Nutrient Signaling and Developmental Timing of Maturation - Current Topics in Developmental Biology - page 55

hemolymph in response to both intrinsic and extrinsic cues that control sys-
temic growth by regulating the pool of insulin in the IPCs. This also high-
lights the importance of basal ecdysone concentrations, lower than those
required to trigger developmental transitions, in regulation of growth.
In addition to the effect on systemic growth, ecdysone signaling in the fat
body cell-autonomously suppresses insulin signaling at the level of PI3K activ-
ity, dFOXO localization and 4E-BP expression ( Colombani et al., 2005;
Delanoue et al., 2010 ). The EcR coactivator, dDOR, is an important factor
for the relationship between insulin and ecdysone signaling ( Francis et al.,
2010 ). Expression of dDOR is suppressed by insulin, whichmeans that insulin
signaling attenuates the ecdysone response. Conversely, ecdysone inhibits
insulin signaling which stimulates dDOR expression demonstrating a positive
feedback where ecdysone potentiates its own genetic response. The antago-
nistic relationship between insulin and ecdysone illustrates a mechanism that
fine-tunes their action to coordinate growth and developmental transitions
and may also prevent run-away synthesis of ecdysone.
4.2. Adjusting circulating DILP activity
Nutrient-dependent systemic insulin signaling is regulated at the level of tran-
scriptional expression and secretion. However, circulating DILP levels are also
fine-tuned by other mechanisms. In the mammalian system, IGF-binding
proteins (IGFBPs) form binary complexes with circulating IGFs and ternary
complexes including the acid-labile subunit (ALS) that regulates the availabil-
ity of circulating IGF ( Hall, Hilding, & Thoren, 1999; Holly & Perks, 2012 ).
Formation of such complexes stabilizes the IGFs and extends their half-life as
well as prevents ligand-receptor interaction ( Fig. 2.3 ). The Drosophila Imp-L2
is a secreted protein, related to the mammalian IGFBPs, that modulates insulin
homeostasis by binding to DILP2 and DILP5 ( Alic, Hoddinott, Vinti, &
Partridge, 2011; Honegger et al., 2008; Sloth Andersen, Hertz Hansen,
Schaffer, & Kristensen, 2000 ). Expression of Imp-L2 is nutrient-dependent
and genetic loss of Imp-L2 is associated with an increased body size without
affecting developmental timing. On the other end, increased levels of Imp-L2
lead to reduction of growth and delays pupariation, implying that Imp-L2 is a
negative regulator of insulin signaling ( Honegger et al., 2008 ). Imp-L2 is
secreted from the fat body under adverse nutrient conditions to reduce insulin
signaling ( Honegger et al., 2008 ). In parallel to the situation in mammals, the
Drosophila ortholog of ALS (dALS) forms a trimeric complex with Imp-L2 and
DILP2 that suppresses insulin-mediated growth ( Arquier et al., 2008 ). Like