Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2α Phosphorylation in <i>Caenorhabditis elegans</i>

Joo

et al. 2019

IJMS

Pheromones are neuronal signals that stimulate conspecific individuals to react to environmental stressors or stimuli. Research on the ascaroside (ascr) pheromones in Caenorhabditis elegans and other nematodes has made great progress since ascr#1 was first isolated and biochemically defined in 2005. In this review, we highlight the current research on the structural diversity, biosynthesis, and pleiotropic neuronal functions of ascr pheromones and their implications in animal physiology. Experimental evidence suggests that ascr biosynthesis starts with conjugation of ascarylose to very long-chain fatty acids that are then processed via peroxisomal β-oxidation to yield diverse ascr pheromones. We also discuss the concentration and stage-dependent pleiotropic neuronal functions of ascr pheromones. These functions include dauer induction, lifespan extension, repulsion, aggregation, mating, foraging and detoxification, among others. These roles are carried out in coordination with three G protein-coupled receptors that function as putative pheromone receptors: SRBC-64/66, SRG-36/37, and DAF-37/38. Pheromone sensing is transmitted in sensory neurons via DAF-16-regulated glutamatergic neurotransmitters. Neuronal peroxisomal fatty acid β-oxidation has important cell-autonomous functions in the regulation of neuroendocrine signaling, including neuroprotection. In the future, translation of our knowledge of nematode ascr pheromones to higher animals might be beneficial, as ascr#1 has some anti-inflammatory effects in mice. To this end, we propose the establishment of pheromics (pheromone omics) as a new subset of integrated disciplinary research area within chemical ecology for system-wide investigation of animal pheromones.

Section: Implications Of Ascr Pheromone Metabolism In Neuroprotectionmentioning

confidence: 99%

Ascaroside Pheromones: Chemical Biology and Pleiotropic Neuronal Functions

Joo

et al. 2019

IJMS

G3 Genes|Genomes|Genetics

“…Ã indicates significant enrichment (P , 0.05; hypergeometric enrichment test). phosph-eIF2a, a marker of cellular stress (Kim et al 2018;Kulalert et al 2017;Taniuchi et al 2016;Pakos-Zebrucka et al 2016). This was indeed the case, and excess 5-HT caused a time-dependent increase in the levels of phosphorylated eIFa ( Figure 5D).…”

Section: Resultsmentioning

confidence: 54%

Global Transcriptome Changes That Accompany Alterations in Serotonin Levels inCaenorhabditis elegans

Cruz-Corchado¹,

Ooi²,

Das³

et al. 2020

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.

“…We previously reported the results of a genetic screen for suppressors of the dauer-constitutive (Daf-c) phenotype of the daf-28(sa191) mutant (Kulalert et al 2017). Incomplete suppression of the Daf-c phenotype of the daf-28(sa191) mutant by daf-3 and daf-16 mutations (Malone, Inoue and Thomas 1996; Li, Kennedy and Ruvkun 2003; Kulalert and Kim 2013) suggested that genetic suppressors of daf-28(sa191) might uncover additional novel pathways functioning in parallel to established signaling pathways activating the dauer developmental decision.…”

Section: Resultsmentioning

confidence: 99%

“…Of note, recent studies have shown a role of Rictor/TORC2 and CaMKI in regulating expression of TGF-ligand and insulin-like proteins in response to food signals in dauer entry (Neal et al 2015;O'Donnell et al 2018). We previously described a genetic strategy to identify novel genes involved in dauer formation by undertaking a screen for suppressors of the daf-28(sa191) mutation (Kulalert and Kim 2013; Kulalert et al 2017), which confers constitutive entry into dauer diapause (Malone, Inoue and Thomas 1996;Li, Kennedy and Ruvkun 2003). Here, we have identified and characterized a c-Jun N-terminal Kinase (JNK)-like mitogen-activated protein kinase (MAPK) KGB-1 pathway that functions in the sensory neurons to promote dauer formation.…”

Section: Introductionmentioning

confidence: 99%

Neuronal KGB-1 JNK MAPK signaling regulates the dauer developmental decision in response to environmental stress in C. elegans

Dogra

Kulalert

Schroeder

et al. 2021

Preprint

Self Cite

In response to stressful growth conditions of high population density, food scarcity and elevated temperature, young larvae of nematode Caenorhabditis elegans can enter a developmentally arrested stage called dauer that is characterized by dramatic anatomic and metabolic remodeling. Genetic analysis of dauer formation of C. elegans has served as an experimental paradigm for the identification and characterization of conserved neuroendocrine signaling pathways. Here, we report the identification and characterization of a conserved JNK-like mitogen-activated protein kinase (MAPK) pathway that is required for dauer formation in response to environmental stressors. We observed that loss-of-function mutations in the MLK-1-MEK-1-KGB-1 MAPK pathway suppress dauer entry. Loss-of-function mutation in the VHP-1 MAPK phosphatase, a known negative regulator of KGB-1 signaling, results in constitutive dauer formation which is dependent on the presence of dauer pheromone but independent of diminished food levels or elevated temperatures. Our data suggest that KGB-1 pathway acts in the sensory neurons, in parallel to established insulin and TGF-β signaling pathways, to transduce the dauer-inducing environmental cues of diminished food levels and elevated temperature.