruit fly Dro- 
sophila, genes and proteins central to biological 
timing are beginning to be recovered and charac- 
terized. Mutations in several genes alter the fruit 
fly's circadian (daily) rhythms of locomotor activ- 
ity, which can be compared to wake/sleep cycles 
in mammals. The same mutations also alter non- 
circadian, high-frequency rhythms. Normal fruit 
flies produce a courtship song composed of 
wing-beating cycles with a periodicity of about a 
minute. At the cellular level, changes in chemical 
and electrical conductances are measured in 
some of the mutants, possibly linking measure- 
ment of time to controlled transmission of signals 
between cells. 
The best-studied gene in the Drosophila clock 
system is the per {period) locus. Three mutant 
forms of per have been recovered that affect the 
pace of the insect's clock. In the per^ mutant, 
circadian rhythms have a long period of 30 rather 
than 24 hours. For the mutant per^, daily cycles 
have a shortened, 19-hour period. The pet*" mu- 
tants have no daily rhythms. Corresponding 
changes are found in the courtship song; an 
80-second song for per^, 40 seconds for per^, and 
song arrhythmicity for per^. For at least some tis- 
sues, per*^ and per^ mutants exhibit lower than 
normal levels of intercellular communication, 
while per^ mutants show hypernormal communi- 
cation. These eff^ects appear to be mediated by 
changes in conductance of specialized channels, 
or gap junctions, between cells. 
The molecular changes associated with the 
mutations have been established. Although per*" 
cannot make a full-length protein, per^ and per' 
each make a per protein that is altered by substi- 
tution of a diff'erent, single amino acid. Compara- 
ble changes in cycle time can also be produced 
by altering the amount of per protein the fly pro- 
duces. For example, Drosophila that have re- 
ceived by microinjection a new gene that under- 
produces the per protein 20-fold have 40-hour 
daily rhythms. 
A variety of experiments have shown us that the 
per protein functions in the nervous system to 
control daily and circaminuten rhythms. Re- 
cently we have become interested in tracking the 
development of the fly's clock, in an eff^ort to 
identify the first cells making the per protein. A 
Drosophila embryo receiving a flash of light only 
hours after its conception will develop into an 
adult fly showing a daily routine of activity in 
phase with the timing of the embryonic light sig- 
nal. The fact that an adult fly can "remember" 
this timing must mean that a clock was running 
when the light signal was received and has been 
running ever since. These experiments show that 
the embryo's circadian clock starts running 
within 1 2 hours of fertilization of the egg, a time 
at which as few as 50 cells may be found making 
the per protein. 
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 other indispens- 
able genes. Of special interest is the soiree gene. 
The soiree mutants are arrhythmic in constant 
darkness but show nocturnal behavior in the pres- 
ence of a light/dark cycle. The per^ mutants are 
diurnal in the same light cycles. In behavioral 
tests of per^ soiree double mutants, the nocturnal 
behavior is expressed, indicating a more central 
role for the new gene. 
Development of Skin, Muscle, and Nerve 
The nervous system and skin are derived from a 
common set of cells in the embryo, the ectoderm. 
Each cell within the ectoderm must choose a fate, 
and in certain mutants of Drosophila the choice 
goes awry. Neurogenic mutants have lost the ca- 
pacity to choose skin, so that only nerve is 
formed. We believe these mutants have lost the 
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