Mammalian Development and Disease 
liver cells that have deleted the transgene repopu- 
late the liver, and when the mice are a few 
months old they seem normal. However, they 
also succumb to liver cancer when they are one to 
two years old. In both cases we postulate that 
liver regeneration in the toxic environment of 
liver injury results in genetic damage that predis- 
poses the liver cells to malignant transformation. 
It is also possible to develop transgenic mice 
that mimic some human genetic diseases. For ex- 
ample, we made a model of human sickle cell 
disease. By introducing into mice both human a- 
and /8-globin genes under control of the locus 
control region (a newly discovered genetic ele- 
ment essential for high-level expression of globin 
genes) , we have made mice that produce as much 
human hemoglobin as mouse hemoglobin. When 
the mutant /3-globin gene from people with sickle 
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 resource for testing experimen- 
tal 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 the catecholamine neurotransmitters: 
dopamine, norepinephrine, and epinephrine. 
The control elements from these genes are being 
tested in conjunction with genes whose products 
can be easily visualized, to assess when and 
where they are expressed during development. 
For example, we have shown that the regulatory 
elements from the gene responsible for mak- 
ing norepinephrine direct the expression of ^- 
galactosidase to certain neurons of the central 
nervous system, the peripheral nervous system, 
the enteric nervous system, and the adrenal me- 
dulla (see figure). Because this marker gene is 
expressed very early during neural development, 
it allows us to visualize the cells while they are 
still migrating to their final destinations and be- 
fore they acquire properties of mature neurons. 
By mating these mice to mice carrying a genetic 
defect that affects the innervation of the bowel 
and results in a condition similar to Hirsch- 
sprung's disease in humans, we have shown that 
neuronal precursors fail to migrate into the distal 
portion of the gut. The lack of innervation of the 
colon results in chronic impaction of fecal mate- 
rial and ultimately death. 
We are also using the control elements from 
these genes to direct the expression of other 
genes (e.g., encoding neurotransmitters, growth 
factors, hormones, proteases, or oncogenes) to 
these neurons with the aim of affecting the deci- 
sions they make during the process of forming 
functional connections with target cells. 
Blue staining reveals the location of cells that ex- 
press a ^ galactosidase transgene in neural precur- 
sors in a 10. 5- day mouse embryo. 
Research and photograph by Raj Kapur in the lab- 
oratory of Richard Palmiter. 
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