Morphogen Gradients and the Control of Body 
Pattern in Drosophila 
Gary Struhl, Ph.D. — Associate Investigator 
Dr. Struhl is also Associate Professor of Genetics and Development at Columbia University College of 
Physicians and Surgeons. He received B.S. and M.S. degrees in biology from the Massachusetts Institute of 
Technology and his Ph.D. degree in genetics from the University of Cambridge, England. His graduate 
studies were carried out with Peter Lawrence at Cambridge. Before joining the faculty at Columbia, he 
conducted molecular and genetic studies on Drosophila in the laboratory of Tom Maniatis at Harvard 
University. In addition to several fellowships, he received the McKnight Neuroscience Development Award. 
SINCE the birth of embryology as an experi- 
mental discipline, it has been apparent that 
the development of cell and body patterns de- 
pends on robust and complex systems of spatial 
information. Yet, until recently, we had little 
idea of the physical nature of such systems or the 
mechanisms by which they are generated or 
interpreted. Considerable attention has been 
given to the possibility that gradients of "form- 
generating" substances, or morphogens, might 
provide this information. For example, a local- 
ized diffusible morphogen could generate a gra- 
dient that would provide a series of concentra- 
tion thresholds, each determining distinct 
cellular behaviors (e.g., the development of par- 
ticular pattern elements) as a function of distance 
from the source. 
Current research in this laboratory is directed 
toward identifying potential morphogen gra- 
dients and determining both how they arise and 
how they control pattern. Over the past 20-30 
years, a variety of embryologic and genetic exper- 
iments have suggested that such gradients play a 
key role in controlling cell and body patterns in 
insects. Indeed, Christiane Niisslein-Volhard and 
her colleagues have identified several such mor- 
phogens involved in specifying the basic body 
plan of the fruit fly Drosophila. 
One of these determinants, the protein product 
of the gene bicoid (bed) , is clearly expressed as a 
gradient that peaks at the anterior pole of the 
early embryo and controls anterior body pattern 
(head and thorax). Another, nanos (nos), is re- 
quired for generating posterior body pattern (ab- 
domen), though its properties are less well un- 
derstood. Our immediate goal during the past 
year or so has been to determine how these two 
systems work. As we describe below, the con- 
trolled expression of a single regulatory protein, 
hunchback (hb), has proved to be the key to un- 
derstanding both molecular mechanisms. 
rior pole to a boundary halfway down the body. 
This event depends critically on the bed morpho- 
gen. Moreover, it is essential for the generation of 
a large portion of anterior pattern, including all 
three thoracic segments. 
In an initial series of experiments, we found 
that bed behaves as a transcriptional regulator, 
capable of directly binding the hb gene and acti- 
vating transcription in a remarkably sensitive, 
concentration-dependent fashion. Hence, when 
the concentration of bed protein exceeds a criti- 
cal threshold, it binds a series of adjacent sites in 
the DNA immediately upstream of the hb pro- 
moter and activates transcription; however, when 
the concentration of bed protein falls beneath 
this threshold, binding does not occur and the hb 
gene remains silent. The concentration gradient 
of bed protein therefore determines where the hb 
gene is transcribed by positioning this threshold 
along the anteroposterior axis. 
In the process of examining how the bed gra- 
dient controls hb gene expression, we created a 
series of hybrid genes that contain only some of 
the binding sites for bed protein normally present 
upstream of the hb promoter. These hybrid 
genes, like hb itself, are activated in anterior por- 
tions of the body under the control of the bed 
protein gradient. However, their domains of ex- 
pression are abbreviated relative to that of hb, 
extending only a quarter or a third of the way 
down the body. These and other experiments 
suggest that the bed gradient can trigger several 
spatially distinct responses, the posterior bound- 
ary of each depending on the affinity of bed pro- 
tein for a given target gene. 
Recently several new genes have been identi- 
fied that appear to be expressed in a series of 
overlapping anterior domains. These genes are 
required for generating particular portions of 
head and thoracic pattern and may constitute 
other direct targets of the bed gradient. 
Anterior Pattern: Transcriptional 
Activation of hb by bed 
Early in embryogenesis, the hb gene is acti- 
vated in a broad domain extending from the ante- 
Posterior Pattern: Translation Repression 
of hb by nos 
Transcriptional activation of the hb gene by 
bed is only one of two sources of hb mRNA in the 
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