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Bacterial purine signaling pathway modulates C. elegans development and stress tolerance via DAF-16

ABSTRACT: The purine signaling pathway is crucial for cellular function and is a conserved metabolic network from prokaryotes to humans. While extensively studied in microorganisms like yeast and bacteria, the impact of perturbing dietary intermediates from the purine signaling pathway on animal development and growth remains poorly understood. We utilized Caenorhabditis elegans as the metazoan model to investigate the mechanisms underlying this deficiency. Through a high-throughput screening of an E. coli mutant library Keio collection, we identified 34 E. coli mutants that delay C. elegans development. Among these mutants, we found that E. coli purE gene is an essential genetic component that promotes host development in a dose-dependent manner. Further metabolites supplementation suggests that bacterial purE downstream metabolite 5-aminoimidazole-4-carboxamide ribotide (AICAR) can inhibit worm growth. Additionally, we found the FoxO transcription factor DAF-16 is indispensable in worm development delay induced by purE mutation, and observed increased nuclear accumulation of DAF-16 when fed E. coli purE- mutants, suggesting the role of DAF-16 in response to purE mutation. RNA-seq analysis and phenotypic assays revealed that worms fed the E. coli purE mutant exhibited elevated lifespan, thermotolerance, and pathogen resistance. These findings collectively suggest that certain intermediates in the bacterial purine signaling pathway can serve as a cue to modulate development and activate the defense response in the nematode C. elegans through DAF-16.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE278640 | GEO | 2024/10/06

REPOSITORIES: GEO

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Project description:Post-embryonic development of the nematode C. elegans is governed by nutrient availability. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This “L1 arrest” (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. daf-16/FOXO had overlapping but distinct effects on gene expression in L1 arrest compared to daf-2/InsR adults. Notably, dbl-1/TGF-β, a ligand for the Sma/Mab pathway, and daf-36, which encodes an upstream component of the daf-12/NHR steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β and daf-36. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype, and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.

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Bacterial purine signaling pathway modulates C. elegans development and stress tolerance via DAF-16

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