Molecular Genetics of Steroid and Thyroid Hormone Receptors 
which are only distantly related to the RARs. At 
least three RXR-related genes (a, |8, and 7) are 
now known to be located at genetically distinct 
loci. Each is capable of transactivating through 
cis-DNA-binding sequences similar to those of the 
RARs. Northern blot analyses of the RXRs indicate 
that each isoform has a unique pattern of expres- 
sion in adult tissue and is temporally and spatially 
expressed in the embryo. Binding experiments 
demonstrate that the RXR protein has low affinity 
for retinoic acid and, taken together with the 
transactivation studies, indicate that the RXR li- 
gand may be a metabolite of retinoic acid. Thus a 
function of the RXRs may both overlap and be 
unique to that of the RARs. These studies suggest 
a role for RXRs in adult physiology and embry- 
onic development. 
The discovery in RXR of a second transduction 
pathway with distinct pharmacological proper- 
ties may lead to a better understanding of how 
retinoids can elicit such an enormous diversity of 
biological responses and suggests that retinoid 
metabolism may provide important clues to the 
identification of new ligands. 
In view of the homology of the RARs and RXRs, 
their genes would seem to have arisen indepen- 
dently during evolution, possibly to cope with 
the increasing demands of ever-more-complex 
evolving organisms. An understanding of the ori- 
gins of these two gene families may afford in- 
sights to their modern roles. Thus, in search of 
invertebrate homologues, we have screened a 
Drosophila genomic library and identified the 
product of a novel steroid-receptor-like gene — 
ultraspiracle (usp) — that bears striking resem- 
blance to RXR in both its DNA- and ligand-bind- 
ing domains. 
Genetic analysis indicates that the usp gene 
product has both maternal and zygotic functions. 
In the germline, it is important for formation of 
the embryonic cuticle choriogenesis and fertiliza- 
tion. In the embryo, it is necessary for larval pu- 
pation. Recent functional studies indicate that 
the usp gene product does not respond to reti- 
noic acid, which suggests that a nonretinoid li- 
gand may exist in Drosophila. This is particularly 
interesting in that its structure may provide clues 
to the identification of the vertebrate usp ligand. 
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