Serotonin targets the DAF-16/FOXO signaling pathway to modulate stress responses.
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.
Liang
Bin
B
Department of Anatomy & Neurobiology, School of Medicine, University of California, Irvine, Irvine, California 92697, USA.
Moussaif
Mustapha
M
Kuan
Chih-Jen
CJ
Gargus
J Jay
JJ
Sze
Ji Ying
JY
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D009490:Neurosecretory Systems / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000276:immunology; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D005473:Fluoxetine; D051858:Forkhead Transcription Factors; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C107483:DAF-2 protein, C elegans