Diet-Induced Developmental Acceleration Independent of TOR and Insulin in C. elegans

Animals maintain their developmental robustness against natural stresses through numerous regulatory mechanisms, including the posttranscriptional regulation of gene expression by microRNAs (miRNAs). Caenorhabditis elegans miRNAs of the let-7 family (let-7-Fam) function semiredundantly to confer robust stage specificity of cell fates in the hypodermal seam cell lineages. Here, we show reciprocal regulatory interactions between let-7-Fam miRNAs and the innate immune response pathway in C. elegans. Upon infection of C. elegans larvae with the opportunistic human pathogen Pseudomonas aeruginosa, the developmental timing defects of certain let-7-Fam miRNA mutants are enhanced. This enhancement is mediated by the p38 MAPK innate immune pathway acting in opposition to let-7-Fam miRNA activity, possibly via the downstream Activating Transcription Factor-7 (ATF-7). Furthermore, let-7-Fam miRNAs appear to exert negative regulation on the worm's resistance to P. aeruginosa infection. Our results show that the inhibition of pathogen resistance by let-7 involves downstream heterochronic genes and the p38 MAPK pathway. These findings suggest that let-7-Fam miRNAs are integrated into innate immunity gene regulatory networks, such that this family of miRNAs modulates immune responses while also ensuring robust timing of developmental events under pathogen stress.let-7 family microRNAs | p38 | Pseudomonas aeruginosa | developmental timing | innate immunity D uring development, animals routinely encounter environmental, physiological, and nutritional challenges that threaten to compromise the robust execution of developmental programs. Therefore, the genetic programming of development includes mechanisms to ensure that developmental events occur flawlessly despite stressful conditions (1, 2). Several studies indicate that microRNAs (miRNAs) are used to maintain the robustness of biological processes under stress conditions (3-10). miRNAs are endogenous, noncoding, small RNAs that posttranscriptionally regulate gene expression primarily through binding to the 3′UTR of target mRNAs, which results in translation inhibition and/or mRNA degradation (11). miRNAs with the same seed sequence (nucleotides 2-7 of the mature miRNA sequence), which are predicated potentially to share the same set of targets (12), are grouped into a family.The miRNA lin-4 and the miRNAs of the let-7 family (let-7-Fam) are central to the regulation of pluripotency and differentiation in many animal systems, including mammals (13-18). Four Caenorhabditis elegans let-7-Fam miRNAs, let-7, mir-48, mir-84, and mir-241, function in concert to repress key heterochronic gene targets, including daf-12, lin-41, and hbl-1, to stagespecifically regulate the timing of the hypodermal seam cell fates (16,(19)(20)(21)(22). In C. elegans, the temporal patterns of cell division and cell fate during larval development are exquisitely invariant, even though larvae develop as free-living inhabitants of a changing environment in soil and decaying plant materials.In the wild, worms...

Section: Significancementioning

confidence: 64%

Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress

Ren

Ambros

2015

“…As our taxonomic survey of C. elegans habitats shows, nematodes encounter complex communities of microbessome beneficial, some detrimental, rather than a single species. Antagonistic bacteria that do not support optimal C. elegans growth rates or cause induction of stress reporters could produce a toxin or virulence factor that actively and perhaps potently suppresses C. elegans growth, or could fail to supply a key micro-or macronutrient [e.g., iron (32) or vitamins (33,34)]. Beneficial bacteria could either supply key nutrients or actively suppress C. elegans stress and immune responses.…”

