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Raf/ERK phosphorylation (
Fig. 2.4
B). The main question, however, still re-
mains:What are downstreameffectors of PTTHsignaling?Biochemical studies
in
Manduca
have demonstrated that the ribosomal protein S6 (RpS6) is a target
of PTTH, suggesting that upregulation of translation is a requirement for max-
imal ecdysone production (
Song&Gilbert, 1995, 1997
). Itwill be interesting to
determine whether RpS6 phosphorylation is genetically dependent on the
PTTH/Ras/ERK pathway. However, there is no doubt that many other
PTTH targets exist, and in a separate section, we will later discuss the recent
discovery that the nuclear receptor DHR4 is regulated by PTTH signaling.
Ultimately, many questions remain: How are the periodic PTTH signals
regulated in the first place? Is PTTH required for all pulses, major and minor,
or can other pathways compensate for a loss of PTTH signaling? Does PTTH
stimulate increased enzyme activity or transcriptional upregulation of the Hal-
loween genes? Is thewithdrawal of PTTHenough to terminate a pulse? Answer-
ing these and other questions will greatly advance our understanding of how
neuropeptide signaling pathways regulate the formation of steroid hormone
pulses.
7. ROLE REVERSAL: THE ECDYSONE HIERARCHY
REGULATES ITS OWN HORMONE
The ecdysone regulatory cascade is best understood at the onset of
metamorphosis, and the finding that some components of the hierarchy
might also play important roles in the production of ecdysone is not entirely
new. One of the first indicators was that
EcR-A
is expressed in the protho-
racic gland but not the other two isoforms encoded by
EcR
(
Talbot et al.,
1993
). Another study reported that USP modulates PTTH-dependent ec-
dysone synthesis in
Manduca
prothoracic glands (
Song & Gilbert, 1998
). To-
gether, these results suggested that EcR and USP may have roles in
ecdysteroidogenesis, possibly through negative feedback regulators in re-
sponse to rising levels of 20E. Finally, a null mutation in
E75A
causes a dra-
matic decrease in ecdysone levels, indicating that E75A plays a dual role,
acting both downstream of ecdysone as an 20E target during the onset of
metamorphosis and also upstream of ecdysone as a regulator of ecdysone
production in the prothoracic gland (
Bialecki et al., 2002
)(
Table 2.1
).
Below, we will summarize recent findings on the novel functions of sev-
eral classic ecdysone hierarchy genes that have roles important for three
