Biology subjects

Baugh, R.

Publications and source records attributed to Baugh, R..

4 recordsLinked to original sources

bioRxiv2025

DAF-18/PTEN protects LIN-35/Rb from CLP-1/CAPN-mediated cleavage to promote starvation resistance

Starvation resistance is a fundamental trait with profound influence on fitness and disease risk. DAF-18, the C. elegans ortholog of the tumor suppressor PTEN, promotes starvation resistance. PTEN is a dual phosphatase, and DAF-18 promotes starvation resistance as a lipid phosphatase by antagonizing insulin/IGF and PI3K signaling, activating the tumor suppressor DAF-16/FoxO. However, if or how DAF-18/PTEN protein-phosphatase activity promotes starvation resistance is unknown. Using genetic, genomic, bioinformatic, and biochemical approaches, we identified the C. elegans retinoblastoma/RB protein homolog, LIN-35/Rb, as a critical mediator of the effect of DAF-18/PTEN on starvation resistance. We show that DAF-18/PTEN protects LIN-35/Rb from cleavage by the -Calpain homolog CLP-1/CAPN, and that LIN-35/Rb together with the repressive DREAM complex promote starvation resistance. We conclude that the tumor suppressors DAF-18/PTEN and LIN-35/Rb function in a linear pathway, with LIN-35/Rb and the rest of the DREAM complex functioning as a transcriptional effector of DAF-18/PTEN protein-phosphatase activity resulting in repression of germline gene expression. This work is significant for revealing a network of tumor suppressors that promote survival during cellular and developmental quiescence.

genetics↗

bioRxiv2024

Structure-specific variation in per- and polyfluoroalkyl substances toxicity among genetically diverse Caenorhabditis elegans strains

BackgroundThere are >14,500 structurally diverse per- and polyfluoroalkyl substances (PFAS). Despite knowledge that these "forever chemicals" are in 99% of humans, mechanisms of toxicity and adverse health effects are incompletely known. Furthermore, the contribution of genetic variation to PFAS susceptibility and health consequences is unknown. ObjectivesWe determined the toxicity of a structurally distinct set of PFAS in twelve genetically diverse strains of the genetic model system Caenorhabditis elegans. MethodsDose-response curves for four perfluoroalkyl carboxylic acids (PFNA, PFOA, PFPeA, and PFBA), two perfluoroalkyl sulfonic acids (PFOS and PFBS), two perfluoroalkyl sulfonamides (PFOSA and PFBSA), two fluoroether carboxylic acids (GenX and PFMOAA), one fluoroether sulfonic acid (PFEESA), and two fluorotelomers (6:2 FCA and 6:2 FTS) were determined in the C. elegans laboratory reference strain, N2, and eleven genetically diverse wild strains. Body length was quantified by image analysis at each dose after 48 hr of developmental exposure of L1 arrest-synchronized larvae to estimate effective concentration values (EC50). ResultsThere was a significant range in toxicity among PFAS: PFOSA > PFBSA {approx} PFOS {approx} PFNA > PFOA > GenX {approx} PFEESA > PFBS {approx} PFPeA {approx} PFBA. Long-chain PFAS had greater toxicity than short-chain, and fluorosulfonamides were more toxic than carboxylic and sulfonic acids. Genetic variation explained variation in susceptibility to PFBSA, PFOS, PFBA, PFOA, GenX, PFEESA, PFPeA, and PFBA. There was significant variation in toxicity among C. elegans strains due to chain length, functional group, and between legacy and emerging PFAS. ConclusionC. elegans respond to legacy and emerging PFAS of diverse structures, and this depends on specific structures and genetic variation. Harnessing the natural genetic diversity of C. elegans and the structural complexity of PFAS is a powerful New Approach Methodology (NAM) to investigate structure-activity relationships and mechanisms of toxicity which may inform regulation of other PFAS to improve human and environmental health.

pharmacology and toxicology↗

bioRxiv2021

Intergenerational adaptations to stress are evolutionarily conserved, stress-specific, and have deleterious trade-offs

Despite reports of parental exposure to stress promoting physiological adaptations in progeny in diverse organisms, there remains considerable debate over the significance and evolutionary conservation of such multigenerational effects. Here, we investigate four independent models of intergenerational adaptations to stress in C. elegans - bacterial infection, eukaryotic infection, osmotic stress and nutrient stress - across multiple species. We found that all four intergenerational physiological adaptations are conserved in at least one other species, that they are stress-specific, and that they have deleterious trade-offs in mismatched environments. By profiling the effects of parental bacterial infection and osmotic stress exposure on progeny gene expression across species we established a core set of 279 highly conserved genes that exhibited intergenerational changes in expression in response to stress in all species tested and provide evidence suggesting that presumed adaptive and deleterious intergenerational effects are molecularly related at the gene expression level. By contrast, we found that these same stresses did not elicit any similarly conserved transgenerational changes in progeny gene expression three generations after stress exposure. We conclude that intergenerational responses to stress play a substantial and evolutionarily conserved role in regulating animal physiology and that the vast majority of the effects of parental stress on progeny gene expression are reversible and not maintained transgenerationally.

genetics↗

bioRxiv2017

Neurohormonal signalling controls insulin sensitivity and specificity in C. elegans

Insulin and insulin-like growth factor signalling regulates a broad spectrum of growth and metabolic responses to a variety of internal and environmental stimuli. Such responses can be tailored to the environment so that changes in insulin signalling result in distinct physiological responses to different stimuli. For example, the inhibition of insulin-like signalling by osmotic stress or by starvation of C. elegans results in physiologically distinct states and patterns of gene expression. How does insulin-like signalling elicit different responses to different environmental stimuli? We report that neurohormonal signalling involving the C. elegans cytosolic sulfotransferase SSU-1 controls developmental arrest in response to osmotic stress but not to starvation; that SSU-1 functions in a single pair of sensory neurons to control signalling via the nuclear hormone receptor NHR-1; that signalling controlled by SSU-1 acts antagonistically to insulin-like signalling; and that the FOXO transcription factor DAF-16, a downstream effector of insulin-like signalling, enters the nucleus in response to osmotic stress but activates gene expression only if SSU-1 is active. We propose that neurohormonal signalling controlled by one or more cytosolic sulfotransferases similarly regulates the specificity of responses to changes in insulin signalling during periods of environmental stress in other organisms and that abnormalities in such sulfotransferase-controlled neurohormonal signalling might contribute to human disorders that involve insulin signalling, such as obesity and type 2 diabetes.

genetics↗