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Donald L Riddle - One of the best experts on this subject based on the ideXlab platform.
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the tor pathway interacts with the insulin signaling pathway to regulate c elegans larval development metabolism and life span
Development, 2004Co-Authors: Kailiang Jia, Di Chen, Donald L RiddleAbstract:The highly conserved target-of-rapamycin (TOR) protein kinases control cell growth in response to nutrients and growth factors. In mammals, TOR has been shown to interact with raptor to relay nutrient signals to downstream translation machinery. We report that in C. elegans , mutations in the genes encoding CeTOR and raptor result in dauer-like larval arrest, implying that CeTOR regulates dauer diapause. The daf-15 (raptor) and let-363 (CeTOR) mutants shift metabolism to accumulate fat, and raptor mutations extend adult life span. daf-15 transcription is regulated by Daf-16, a FOXO transcription factor that is in turn regulated by daf-2 insulin/IGF signaling. This is a new mechanism that regulates the TOR pathway. Thus, DAF-2 insulin/IGF signaling and nutrient signaling converge on DAF-15 (raptor) to regulate C. elegans larval development, metabolism and life span.
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daf 9 a cytochrome p450 regulating c elegans larval development and adult longevity
Development, 2002Co-Authors: Patrice S Albert, Donald L RiddleAbstract:The daf-9 gene functions to integrate transforming growth factor-β and insulin-like signaling pathways to regulate Caenorhabditis elegans larval development. Mutations in daf-9 result in transient dauer-like larval arrest, abnormal reproductive development, molting defects and increased adult longevity. The phenotype is sterol-dependent, and dependent on the activity of DAF-12, a nuclear hormone receptor. Genetic tests show that daf-9 is upstream of daf-12 in the genetic pathways for larval development and adult longevity. daf-9 encodes a cytochrome P450 related to those involved in biosynthesis of steroid hormones in mammals. We propose that it specifies a step in the biosynthetic pathway for a DAF-12 ligand, which might be a steroid. The surprising cellular specificity of daf-9 expression (predominantly in two sensory neurons) supports a previously unrecognized role for these cells in neuroendocrine control of larval development, reproduction and life span.
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two pleiotropic classes of daf 2 mutation affect larval arrest adult behavior reproduction and longevity in caenorhabditis elegans
Genetics, 1998Co-Authors: Pamela L. Larsen, Amy J Sutton, Mark L Sundermeyer, Patrice S Albert, Kevin V King, Mark L Edgley, David Gems, Donald L RiddleAbstract:The nematode Caenorhabditis elegans responds to overcrowding and scarcity of food by arresting development as a dauer larva, a nonfeeding, long-lived, stress-resistant, alternative third-larval stage. Previous work has shown that mutations in the genes daf-2 (encoding a member of the insulin receptor family) and age-1 (encoding a PI 3-kinase) result in constitutive formation of dauer larvae (Daf-c), increased adult longevity (Age), and increased intrinsic thermotolerance (Itt). Some daf-2 mutants have additional developmental, behavioral, and reproductive defects. We have characterized in detail 15 temperature-sensitive and 1 nonconditional daf-2 allele to investigate the extent of daf-2 mutant defects and to examine whether specific mutant traits correlate with each other. The greatest longevity seen in daf-2 mutant adults was approximately three times that of wild type. The temperature-sensitive daf-2 mutants fell into two overlapping classes, including eight class 1 mutants, which are Daf-c, Age, and Itt, and exhibit low levels of L1 arrest at 25.5 degrees. Seven class 2 mutants also exhibit the class 1 defects as well as some or all of the following: reduced adult motility, abnormal adult body and gonad morphology, high levels of embryonic and L1 arrest, production of progeny late in life, and reduced brood size. The strengths of the Daf-c, Age, and Itt phenotypes largely correlated with each other but not with the strength of class 2-specific defects. This suggests that the DAF-2 receptor is bifunctional. Examination of the null phenotype revealed a maternally rescued egg, L1 lethal component, and a nonconditional Daf-c component. With respect to the Daf-c phenotype, the dauer-defective (Daf-d) mutation daf-12(m20) was epistatic to daf-2 class 1 alleles but not the severe class 2 alleles tested. All daf-2 mutant defects were suppressed by the daf-d mutation Daf-16(m26). Our findings suggest a new model for daf-2, age-1, daf-12, and Daf-16 interactions.
