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aspects of ecdysone synthesis: (a) coordinating cholesterol availability in pro-
thoracic glands, (b) integration of PTTH signaling and ecdysone biosynthe-
sis, and (c) modulation of the expression of the ecdysone biosynthetic
enzymes (
Figs. 2.3 and 2.4
;
Table 2.1
).
8. broad CONTROLS A KEY COMPONENT OF CELLULAR
CHOLESTEROL TRANSPORT
A recent study has shown that
broad
serves as a key regulator for
coordinating available cholesterol levels required for ecdysone synthesis in
Drosophila
prothoracic glands (
Xiang et al., 2010
).
Drosophila
, like all other
insects, is a cholesterol auxotroph and must obtain cholesterol or other suit-
able sterols directly from a dietary source (
Carvalho et al., 2010; Clayton,
1964
). Therefore, cholesterol uptake and transport by the prothoracic gland
represent critical steps for the synthesis of steroid hormones in insects.
The study published by Xiang and colleagues shows that
broad
positively
regulates the expression of
Npc1a
in the prothoracic gland
,
a cholesterol
transporter gene (
Xiang et al., 2010
). In humans, mutations in the
NPC1
gene cause Niemann-Pick Type C disease, a fatal neurodegenerative disor-
der where patients accumulate free cholesterol in lysosomes and display
defects in glycolipid sorting (
Sturley, Patterson, Balch, & Liscum, 2004
).
NPC1 proteins are highly conserved and have a sterol-sensing domain that
presumably recognizes free sterols and assists cholesterol to move out of ly-
sosomes (
Davies & Ioannou, 2000
). The
Drosophila
genome encodes two
NPC1 homologs, NPC1a and NPC1b, which exhibit 42% and 35% identity
to the human NPC1 protein, respectively (
Carstea et al., 1997; Fluegel,
Parker, & Pallanck, 2006; Loftus et al., 1997
). In contrast to NPC1b, which
is restricted to the gut, the
Drosophila Npc1a
gene is ubiquitously expressed,
and a null allele of
Npc1a
results in early larval lethality (
Fluegel et al., 2006;
Huang, Suyama, Buchanan, Zhu, & Scott, 2005
). Interestingly, the lethal
phenotype of
Npc1a
mutants can be partially rescued by rearing animals
on a high cholesterol diet or by adding the insect steroid hormone 20E
to the medium, suggesting that
Npc1a
mutants are ecdysone deficient
(
Huang et al., 2005
).
Npc1a
transcripts are significantly downregulated in the ring gland of
both
broad
mutants (
npr
alleles) and ring gland-specific
broad
RNAi animals,
but not affected by mutations in other transcription factor genes including
ftz-f1
,
woc
,
mld
, and
ecd1
(see
Table 2.1
), suggesting that cholesterol uptake is
transcriptionally controlled by
broad
. This raised the possibility that
npr
