Mammalian Development and Disease 
that inactivate the protease-encoding transgene. 
These cells grow and repopulate the liver, and 
the mice seem normal. However, they also suc- 
cumb to liver cancer when they are one to two 
years old. In both cases, we postulate that liver 
regeneration in a toxic environment of liver in- 
jury results in genetic damage that predisposes 
the cells to malignant transformation. 
It is also possible to develop transgenic mice 
that mimic some human genetic diseases. For ex- 
ample, we have recently made a model of human 
sickle cell disease. By introducing into mice both 
human a- and /3-globin genes under control of the 
locus control region (a newly discovered genetic 
element essential for high-level expression of the 
j8-globin gene) , we have generated mice that pro- 
duce as much human hemoglobin as mouse he- 
moglobin. When the mutant |S-globin gene from 
people with sickle cell disease is substituted for 
the normal gene in these experiments, the red 
blood cells of the mice sickle under appropriate 
conditions. These mice may be a valuable re- 
source for testing experimental therapies. 
A long-range goal is to use transgenic mice to 
study aspects of neural development. We have 
started by cloning the genes involved in the syn- 
thesis of catecholamine neurotransmitters: dopa- 
mine, norepinephrine, and epinephrine. These 
genes are expressed in certain neurons of the 
central nervous system, in the peripheral nervous 
system, and in the adrenal medulla. The control 
elements from these genes are being tested in 
conjunction with reporter genes whose products 
can be easily visualized to assess when and where 
they are expressed during development. Subse- 
quently, we intend to use the control elements to 
direct the expression of other genes to these neu- 
rons with the aim of affecting the decisions they 
make during the process of forming functional 
connections with target cells. 
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