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two pleiotropic classes of daf 2 mutation affect larval arrest adult behavior reproduction and longevity in caenorhabditis elegans
Genetics, 1998Co-Authors: Pamela L. Larsen, Amy J Sutton, Mark L Sundermeyer, Patrice S Albert, Kevin V King, Mark L Edgley, David Gems, Donald L RiddleAbstract:The nematode Caenorhabditis elegans responds to overcrowding and scarcity of food by arresting development as a dauer larva, a nonfeeding, long-lived, stress-resistant, alternative third-larval stage. Previous work has shown that mutations in the genes daf-2 (encoding a member of the insulin receptor family) and age-1 (encoding a PI 3-kinase) result in constitutive formation of dauer larvae (Daf-c), increased adult longevity (Age), and increased intrinsic thermotolerance (Itt). Some daf-2 mutants have additional developmental, behavioral, and reproductive defects. We have characterized in detail 15 temperature-sensitive and 1 nonconditional daf-2 allele to investigate the extent of daf-2 mutant defects and to examine whether specific mutant traits correlate with each other. The greatest longevity seen in daf-2 mutant adults was approximately three times that of wild type. The temperature-sensitive daf-2 mutants fell into two overlapping classes, including eight class 1 mutants, which are Daf-c, Age, and Itt, and exhibit low levels of L1 arrest at 25.5 degrees. Seven class 2 mutants also exhibit the class 1 defects as well as some or all of the following: reduced adult motility, abnormal adult body and gonad morphology, high levels of embryonic and L1 arrest, production of progeny late in life, and reduced brood size. The strengths of the Daf-c, Age, and Itt phenotypes largely correlated with each other but not with the strength of class 2-specific defects. This suggests that the DAF-2 receptor is bifunctional. Examination of the null phenotype revealed a maternally rescued egg, L1 lethal component, and a nonconditional Daf-c component. With respect to the Daf-c phenotype, the dauer-defective (Daf-d) mutation daf-12(m20) was epistatic to daf-2 class 1 alleles but not the severe class 2 alleles tested. All daf-2 mutant defects were suppressed by the daf-d mutation Daf-16(m26). Our findings suggest a new model for daf-2, age-1, daf-12, and Daf-16 interactions.
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genes that regulate both development and longevity in caenorhabditis elegans
Genetics, 1995Co-Authors: Pamela L. Larsen, Patrice S Albert, Donald L RiddleAbstract:The nematode Caenorhabditis elegans responds to conditions of overcrowding and limited food by arresting development as a dauer larva. Genetic analysis of mutations that alter dauer larva formation (daf mutations) is presented along with an updated genetic pathway for dauer vs. nondauer development. Mutations in the daf-2 and daf-23 genes double adult life span, whereas mutations in four other dauer-constitutive genes positioned in a separate branch of this pathway (daf-1, daf-4, daf-7 and daf-8) do not. The increased life spans are suppressed completely by a Daf-16 mutation and partially in a daf-2; daf-18 double mutant. A genetic pathway for determination of adult life span is presented based on the same strains and growth conditions used to characterize Daf phenotypes. Both dauer larva formation and adult life span are affected in daf-2; daf-12 double mutants in an allele-specific manner. Mutations in daf-12 do not extend adult life span, but certain combinations of daf-2 and daf-12 mutant alleles nearly quadruple it. This synergistic effect, which does not equivalently extend the fertile period, is the largest genetic extension of life span yet observed in a metazoan.
