By combining regulatory regions of one gene with a 
structural gene coding for a particular protein, the 
expression of the structural gene can be regulated 
in novel ways. With this approach it has been possi- 
ble for these researchers to demonstrate a number 
of interesting biological phenomena. These include 
1) increasing the growth of mice by directing the 
expression of growth hormone to large organs such 
as the liver, 2) promoting tumorigenesis by direct- 
ing the expression of oncogenes to specific cell 
types, 3) deleting specific cells by directing the ex- 
pression of a toxin to those cells, 4) directly visual- 
izing certain developmental processes by using a 
receptor gene that codes for an easily detectable 
product, 5) demonstrating the functions of certain 
genes suspected of being involved in disease pro- 
cesses, and 6) experimentally mimicking certain ge- 
netic diseases. 
Assistant Investigator Philippe M. Soriano, Ph.D. 
(Baylor College of Medicine) and his colleagues are 
using retroviral mosaics and the consequences of 
certain insertional mutations in developmental 
genes to study cell lineages during early mouse de- 
velopment. They have constructed new retroviral 
vectors in which a reporter gene, coding for the 
bacterial en2yme P-galactosidase, is placed under 
the control of an internal promoter allowing ex- 
pression of the gene in the early embryo. They are 
also generating transgenic mice that are screened 
for instances of insertional mutagenesis by infec- 
tion of mouse embryos or embryonic stem (ES) 
cells. The technique of homologous recombination 
has been used in ES cells to achieve targeted muta- 
genesis of the gene encoding c-src. The resulting 
chimeras are now being tested for germline contri- 
bution. 
The laboratory of Assistant Investigator Paul A. 
Overbeek, Ph.D. (Baylor College of Medicine) also 
makes use of transgenic mice to study mammalian 
development. Two of the transgenic families under 
study in his laboratory have developmental abnor- 
malities caused by insertional mutations. One mu- 
tation causes a defect in hair follicle formation; the 
other results in a defect in sperm maturation. For 
both of these new strains, the genomic sequences 
flanking the transgenic inserts have been cloned 
and are being used to examine the inactivated 
genes. In addition to the insertional mutants, a 
crystallin promoter has been used to direct lens- 
specific expression in transgenic mice. Two differ- 
ent constructs have been studied in some detail: 
one encodes a truncated SV40 early region, which 
causes microphthalmia; the other codes for a 
growth factor that causes abnormal development of 
the iris of the eye. 
Transgenic animals are also used in the labora- 
tory of Assistant Investigator Robert E. Hammer, 
Ph.D. (University of Texas Southwestern Medical 
Center at Dallas) to investigate the regulation of eu- 
karyotic gene expression and to examine the physi- 
ologic consequences of selected gene expression. 
Of special interest is the function of the human 
low-density lipoprotein (LDL) receptor in transge- 
nic mice and rabbits. Fusion genes containing the 
LDL receptor under the direction of various pro- 
moter/enhancer elements, including the mouse 
transferrin or the human p^-microglobulin pro- 
moter, have been expressed in mice, and lines of 
animals are being used to investigate such ques- 
tions as the differences in LDL receptor internaliza- 
tion in various somatic tissues as well as the nature 
of receptor-mediated endocytosis of plasma lipo- 
proteins by peritoneal macrophages. Transgenic 
mice containing and expressing a variant form of 
LDL, Lp(a), will be used to investigate the role of 
Lp(a) in the progression of atherosclerosis. 
Embryonic development is controlled by a net- 
work of interacting regulatory genes. Many of the 
genes are active in some parts of the embryo but 
not in others, thus causing cells in different places 
to do different things. The regulatory genes coordi- 
nate cell division and migration as well as the pro- 
duction and localization of specialized products. 
The molecular mechanisms through which genes 
interact and the nature of the proteins that do the 
regulating are being studied in the fruit fly Dro- 
sophila by the laboratory of Associate Investigator 
Matthew P Scott, Ph.D. (University of Colorado at 
Boulder). Some regulatory genes encode proteins 
that control the activation of banks of other genes 
in specific cells. Other genes encode proteins in- 
volved in communication among cells. 
Many of the genes involved in the early develop- 
ment of Drosophila have been identified, and a sig- 
nificant number of these genes contain a homeo- 
domain, a DNA-binding motif also present in the 
genomes of mammals. Assistant Investigator Claude 
Desplan, Ph.D. (The Rockefeller University) and his 
colleagues have asked how proteins with related 
sequences perform their specific roles during devel- 
opment. They have found that a single amino acid 
of the homeodomain determines its DNA-binding 
specificity and therefore its function. Another level 
of specificity is achieved by the role of the proteins 
on transcription. Thus the homeodomain protein 
Engrailed represses transcription in vitro, whereas 
Continued 
140 
