Serotonin targets the DAF-16/FOXO signaling pathway to modulate stress responses

Cell Metab. 2006 Dec;4(6):429-40. doi: 10.1016/j.cmet.2006.11.004.

Abstract

Stress response is a fundamental form of behavioral and physiological plasticity. Here we describe how serotonin (5HT) governs stress behavior by regulating DAF-2 insulin/IGF-1 receptor signaling to the DAF-16/FOXO transcription factor at the nexus of development, metabolism, immunity, and stress responses in C. elegans. Serotonin-deficient tph-1 mutants, like daf-2 mutants, exhibit DAF-16 nuclear accumulation and constitutive physiological stress states. Exogenous 5HT and fluoxetine (Prozac) prevented DAF-16 nuclear accumulation in wild-type animals under stresses. Genetic analyses imply that DAF-2 is a downstream target of 5HT signaling and that distinct serotonergic neurons act through distinct 5HT receptors to influence distinct DAF-16-mediated stress responses. We suggest that modulation of FOXO by 5HT represents an ancient feature of stress physiology and that the C. elegans is a genetically tractable model that can be used to delineate the molecular mechanisms and drug actions linking 5HT, neuroendocrine signaling, immunity, and mitochondrial function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Fluoxetine / pharmacology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Models, Animal
  • Mutation
  • Neurons / metabolism*
  • Neurosecretory Systems / metabolism
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / immunology
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Serotonin / genetics
  • Serotonin / metabolism*
  • Serotonin Uptake Inhibitors / pharmacology
  • Signal Transduction* / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Caenorhabditis elegans Proteins
  • Forkhead Transcription Factors
  • Serotonin Uptake Inhibitors
  • Transcription Factors
  • daf-16 protein, C elegans
  • Fluoxetine
  • Serotonin
  • DAF-2 protein, C elegans
  • Receptor, IGF Type 1
  • Receptor, Insulin