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throttling the expression of ecdysone biosynthetic genes. It is reasonable to
assume that the expression of ecdysone biosynthetic enzymes is somehow
tied into cellular cholesterol levels, as it would be rather wasteful to express
these genes at high levels when cholesterol is in short supply. To test this
possibility, one could examine whether ring gland-specific knockdown of
Npc1a causes downregulation of ecdysone biosynthetic genes. Previous
studies have shown that NPC2 family members NPC2a and NPC2b play
essential roles in the prothoracic gland. Drosophila Npc2a and Npc2b double
mutants display similar phenotype as the Npc1a mutant, and were fully res-
cued by supplying 20E, suggesting that these animals lack ecdysone ( Huang,
Warren, Buchanan, Gilbert, & Scott, 2007 ). Therefore, it will be intriguing
to see whether Npc2a / Npc2b double mutants affect the expression of genes
involved in ecdysteroidogenesis. Experiments along these lines would test
whether cellular cholesterol levels are sensed in the ring gland, and whether
changes in available cholesterol affect the expression of the Halloween
genes.
9. DHR4 IS A KEY MEDIATOR OF PTTH SIGNALING
As mentioned earlier, PTTH-mediated stimulation of ecdysone syn-
thesis is best established for the last major larval ecdysone pulse that triggers
the onset of metamorphosis. However, whether the three minor ecdysone
pulses during the last larval instar are also controlled in this manner remained
unexplored. Recently, our group has demonstrated that DHR4 , which we
discussed earlier as an ecdysone hierarchy gene, is a target of PTTH signaling
in the Drosophila prothoracic gland cells and plays a key role in the proper
timing of ecdysone pulses.
DHR4 is expressed in three major larval tissues: the prothoracic gland,
the salivary glands, and the fat body. A hypomorphic mutation in DHR4
causes two distinct phenotypes. First, larvae stop feeding prematurely, which
results in small animals, and second, animals arrest development in the early
prepupal stage, indicating that DHR4 has critical roles in larvae as well as
during the prepupal stage ( King-Jones et al., 2005 ). This duality was later
confirmed by tissue-specific knockdown of DHR4 ( Ou et al., 2011 ). When
DHR4 function is reduced specifically in the ring gland, larvae stop feeding
prematurely and enter early into metamorphosis, while knockdown of
DHR4 in the fat body results in prepupal lethality, but timing is normal.
Closer inspection of DHR4 expression in the ring gland revealed that the
protein oscillates with 8-16 h ultradian cycle times between cytoplasm
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