Pervasive positive and negative feedback regulation of insulin like signaling in Caenorhabditis elegans

Abstract

The C. elegans insulin-like signaling network supports homeostasis and developmental plasticity. The genome encodes 40 insulin-like peptides and one receptor. Feedback regulation has been reported, but the extent of feedback and its effect on signaling dynamics during a state transition has not been determined. We measured mRNA expression for each insulin-like peptide, the receptor daf-2, components of the PI3K pathway, and its transcriptional effectors daf-16/FoxO and skn-1/Nrf at high temporal resolution during transition from a starved, quiescent state to a fed, growing state in wild type and mutants affecting daf-2/InsR and daf-16/FoxO. We also analyzed the effect of temperature on insulin-like gene expression. We found that numerous PI3K pathway components and insulin-like peptides are affected by signaling activity, revealing pervasive positive and negative feedback regulation. Reporter gene analysis demonstrated that the daf-2/InsR agonist daf-28 positively regulates its own expression and that other agonists cross-regulate daf-28 transcription through feedback. Our results show that feedback regulation of insulin-like signaling is widespread, suggesting a critical role of feedback in signaling dynamics in this endocrine network and likely others.