Serotonin (5-hydroxytryptamine, 5-HT), is a phylogenetically ancient molecule best characterized as a neurotransmitter that modulates multiple aspects of mood and social cognition. The roles that 5-HT plays in normal and abnormal behavior are not fully understood but have been posited to be due to its common function as a ‘defense signal’. However, 5-HT levels also systemically impact cell physiology, modulating cell division, migration, apoptosis, mitochondrial biogenesis, cellular metabolism and differentiation. Whether these diverse cellular effects of 5-HT also share a common basis is unclear. C. elegans provides an ideal system to interrogate the systemic effects of 5-HT, since lacking a blood-brain barrier, 5-HT synthesized and released by neurons permeates the organism to modulate neuronal as well as non-neuronal cells throughout the body. Here we used RNA-Seq to characterize the systemic changes in gene expression that occur in C. elegans upon altering 5-HT levels, and compared the transcriptomes to published datasets. We find that an acute increase in 5-HT is accompanied by a global decrease in gene expression levels, upregulation of genes involved in stress pathways, changes that significantly correlate with the published transcriptomes of animals that have activated defense and immune responses, and an increase in levels of phosphorylated eukaryotic initiation factor, eIF2α. In 5-HT deficient animals lacking tryptophan hydroxylase (tph-1(mg280) II) there is a net increase in gene expression, with an overrepresentation of genes related to development and chromatin. Surprisingly, the transcriptomes of animals with acute increases in 5-HT levels, and 5-HT deficiency do not overlap with transcriptomes of mutants with whom they share striking physiological resemblance. These studies are the first to catalog systemic transcriptome changes that occur upon alterations in 5-HT levels. They further show that in C. elegans changes in gene expression upon altering 5-HT levels, and changes in physiology, are not directly correlated.

Metazoan growth and development requires the coordination of cell cycle progression and metabolism with nutrient availability1-3. Here, we show that in C. elegans, amphid neurons regulate the animals developmental decision to continue reproductive growth or arrest as quiescent dauer larvae in response to food, by controlling the activity of C. elegans p53-like ortholog, CEP-1. Specifically, upon food availability, larval neurons secrete a mammalian IL-17 ortholog, ILC-17.1, and ILC-17.1 signaling is needed for C. elegans to progress through development into reproductive adults. ILC-17.1 deficiency activates CEP-1/p53 in larval blast cells, and causes larvae to arrest as stress-resistant, quiescent dauers by activating DAF-16/FOXO, decreasing cytochrome C levels, decreasing glucose utilization and upregulating cell cycle inhibitors. Increasing ILC-17.1 levels represses CEP-1/p53 and promotes anabolic growth, but also inhibits apoptosis upon genotoxic stress. IL-17 also represses p53 in human epithelial cells. These studies describe a role for the tumor suppressor p53-like proteins in controlling developmental quiescence of a metazoan in response to neuronal activity and immunometabolic signals and are relevant to our understanding of neuroimmune mechanisms in cancer. This novel role for p53-like proteins in C. elegans supports the argument that their developmental function was a main driving force in their evolution4,5