Function of Oncogenes in Early Emhryogenesis 
Roel Nusse, Ph.D. — Associate Investigator 
Dr. Nusse is also Associate Professor of Developmental Biology at the Stanford University School of 
Medicine. He obtained his Ph.D. degree from the University of Amsterdam and was a postdoctoral fellow 
with Harold Varmus at the University of California, San Francisco, before returning to Amsterdam, where 
he became head of the Department of Molecular Biology at the Netherlands Cancer Institute. Several years 
ago he moved to the Beckrnan Center of Stanford University and the Howard Hughes Medical Institute. 
Dr. Nusse is a member of the European Molecular Biology Organization (EMBO ). 
IT is now well established that genes whose al- 
tered expression can lead to cancer (generally 
called oncogenes or proto-oncogenes) are indis- 
pensable regulators of normal cell proliferations. 
Many oncogenes participate in the cells' deci- 
sions whether to divide or remain quiescent. 
Apart from the regulation of cell proliferation, 
growth in a normal organism obviously needs 
control at another level: during the formation of 
patterns in which cells become properly 
arranged. Over the past few years, it has become 
increasingly clear that oncogenes are among the 
key regulators of this aspect of growth control 
also. 
The evidence for such controlling functions 
has primarily come from the genetic dissection of 
morphogenesis in organisms such as Drosophila 
and Caenorhabditis elegans. Many of the devel- 
opmental genes isolated from those animals are 
highly homologous to mammalian oncogenes, in 
particular those that encode signaling molecules 
involved in cell-to-cell communications during 
embryogenesis. Now, with the increasing possi- 
bilities to identify developmental genes in the 
mouse as well, additional examples have 
emerged for a link between cancerous growth 
and the control of normal development. 
The Wnt/wingless gene family is a paradigm 
for the connections between tumorigenesis and 
embryogenesis. The prototypic member of this 
group, Wnt-l, is an oncogene frequently acti- 
vated in mouse mammary cancer. The Wnt-l 
gene is normally not expressed in the mammary 
gland or in most other adult tissues. In tumors, 
however, its transcription is induced by nearby 
insertion of proviral DNA of a retrovirus, the 
mouse mammary tumor virus. Proof that Wnt-l is 
an oncogene came from transfection experiments 
and from the finding that introduction of Wnt-l 
as a transgene into the germline of mice can lead 
to tumor induction. Wnt-l is part of a family of 
genes that in the mouse consists of at least 10 
members. All of these genes encode secreted pro- 
teins rich in cysteine residues. 
Over the past few years, evidence that the Wnt 
genes are prime determinants for early develop- 
ment has accumulated from many different 
corners. For example, most of these Wnt genes 
have a very restricted pattern of expression dur- 
ing early developmental stages, in organisms 
ranging from mice to fruit flies. More telling are 
the findings that Wnt gene mutations prevent 
normal development of the mouse brain and nor- 
mal segmentation of Drosophila embryos. More- 
over, it has been shown that ectopic expression 
of Wnt genes induces axis duplication in frog 
embryos. 
The work in our group is focused on the role of 
several members of the Wnt gene family in the 
development of the mouse, along with investiga- 
tions of Wnt genes in the fruit fly. In the mouse 
we perform detailed in situ RNA hybridization 
analysis of the expression of Wnt-5 and a highly 
related gene, Wnt-5A. Both genes are expressed 
in the developing neural tube. 
In particular, the anterior boundary of expres- 
sion of Wnt-5 and Wnt-5A is interesting. The 
genes are expressed in the diencephalon and in 
the cerebral hemispheres, suggesting that they 
play important roles in establishing these com- 
partments in the developing brain. For example, 
Wnt-5 is expressed in the D2 neuromere of the 
developing diencephalon during day 9 and 1 2 of 
embryogenesis. The expression precedes the sub- 
division of the diencephalon into the ventral and 
dorsal thalamus (see figure), suggesting a func- 
tional role for Wnt-5 in this process. Another re- 
markably restricted expression pattern of Wnt-5 
is seen in the cerebellum, where the gene is ex- 
clusively expressed in the Purkinje cells. 
Understanding the mechanism of action of the 
Wnt-l gene family during embryogenesis has 
been complicated by difficulties in characteriz- 
ing the Wnt proteins. We wish, for example, to 
identify the receptors for these secreted mole- 
cules, but as no biologically active Wnt gene 
product is available, the nature of the receptors 
remains elusive. In parallel to these biochemical 
experiments, we study the interactions between 
Wnt and other genes by taking advantage of the 
extensive genetic analysis of Drosophila embryo- 
genesis. Some years ago we made the surprising 
finding that the Drosophila Wnt-l homologue is 
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