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
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Research Support, N.I.H., Extramural
MeSH terms
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Active Transport, Cell Nucleus / genetics
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Animals
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Animals, Genetically Modified
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / metabolism*
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism*
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Fluoxetine / pharmacology
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Models, Animal
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Mutation
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Neurons / metabolism*
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Neurosecretory Systems / metabolism
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / immunology
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Receptor, Insulin / genetics
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Receptor, Insulin / metabolism
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Serotonin / genetics
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Serotonin / metabolism*
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Serotonin Uptake Inhibitors / pharmacology
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Signal Transduction* / drug effects
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Caenorhabditis elegans Proteins
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Forkhead Transcription Factors
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Serotonin Uptake Inhibitors
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Transcription Factors
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daf-16 protein, C elegans
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Fluoxetine
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Serotonin
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DAF-2 protein, C elegans
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Receptor, IGF Type 1
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Receptor, Insulin