Homeotic Gene Action in Drosophila 
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Philip A. Beachy, Ph.D. — Assistant Investigator 
Dr. Beachy is also Assistant Professor in the Department of Molecular Biology and Genetics at the Johns 
Hopkins University School of Medicine. He did his graduate work in the Department of Biochemistry at 
Stanford University School of Medicine with David Hogness. Before joining the Hughes Institute at Johns 
Hopkins, he spent two years as Staff Associate at the Carnegie Institution's Department of Embryology. 
He has been the recipient of several fellowships, including a Sloan Foundation Fellowship in Neuroscience. 
THE most prevalent developmental strategy in 
the animal kingdom is segmentation — that 
is, division of the embryo into a series of similar 
segments that later differentiate and become spe- 
cialized for particular functions. The underlying 
molecular events are best understood in the fruit 
fly Drosophila, w^here segmentation and segmen- 
tal differentiation are governed by genes ex- 
pressed in a temporally and spatially ordered hier- 
archy. Many of the 50-some genes within this 
hierarchy have been characterized at the molecu- 
lar level; most encode proteins implicated in the 
control of gene expression. Much progress has 
been made in learning how these regulatory 
genes and their products interact to specify each 
other's expression and thereby generate a de- 
tailed system of spatial information. 
Little is known, however, about how this spa- 
tial information (in the form of localized regula- 
tory proteins) is used to assemble precisely the 
complex pattern of structures that arise in the 
course of embryogenesis. My laboratory's long- 
term goal is to extend knowledge of this genetic 
hierarchy by identifying and characterizing target 
genes whose products are more directly involved 
in the construction of the embryo than are pro- 
teins within the regulatory hierarchy. We are also 
studying the mechanisms by which such target 
genes are differentially regulated. 
The first tiers of the regulatory hierarchy con- 
tain maternally expressed genes, whose products 
establish broad polarities within the embryo. The 
segmentation genes of the middle tiers subdivide 
the embryo along the anterior/posterior axis into 
a linear array of homologous segments. The eight 
homeotic genes of the final tier are regulated by 
the segmentation genes and function to produce 
the specialized structures that distinguish the 
segments. 
The basic morphogenetic pathways for the re- 
peated segmental unit appear to be controlled, at 
least in part, by regulatory input from segmenta- 
tion genes. Homeotic genes, however, are the lab- 
oratory's current focus because of their unique 
roles in channeling the processes of morphogen- 
esis into pathways that produce the diversity of 
structures distinguishing the segments. The pro- 
teins encoded by homeotic genes each contain 
the homeodomain, a 61 -amino acid segment as- 
sociated with DNA-binding activity that is also 
present in some of the segmentation and polarity 
genes. Homeodomain proteins have sequence- 
specific DNA-binding properties and are gener- 
ally involved in control of gene expression at the 
level of transcription. 
The homeodomain, first identified in Drosoph- 
ila, has been found in all other multicellular ani- 
mals examined, including vertebrates. Perhaps 
the most striking aspect of this evolutionary con- 
servation is that in vertebrates, homeodomain 
genes closely related to the Drosophila homeotic 
genes (as judged from conservation of homeodo- 
main sequences) are clustered in the same linear 
order found in the Drosophila homeotic gene 
complexes. In addition, expression along the 
body axis is colinear, with locations of particular 
genes within the vertebrate clusters in a manner 
strikingly similar to that in Drosophila. These ob- 
servations suggest that some of the mechanisms 
of positional specification, and perhaps even 
some aspects of segmentation and segmental dif- 
ferentiation, are conserved between insects and 
vertebrates. 
Diflferential Recognition of DNA Sequence 
by Homeotic Proteins 
A major determinant of a regulatory protein's 
effect upon a target gene is the affinity of that 
protein's interactions with nearby DNA se- 
quences. Therefore a key component of any tran- 
scriptional regulator's biological properties is 
the regulator's sequence preferences in binding 
to DNA. The proteins encoded by Drosophila ho- 
meotic genes pose something of a puzzle in this 
regard because, despite great sequence similari- 
ties between their homeodomains, they all have 
distinct biological functions (i.e., they each im- 
plement distinct segmental differentiation path- 
ways). To enable systematic evaluation of DNA 
sequence preferences, we have developed a 
method by which the optimal DNA-binding se- 
quence for a particular protein can be selected 
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