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a recent report found that EcR forms functional dimers with DHR38 as well
(
Zoglowek et al., 2012
). In addition, genetic evidence shows that
usp
is
not required for the ecdysone-dependent induction of the larval glue genes,
raising the possibility that EcR requires a different partner for this response
(
Costantino et al., 2008
). The ability of nuclear receptors to form multiple
heterodimers adds another layer of regulatory complexity that will be fasci-
nating to unravel in the future.
4. THE ECDYSONE HIERARCHY II: EARLY RESPONSE
GENES
The molecular characterization of three early ecdysone-inducible genes
BR-C
,
E74
,and
E75
revealed that all of them encode transcription factors,
albeit belonging to different DNA-binding protein families (
Thummel,
1990
). These primary ecdysone response genes are key regulators of the
ecdysone genetic hierarchy, which induce the transcription of secondary
response genes that in turn execute the appropriate biological effects in
response to an ecdysone pulse at the onset of metamorphosis (
Fig. 2.1
B).
Mutations that disrupt all
BR-C
functions (
npr1
alleles) result in larval
lethality, indicating that
BR-C
is an essential gene for entry into metamor-
phosis (
Kiss, Beaton, Tardiff, Fristrom, & Fristrom, 1988
). The
broad
gene
(hereafter referred to as
Broad-Complex
or
BR-C
) maps to the 2B5 early puff
and is undoubtedly the most complex of the early genes. FlyBase currently
acknowledges 14 transcript isoforms (
McQuilton, St Pierre, & Thurmond,
2012
), and genetically the locus contains up to four complementation
groups (
DiBello et al., 1991
).
BR-C
produces four protein classes, dependent
on which zinc finger module, designated Z1 to Z4, is incorporated into a
given isoform. The common N-terminal region comprises a BTB/POZ do-
main, which is a protein-protein interaction domain commonly found in
chromatin and transcription factors. The zinc fingers are believed to confer
target specificity (
DiBello et al., 1991; Zollman, Godt, Prive, Couderc, &
Laski, 1994
). However, high-affinity DNA binding was never established
for BR-C proteins, and existing EMSA (
Xiang, Liu, & Huang, 2010
) and
footprinting (
von Kalm, Crossgrove, Von Seggern, Guild, & Beckendorf,
1994
) studies all used uncommonly high BR-C concentrations to achieve
DNA binding. Future studies will have to address whether BR-C recognizes
its target genes via binding to DNA elements or through interactions with
other chromatin-bound proteins, in which case the zinc finger domains may
have a less direct role in target gene recognition.