Adam Antebi - One of the best experts on this subject based on the ideXlab platform.
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comparative metabolomics reveals endogenous ligands of daf 12 a nuclear hormone receptor regulating c elegans development and lifespan
Cell Metabolism, 2014Co-Authors: Parag Mahanti, Joshua Wollam, Kathleen J. Dumas, Neelanjan Bose, Axel Bethke, Joshua C Judkins, Anna M Zimmerman, Sydney L Campbell, Patrick J Hu, Adam AntebiAbstract:Summary Small-molecule ligands of nuclear hormone receptors (NHRs) govern the transcriptional regulation of metazoan development, cell differentiation, and metabolism. However, the physiological ligands of many NHRs remain poorly characterized, primarily due to lack of robust analytical techniques. Using comparative metabolomics, we identified endogenous steroids that act as ligands of the C. elegans NHR, DAF-12, a vitamin D and liver X receptor homolog regulating larval development, fat metabolism, and lifespan. The identified molecules feature unexpected chemical modifications and include only one of two DAF-12 ligands reported earlier, necessitating a revision of previously proposed ligand biosynthetic pathways. We further show that ligand profiles are regulated by a complex enzymatic network, including the Rieske oxygenase DAF-36, the short-chain dehydrogenase DHS-16, and the hydroxysteroid dehydrogenase HSD-1. Our results demonstrate the advantages of comparative metabolomics over traditional candidate-based approaches and provide a blueprint for the identification of ligands for other C. elegans and mammalian NHRs.
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a steroid receptor microrna switch regulates life span in response to signals from the gonad
Science, 2012Co-Authors: Yidong She, Joshua Wollam, Daniel Magne, Oezlem Karalay, Adam AntebiAbstract:Although the gonad primarily functions in procreation, it also affects animal life span. Here, we show that removal of the Caenorhabditis elegans germ line triggers a switch in the regulatory state of the organism to promote longevity, co-opting components involved in larval developmental timing circuits. These components include the DAF-12 steroid receptor, which is involved in the larval stage two–to–stage three (L2-L3) transition and up-regulates members of the let-7 microRNA (miRNA) family. The miRNAs target an early larval nuclear factor lin-14 and akt-1/kinase, thereby stimulating Daf-16/FOXO signaling to extend life. Our studies suggest that metazoan life span is coupled to the gonad through elements of a developmental timer.
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A bile acid-like steroid modulates Caenorhabditis elegans lifespan through nuclear receptor signaling
Proceedings of the National Academy of Sciences, 2007Co-Authors: B. Gerisch, V. Rottiers, Christopher L. Cummins, Daniel L Motola, Dichen Li, Hans Lehrach, Adam AntebiAbstract:Broad aspects of Caenorhabditis elegans life history, including larval developmental timing, arrest at the dauer diapause, and longevity, are regulated by the nuclear receptor DAF-12. Endogenous DAF-12 ligands are 3-keto bile acid-like steroids, called dafachronic acids, which rescue larval defects of hormone-deficient mutants, such as daf-9/cytochrome P450 and daf-36/Rieske oxygenase, and activate DAF-12. Here we examined the effect of dafachronic acid on pathways controlling lifespan. Dafachronic acid supplementation shortened the lifespan of long-lived daf-9 mutants and abolished their stress resistance, indicating that the ligand is "proaging" in response to signals from the dauer pathways. However, the ligand extended the lifespan of germ-line ablated daf-9 and daf-36 mutants, showing that it is "antiaging" in the germ-line longevity pathway. Thus, dafachronic acid regulates C. elegans lifespan according to signaling state. These studies provide key evidence that bile acid-like steroids modulate aging in animals.
