now be displayed simultaneously and with remark- 
able clarity with techniques developed by Dr. Pad- 
dock, Jim Langeland, and Peter DeVries. 
Dr. Carroll is also Associate Professor of Molecu- 
lar Biology, Genetics, and Medical Genetics at the 
University of Wisconsin-Madison. 
Articles 
Brown, N.L., Sattler, C.A., Markey, D.R., and 
Carroll, S.B. 1991. hairy gene function in the 
Drosophila eye: normal expression is dispensable 
but ectopic expression alters cell fates. Develop- 
ment 113:1245-1256. 
Skeath, J.B., and Carroll, S.B. 1992. Regulation of 
proneural gene expression and cell fate during 
neuroblast segregation in the Drosophila em- 
bryo. Development 114:939-946. 
Williams, J.A., Bell, J.B., and Carroll, S.B. 1991. 
Control of Drosophila wing and haltere develop- 
ment by the nuclear vestigial gene product. 
Genes Dev 5:2481-2495. 
HORMONAL REGULATION OF GENE EXPRESSION 
William W. Cidn, M.D., Investigator 
Dr. Chin and his laboratory are defining the mo- 
lecular mechanisms by which hormones regulate 
gene expression. Specifically, he has focused on the 
role of nuclear receptors and auxiliary proteins in 
thyroid hormone (TH) action. Further knowledge in 
this area will increase understanding of the mecha- 
nisms of action of ligand-regulated transcription 
factors such as TH receptor (TR) and the role of TR 
and other factors in TH action in health and, in par- 
ticular, in syndromes of TH resistance. 
Thyroid Hormone Receptors 
and Related Forms 
TH exerts its diverse physiological actions largely 
by binding to specific high-affinity nuclear recep- 
tors. At least three nuclear TRs have been identified 
and characterized in the rat: TRal, TR|S1, and TR|S2. 
The /3 forms of the receptor are products of alterna- 
tive promoter choice and RNA splicing of transcripts 
derived from a gene that, for human TRjS, is located 
on chromosome 3; TR«1 is encoded by a separate 
gene on chromosome 17. Alternative splicing of the 
TRa gene also generates a non-TH-binding protein, 
c-erbAa2, which differs from TRal only at the car- 
boxyl terminus. Although it does not bind TH, c- 
erbAa2 has been shown in transient transfection ex- 
periments to block the effect of co-transfected TR in 
facilitating TH regulation of a third co-transfected 
reporter gene. All forms of TR, along with c-erbAa;2, 
show significant homology to other members of the 
steroid thyroid hormone receptor superfamily, in 
particular to the vitamin D and retinoic acid recep- 
tors. The three forms of TR have different tissue dis- 
tributions: TR|S1 is widely expressed in many differ- 
ent tissues; TR|S2 is detected in the pituitary and 
limited regions of the central nervous system; TRal , 
which is expressed in most TH-responsive tissues, is 
most abundant in skeletal muscle and brown fat. 
Structure-Function of Thyroid 
Hormone Receptors 
The ligand-binding domain of TR contains poorly 
characterized subdomains involved with ligand 
binding, transactivation, and protein-protein inter- 
actions. The region between residues 288-331 of 
rat TRal was analyzed by modeling and site- 
directed mutagenesis. These results suggest that 
part of this sequence adopts an amphipathic a-heli- 
cal conformation. The integrity of the putative helix 
is important for TH binding but not necessarily for 
heterodimerization with nuclear factor(s). Mutants 
defective for both activities were found clustered in 
a region overlapping the carboxyl-terminal portion 
of the helix and further downstream. The sequence 
conservation of this particular region among the en- 
tire superfamily suggests a similar role in dimeriza- 
tion in other receptors. 
TR Isoform-Specific Antibodies 
To examine the expression of these TRs at the 
protein level. Dr. Chin and his colleagues prepared 
isoform-specific polyclonal antibodies against the 
rat TRs and c-erbAa2. Anti-TR^l and anti-TRa- 
common antibodies immunoprecipitate TR;S1 or 
TRal, respectively, in transfected COS-7 cells and 
immunostain almost all of the rat and human ante- 
rior pituitary cells, suggesting that TRal, TR;8l, 
TR|82, and c-erbAa2 are most likely expressed in all 
anterior pituitary cell types in rats and humans. The 
staining by the anti-TRjS antibodies was primarily 
CELL BIOLOGY AND REGULATION 35 
