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these peaks likely coordinate developmental and behavioral transitions dur-
ing the third instar. Potentially each checkpoint control mechanism may be
translated into one of the low-level ecdysone peaks which ensure that the
molecular events are correctly ordered for unidirectional developmental
progression. Alternatively, passing all checkpoints may activate a neuroen-
docrine switch to an autonomous program that produces the successive
pulses of ecdysone. While it is obvious that the onset of metamorphosis is
regulated by a number of cues from both the external and internal environ-
ment, further studies are needed to decipher how these cues are integrated to
produce the sequential pulses of ecdysone.
Despite recent advances, the secreted FDSs have not been identified.
The identification of the FDSs is the key to a more comprehensive under-
standing of how peripheral nutritional signals coordinate timing of ecdysone
production. In this regard, the increasing prevalence of childhood obesity in
humans has been associated with premature onset of puberty and reproduc-
tive dysfunction (
Ahmed, Ong, & Dunger, 2009; Kaplowitz, 2008
). Like
developmental timing in insects, nutritional regulation of human pubertal
timing is influenced by peripheral nutritional signals from adipose tissues
similar to the fat body. We note a study by Norbert Perrimon's group iden-
tifying Unpaired 2 as a secreted FDS, functionally equivalent to human lep-
tin, that regulates systemic growth presumably through its effect on insulin
release from the IPCs (note added in proof).
The insulin-like molecules seem to be part of a conserved genetic mech-
anism that controls timing of maturation. In
C. elegans
, mutations disrupting
insulin signaling result in dauer formation and arrest before the sexual mat-
uration independent of the environmental conditions (
Kimura, Tissenbaum,
Liu, &Ruvkun, 1997
). Moreover, puberty is delayed by mutations affecting
insulin-like growth factor (IGF) signaling and in children diagnosed with
certain types of diabetes (
Divall et al., 2010; Domene et al., 2009; Kjaer,
Hagen, Sando, & Eshoj, 1992; Messina et al., 2011
). The discovery that
Dilp8 coordinates tissue growth with developmental timing further high-
lights the central role for these conserved molecules in the control of body
size, maturation, and metabolism.
How insulin/TOR and PTTH signaling interact in the PG to coordinate
the timing of ecdysone pulses remain poorly understood. Insulin may work
upstream of PTTH either by producing the critical weight ecdysone peak
that allows subsequent PTTH release or by mediating glandular growth that
provides competence to respond to PTTH. Because the PG neurons are
anatomically developed earlier, regulating the PG competence might be
