Articles 
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1101. 
TRANSGENIC APPROACHES FOR STUDYING DEVELOPMENT 
Richard D. Palmiter, Ph.D., Investigator 
During the past year this laboratory has continued 
a productive collaboration with Dr. Ralph Brinster's 
laboratory at the University of Pennsylvania. Most 
projects involve introduction of foreign genes into 
the germline of mice as a means of studying the ef- 
fects on development. These studies are currently 
directed toward germ cell development, neuronal 
development, and metallothionein gene regulation. 
This report covers the latter two areas. The work is 
supported in part by grants from the National Insti- 
tutes of Health. 
Neuronal Development 
A major goal of this research is to study the devel- 
opment of neurons that use catecholamines as neu- 
rotransmitters. To gain experimental access to these 
neurons, the genes involved in catecholamine bio- 
synthesis were cloned. Their regulatory regions are 
then used to direct the expression of reporter genes 
(e.g., the Escherichia coli lacZ gene) to neurons, 
which provides a facile means of identifying the cat- 
echolaminergic neurons in whole embryos or histo- 
logical sections. This analysis was started with the 
human dopamine /3- hydroxylase (DBH) gene, which 
was shown to direct expression of lacZ to noradren- 
ergic neurons and chromaffin cells. More recently 
the 5'-flanking regions of the mouse phenyleth- 
anolamine A^-methyltransferase (PNMT) gene was 
shown to direct lacZ expression to adrenergic neu- 
rons and chromaffin cells. 
Having demonstrated that the 5'-flanking regions 
of these genes can direct appropriate expression of 
reporter genes, the next step was to use those se- 
quences to direct the expression of other genes that 
might influence neuronal development. The most 
extreme examples of this approach are experiments 
in which the 5'-flanking region of the PNMT gene 
was used to direct the expression of diphtheria 
toxin to cells that normally would express PNMT. 
The consequence was the ablation of adrenal chro- 
maffin cells, some retinal cells, and the adrenergic 
neurons of the brainstem. As expected, there was no 
PNMT activity and no epinephrine in these mice. 
When they were crossed with mice expressing 
PNMT-lacZ, there was no /3-galactosidase activity. 
These mice now provide a model system in which to 
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