Section: Resultsmentioning

confidence: 99%

Caenorhabditis elegans responses to bacteria from its natural habitats

Samuel

Rowedder

Braendle

et al. 2016

359

479

Most Caenorhabditis elegans studies have used laboratory Escherichia coli as diet and microbial environment. Here we characterize bacteria of C. elegans' natural habitats of rotting fruits and vegetation to provide greater context for its physiological responses. By the use of 16S ribosomal DNA (rDNA)-based sequencing, we identified a large variety of bacteria in C. elegans habitats, with phyla Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria being most abundant. From laboratory assays using isolated natural bacteria, C. elegans is able to forage on most bacteria (robust growth on ∼80% of >550 isolates), although ∼20% also impaired growth and arrested and/or stressed animals. Bacterial community composition can predict wild C. elegans population states in both rotting apples and reconstructed microbiomes: alpha-Proteobacteria-rich communities promote proliferation, whereas Bacteroidetes or pathogens correlate with nonproliferating dauers. Combinatorial mixtures of detrimental and beneficial bacteria indicate that bacterial influence is not simply nutritional. Together, these studies provide a foundation for interrogating how bacteria naturally influence C. elegans physiology.Caenorhabditis elegans | host-microbe interactions | ecology B iological organisms constantly live in contact with other organisms in a complex web of ecological interactions, which include prey-predator, host-parasite, competitive, or positive symbiotic relationships. Bacteria are now considered key players in multiple aspects of the biology of multicellular organisms (1-3). The richness and importance of these interactions were so far neglected because laboratory biology had succeeded in simplifying and standardizing the environment of the model organisms, providing in most cases a single microbe as a food source, and not necessarily even a naturally encountered one. The many aspects of organismal biology that were shaped by evolution in natural environments are thus undetectable in the artificial laboratory environment and can only be revealed in the presence of other interacting species. Examples include feeding behavior, metabolism of diverse natural food sources, interactions with natural pathogens that have shaped the organism's immune system, behavioral traits, and regulation of development and reproduction. At the genomic level, many individual genes may not be required in a standard laboratory environment but their role may be revealed by using more diverse and relevant environments (4, 5).The nematode Caenorhabditis elegans is a typical example of a model organism that has been disconnected from its natural ecology: although the species has been studied intensively in the laboratory for half a century, its habitat and natural ecology-what it naturally feeds on, its natural predators and pathogens,

“…In C. elegans, the sensory influence depends on the recognition of food types, which can have different effects on lifespan (30,(34)(35)(36)(37). In Drosophila, the foodtype effect on lifespan has been demonstrated through alterations in the protein composition of its food source.…”

Section: Discussionmentioning

confidence: 99%

“…Besides food levels, the nature of the food source has also been shown to influence an animal's lifespan (30,(34)(35)(36)(37). Because yeast is a component of fly food that can shorten fly lifespan (36) partly through an olfaction-mediated mechanism (3), we asked whether the effect of yeast on lifespan also acts via taste inputs.…”

Section: Significancementioning

confidence: 99%

Positive and negative gustatory inputs affect Drosophila lifespan partly in parallel to dFOXO signaling

Ostojić

Boll

Waterson³

et al. 2014

In Caenorhabditis elegans, a subset of gustatory neurons, as well as olfactory neurons, shortens lifespan, whereas a different subset of gustatory neurons lengthens it. Recently, the lifespan-shortening effect of olfactory neurons has been reported to be conserved in Drosophila. Here we show that the Drosophila gustatory system also affects lifespan in a bidirectional manner. We find that taste inputs shorten lifespan through inhibition of the insulin pathway effector dFOXO, whereas other taste inputs lengthen lifespan in parallel to this pathway. We also note that the gustatory influence on lifespan does not necessarily depend on food intake levels. Finally, we identify the nature of some of the taste inputs that could shorten versus lengthen lifespan. Together our data suggest that different gustatory cues can modulate the activities of distinct signaling pathways, including different insulin-like peptides, to promote physiological changes that ultimately affect lifespan.sensory system | insulin signaling | physiology | gustatory receptors | aging A ging is a universal process that causes deterioration in the biological functions of an organism over the progression of its lifetime. This process is affected by genetic and environmental factors, whose interaction could be mediated by the sensory system, which perceives and transmits environmental information to modulate the signaling activities of downstream target tissues. Accordingly, external sensory cues and sensory neuron activities have been shown to alter the lifespan of both Caenorhabditis elegans and Drosophila melanogaster (1-6).In C. elegans, the laser ablation of a specific subset of gustatory or olfactory neurons extends lifespan, whereas ablation of a different subset of gustatory neurons shortens it (1). Interestingly, at least part of this sensory influence on lifespan has also been observed in other animals. In Drosophila, impairment of olfaction through a mutation in Or83b, which encodes a broadly expressed atypical odorant receptor (7), increases lifespan (3). In addition, exposure of dietary-restricted flies to food odors, like live yeast, can partly suppress their long-life phenotype (3). The conservation of the olfactory influence on lifespan is thus consistent with the possibility that gustatory inputs will also bidirectionally alter the lifespan of both C. elegans and D. melanogaster.The effects of sensory neurons on C. elegans lifespan have been shown to be partly mediated by insulin/IGF signaling (1, 2, 8). The insulin/IGF pathway also affects fly lifespan: down-regulation of the activities of the insulin receptor InR and the receptor substrate, CHICO, extends lifespan (9, 10). Moreover, an increase in activity of the downstream transcription factor dFOXO, which is negatively regulated by both InR and CHICO, increases fly lifespan (11,12). Consistent with these observations, mutations in several of the Drosophila insulin-like peptide (dilp) genes (13), which are expressed in the median neurosecretory cells (mNSCs) in the fly brain (14-1...