on development and differentiation. However, 
these results suggest they may control overlapping 
in gene networks and lead to a reexamination of 
the relationships of these two hormones. 
Two homologues of the human RAR in the fruit 
fly Drosophila have been identified. One locus, 
knirps-related, may carry out important events in 
establishing pattern formation in the early Dro- 
sophila embryo. In situ hybridization reveals that 
this gene is expressed in maternally derived RNA 
and is widely distributed, but in the early zygote 
transcript accumulation becomes localized. It is ex- 
pressed in a broad anteroventral domain before the 
cellular blastoderm stage and then acquires two ad- 
ditional circumferential bands of expression after 
blastoderm formation. 
A second Drosophila gene product, 2C, has been 
identified and is embedded in the genetically well- 
defined locus. This gene shares homology with a 
novel human receptor expressed during early em- 
bryonic development in vertebrates. This observa- 
tion suggests that a new regulatory system might be 
identified in Drosophila, which could lead to the 
identification of a new human morphogenetic 
system. 
III. Conditional Ablation in Transgenic Mice. 
Transgenic animals have been created as a strat- 
egy to study vertebrate development. Tissue-spe- 
cific promoters and enhancers make it possible to 
direct expression in cloned genes to restricted cell 
types, enabling the experimental manipulation of 
cellular and organ physiology. The reciprocal to 
this augmentation approach would be the creation 
of a transgenic hypomorph (i.e., a mouse deficient 
in a particular cellular function). Transgenic hypo- 
morphs were created that result in the conditional 
ablation of specific cell types during defined peri- 
ods of development and differentiation. Toxicity is 
based on the targeted expression of the herpes sim- 
PUBLICATIONS 
plex virus thymidine kinase (HSV-TK) gene product. 
The ablation is induced by treating transgenic ani- 
mals expressing this gene with the antiherpetic 
ganciclovir. In tissues of mice expressing HSV-TK, 
administration of ganciclovir leads to the rapid ac- 
cumulation of toxic intermediates, disrupting cellu- 
lar DNA replication and ultimately leading to rapid 
cell death. The ability to control and direct ablation 
allows for creation of conditional mutant pheno- 
types at precise periods of development. This tech- 
nique also provides a potential means to enrich 
stem cell populations as well as permitting the cre- 
ation of animal models for particular pathological 
conditions. 
The thymidine kinase obliteration (TKO) ap- 
proach has been employed to generate animals 
with controlled amino deficiency. After seven days 
of treatment with ganciclovir, animals expressing 
HSV-TK off an immunoglobulin promoter have 
greatly depleted B cells and are completely defi- 
cient in their T cell population. 
In a similar study the HSV-TK gene has been ex- 
pressed under control of the rat growth hormone 
or rat prolactin promoter. If transgenic mice ex- 
pressing TK in somatotrophs are treated with 
ganciclovir, they develop as dwarfs. The anterior pi- 
tuitary in these animals is nearly devoid of both 
somatotrophs and lactotrophs. By employing vari- 
ous concentrations of drug exposure and by initiat- 
ing treatment at a variety of times after birth. Dr. 
Evans and his colleagues were able to conclude 
that both somatotrophs and lactotrophs derive 
from a common stem cell that exists in the adult 
and is capable of repopulating the pituitaries of 
treated animals with mature growth hormone and 
prolactin-producing cells. 
Dr. Evans is also Professor, Gene Expression Lab- 
oratory, The Salk Institute for Biological Studies 
and Adjunct Professor of Biology at the University 
of California at San Diego. 
Books and Chapters of Books 
Evans, R.M. 1989. The contributions of the steroid receptor superfamily to development, physiology and 
medicine. In Proceedings of the Second International CTB Symposium (Gustafsson, J.A., Eriksson, H., and 
Carlstedt-Duke, J., Eds.). Stockholm: Birkauser Verlag, pp 11-28. 
Articles 
Arriza, J.L., Simerly R.B., Swanson, L.W, and Evans, R.M. 1988. The neuronal mineralocorticoid receptor as a 
mediator of glucocorticoid response. Neuron 1:887-900. 
Continued 
482 
