Biology Reference
In-Depth Information
EcR requires heterodimerization with another nuclear receptor,
Ultraspiracle (USP) to form a functional ecdysteroid receptor capable of
binding to 20E with high affinity (
Thomas, Stunnenberg, & Stewart,
1993; Yao et al., 1993
).
EcR
encodes three protein isoforms, EcR-A,
EcR-B1, and EcR-B2, as a result of two promoters and alternative splicing
(
Talbot, Swyryd, & Hogness, 1993
). All three EcR isoforms are able to in-
teract with USP, and all can bind to 20E with similar affinity. The crystal
structure of the EcR LBD suggested that USP is required for forming a
ligand-binding conformation, corroborating the observation that EcR alone
cannot transcriptionally activate genes (
Billas et al., 2003; Hu, Cherbas, &
Cherbas, 2003
). Likewise, structural studies demonstrated that the LBD
of dipteran and lepidopteran USP is locked in an inactive conformation,
consistent with the idea that ecdysteroids achieve transcriptional activation
through binding to EcR (
Billas, Moulinier, Rochel, & Moras, 2001;
Clayton, Peak-Chew, Evans, & Schwabe, 2001
).
The EcR/USP heterodimer functions at the top of ecdysone regulatory
cascade and triggers the transcription of primary and secondary response
genes in ecdysone target tissues that play more direct functions during de-
velopment (
Fig. 2.1
B). Mutations affecting the region common to all
isoforms of
EcR
are embryonic lethal, consistent with the finding that ecdy-
sone signaling plays a critical role during germ-band retraction in the devel-
oping
Drosophila
embryo (
Bender, Imam, Talbot, Ganetzky, & Hogness,
1997; Kozlova & Thummel, 2003
).
EcR-B1
is predominantly expressed
in larval tissues that do not contribute to adult structures, and loss of
EcR-
B1
function blocks the ecdysone responses in these tissues, resulting in a fail-
ure to complete metamorphosis (
Bender et al., 1997; Schubiger, Wade,
Carney, Truman, & Bender, 1998
). In contrast, the
EcR-A
isoform is
expressed in imaginal disks and the ring gland, and animals mutant for
EcR-A
arrest development during late stages of pupal development
(
Davis, Carney, Robertson, & Bender, 2005; Talbot et al., 1993
), indicating
that the different EcR isoforms have distinct functions during development.
The EcR dimerization partner USP is the fly homolog of vertebrate
RXR (
Henrich, Sliter, Lubahn, MacIntyre, & Gilbert, 1990; Oro,
McKeown, & Evans, 1990
). Like EcR, USP is required during embryogen-
esis and metamorphosis, consistent with the idea that USP acts as a key
partner for EcR throughout development (
Hall & Thummel, 1998; Oro,
McKeown, & Evans, 1992; Perrimon, Engstrom, & Mahowald, 1985
).
USP also dimerizes with the nuclear receptors DHR38 and Seven-up
(
Baker et al., 2003; Zelhof, Yao, Chen, Evans, & McKeown, 1995
), and