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hormonal control of c elegans dauer formation and life span by a rieske like oxygenase
Developmental Cell, 2006Co-Authors: V. Rottiers, B. Gerisch, Daniel L Motola, Carolyn L Cummins, Kiyoji Nishiwaki, David J Mangelsdorf, Adam AntebiAbstract:C. elegans diapause, gonadal outgrowth, and life span are regulated by a lipophilic hormone, which serves as a ligand to the nuclear hormone receptor DAF-12. A key step in hormone production is catalyzed by the CYP450 DAF-9, but the extent of the biosynthetic pathway is unknown. Here, we identify a conserved Rieske-like oxygenase, DAF-36, as a component in hormone metabolism. Mutants display larval developmental and adult aging phenotypes, as well as patterns of epistasis similar to that of daf-9. Larval phenotypes are potently reversed by crude lipid extracts, 7-dehydrocholesterol, and a recently identified DAF-12 sterol ligand, suggesting that DAF-36 works early in the hormone biosynthetic pathway. DAF-36 is expressed primarily within the intestine, a major organ of metabolic and endocrine control, distinct from DAF-9. These results imply that C. elegans hormone production has multiple steps and is distributed, and that it may provide one way that tissues register their current physiological state during organismal commitments.
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a novel nuclear receptor coregulator complex controls c elegans lipid metabolism larval development and aging
Genes & Development, 2004Co-Authors: Andreas H Ludewig, B. Gerisch, Cindy Weitzel, Corinna Kobereisermann, Axel Bethke, Kerstin Neubert, Harald Hutter, Adam AntebiAbstract:Environmental cues transduced by an endocrine network converge on Caenorhabditis elegans nuclear receptor DAF-12 to mediate arrest at dauer diapause or continuous larval development. In adults, DAF-12 selects long-lived or short-lived modes. How these organismal choices are molecularly specified is unknown. Here we show that coregulator DIN-1 and DAF-12 physically and genetically interact to instruct organismal fates. Homologous to human corepressor SHARP, DIN-1 comes in long (L) and short (S) isoforms, which are nuclear localized but have distinct functions. DIN-1L has embryonic and larval developmental roles. DIN-1S, along with DAF-12, regulates lipid metabolism, larval stage-specific programs, diapause, and longevity. Epistasis experiments reveal that din-1S acts in the dauer pathways downstream of lipophilic hormone, insulin/IGF, and TGFβ signaling, the same point as daf-12. We propose that the DIN-1S/DAF-12 complex serves as a molecular switch that implements slow life history alternatives in response to diminished hormonal signals.
Cynthia Kenyon - One of the best experts on this subject based on the ideXlab platform.
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direct and indirect gene regulation by a life extending foxo protein in c elegans roles for gata factors and lipid gene regulators
Cell Metabolism, 2013Co-Authors: Peichuan Zhang, Meredith E Judy, Seungjae Lee, Cynthia KenyonAbstract:Summary In long-lived C. elegans insulin/IGF-1 pathway mutants, the life-extending FOXO transcription factor Daf-16 is present throughout the animal, but we find that its activity in a single tissue can delay the aging of other tissues and extend the animal's life span. To better understand the topography of Daf-16 action among the tissues, we analyzed a collection of Daf-16 - regulated genes. Daf-16 regulated most of these genes in a cell-autonomous fashion, often using tissue-specific GATA factors to direct their expression to specific tissues. Daf-16 could also act cell nonautonomously to influence gene expression. Daf-16 affected gene expression in other cells, at least in part, via the lipid-gene regulator MDT-15. Daf-16, and probably MDT-15, could act cell nonautonomously in the endoderm to ameliorate the paralysis caused by expressing Alzheimer's Aβ protein in muscles. These findings suggest that MDT-15-dependent intercellular signals, possibly lipid signals, can help to coordinate tissue physiology, enhance proteostasis, and extend life in response to Daf-16/FOXO activity.
