Local requirement of the Drosophila insulin binding protein imp-L2 in coordinating developmental progression with nutritional conditions

Abstract

In Drosophila, growth takes place during the larval stages until the formation of the pupa. Starvation delays pupariation to allow prolonged feeding, ensuring that the animal reaches an appropriate size to form a fertile adult. Pupariation is induced by a peak of the steroid hormone ecdysone produced by the prothoracic gland (PG) after larvae have reached a certain body mass. Local downregulation of the insulin/insulin-like growth factor signaling (IIS) activity in the PG interferes with ecdysone production, indicating that IIS activity in the PG couples the nutritional state to development. However, the underlying mechanism is not well understood. In this study we show that the secreted Imaginal morphogenesis protein-Late 2 (Imp-L2), a growth inhibitor in Drosophila, is involved in this process. Imp-L2 inhibits the activity of the Drosophila insulin-like peptides by direct binding and is expressed by specific cells in the brain, the ring gland, the gut and the fat body. We demonstrate that Imp-L2 is required to regulate and adapt developmental timing to nutritional conditions by regulating IIS activity in the PG. Increasing Imp-L2 expression at its endogenous sites using an Imp-L2-Gal4 driver delays pupariation, while Imp-L2 mutants exhibit a slight acceleration of development. These effects are strongly enhanced by starvation and are accompanied by massive alterations of ecdysone production resulting most likely from increased Imp-L2 production by neurons directly contacting the PG and not from elevated Imp-L2 levels in the hemolymph. Taken together our results suggest that Imp-L2-expressing neurons sense the nutritional state of Drosophila larvae and coordinate dietary information and ecdysone production to adjust developmental timing under starvation conditions.

Nutritional regimens with periodically recurring phases of dietary restriction extend lifespan in Drosophila

“…ImpL2 is released into the circulation, where it binds insulin‐like peptides and thus inhibits insulin signaling independent from the mechanisms that regulate insulin release. Moreover, it acts as a local signal that modifies insulin signaling in response to adverse nutritional cues (64). Thus, the observation that DR led to reduced insulin release and enhanced impL2 expression implies that insulin signaling was further dampened by these synergistically acting mechanisms.…”

Dpp regulates autophagy-dependent midgut removal and signals to block ecdysone production

“…The insulin/IGF antagonist, Imaginal morphogenesis protein-Late 2 (ImpL2) acts as a sensor of the nutritional state of larvae and coordinates dietary information and ecdysone production to modulate developmental transitions [41]. In the adult, ImpL2 is secreted from intestinal tumors that mediates organ wasting [42,43].…”

Steroid signaling mediates nutritional regulation of juvenile body growth via IGF-binding protein in Drosophila

“…Flies deficient in Imp-L2 are larger in size and more vulnerable to starvation than wild-type flies (8), whereas increased expression of Imp-L2 extends the fly lifespan (11,12). Moreover, Imp-L2 expressed in a subset of neurons ensures the proper activity of insulin signaling in the brain and its associated glands (13,14). Other recent studies have further revealed the role of Imp-L2 in cachexia-like syndromes, where malignant tumors induce organ wasting (15,16).…”