RRC ID 59363
Author Kaplan REW, Maxwell CS, Codd NK, Baugh LR.
Title Pervasive Positive and Negative Feedback Regulation of Insulin-Like Signaling in Caenorhabditis elegans.
Journal Genetics
Abstract The Caenorhabditis elegans 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 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 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 daf-2/InsR agonist daf-28 positively regulates its own transcription and that the putative agonist ins-6 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.
Volume 211(1)
Pages 349-361
Published 2019-1-1
DOI 10.1534/genetics.118.301702
PII genetics.118.301702
PMID 30425043
PMC PMC6325697
MeSH Animals Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Feedback, Physiological* Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism NF-E2-Related Factor 1 / genetics NF-E2-Related Factor 1 / metabolism Receptor, Insulin / genetics Receptor, Insulin / metabolism* Signal Transduction* Somatomedins / genetics Somatomedins / metabolism*
IF 3.564
Times Cited 3
C.elegans tm2308 tm3620 tm2416