Pervasive Positive and Negative Feedback Regulation of Insulin-Like Signaling in Caenorhabditis elegans

The insulin-like signaling network supports homeostasis and developmental plasticity. The genome encodes 40 insulin-like peptides and one known receptor. Feedback regulation has been reported, but the extent of feedback and its effect on signaling dynamics in response to changes in nutrient availability has not been determined. We measured messenger RNA expression for each insulin-like peptide, the receptor , components of the PI3K pathway, and its transcriptional effectors /FoxO and /Nrf at high temporal resolution during transition from a starved, quiescent state to a fed, growing state in wild type and mutants affecting /InsR and /FoxO. We also analyzed the effect of temperature on insulin-like gene expression. We found that most PI3K pathway components and insulin-like peptides are affected by signaling activity, revealing pervasive positive and negative feedback regulation at intra- and intercellular levels. Reporter gene analysis demonstrated that the /InsR agonist positively regulates its own transcription and that the putative agonist cross-regulates DAF-28 protein expression through feedback. Our results show that positive and negative feedback regulation of insulin-like signaling is widespread, giving rise to an organismal FoxO-to-FoxO signaling network that supports homeostasis during fluctuations in nutrient availability.