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tissue entrainment by feedback regulation of insulin gene expression in the endoderm of caenorhabditis elegans
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Coleen T Murphy, Seungjae Lee, Cynthia KenyonAbstract:How are the rates of aging of different tissues coordinated? In Caenorhabditis elegans, decreasing insulin/IGF-1 signaling extends lifespan by activating the transcription factor Daf-16/FOXO. If Daf-16 levels are experimentally increased in one tissue, such as the intestine, Daf-16 activity in other tissues rises. Here we test the hypothesis that this "FOXO-to-FOXO" signaling occurs via feedback regulation of ins-7 insulin gene expression. We find that Daf-16 regulates ins-7 expression in the intestine, and that preventing this regulation blocks FOXO-to-FOXO signaling from the intestine to other tissues. Our findings show that feedback regulation of insulin gene expression coordinates Daf-16 activity among the tissues, and they establish the intestine, which is the animal's entire endoderm, as an important insulin-signaling center.
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germ cell loss extends c elegans life span through regulation of daf 16 by kri 1 and lipophilic hormone signaling
Cell, 2006Co-Authors: Jennifer R Berman, Cynthia KenyonAbstract:In C. elegans, removing the germ cells extends life span by triggering the nuclear localization and activation of the Daf-16/FOXO transcription factor in the intestine. In this study, we identify and analyze genes required for germline removal to extend life span. We find that the reproductive system communicates with the intestine through lipophilic-hormone signaling and that a gene called kri-1 is likely to act in the intestine to promote Daf-16 nuclear localization in response to this signal. This lipophilic-signaling pathway and kri-1 are not required for Daf-16's nuclear localization and life-span extension in animals with decreased insulin/IGF-1 signaling. Thus, this pathway specifically enables the integration of cues from the reproductive system with central Daf-16-activation pathways to influence the aging of the animal.
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tissue specific activities of c elegans daf 16 in the regulation of lifespan
Cell, 2003Co-Authors: Nataliya Libina, Jennifer R Berman, Cynthia KenyonAbstract:Abstract In C. elegans , the transcription factor Daf-16 promotes longevity in response to reduced insulin/IGF-1 signaling or germline ablation. In this study, we have asked how different tissues interact to specify the lifespan of the animal. We find that several tissues act as signaling centers. In particular, Daf-16 activity in the intestine, which is also the animal's adipose tissue, completely restores the longevity of Daf-16(−) germline-deficient animals, and increases the lifespans of Daf-16(−) insulin/IGF-1-pathway mutants substantially. Our findings indicate that Daf-16 may control two types of downstream signals: Daf-16 activity in signaling cells upregulates Daf-16 in specific responding tissues, possibly via regulation of insulin-like peptides, and also evokes Daf-16-independent responses. We suggest that this network of tissue interactions and feedback regulation allows the tissues to equilibrate and fine-tune their expression of downstream genes, which, in turn, coordinates their rates of aging within the animal.
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regulation of the caenorhabditis elegans longevity protein daf 16 by insulin igf 1 and germline signaling
Nature Genetics, 2001Co-Authors: Honor Hsin, Natasha Libina, Cynthia KenyonAbstract:The lifespan of Caenorhabditis elegans is regulated by the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2, which signals through a conserved phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway1,2,3,4,5,6,7. Mutants in this pathway remain youthful and active much longer than normal animals and can live more than twice as long. This lifespan extension requires Daf-16, a forkhead/winged-helix transcription factor8,9. Daf-16 is thought to be the main target of the DAF-2 pathway. Insulin/IGF-1 signaling is thought to lead to phosphorylation of Daf-16 by AKT activity, which in turn shortens lifespan. Here, we show that the DAF-2 pathway prevents Daf-16 accumulation in nuclei. Disrupting Akt-consensus phosphorylation sites in Daf-16 causes nuclear accumulation in wild-type animals, but, surprisingly, has little effect on lifespan. Thus the DAF-2 pathway must have additional outputs. Lifespan in C. elegans can be extended by perturbing sensory neurons or germ cells10,11. In both cases, lifespan extension requires Daf-16. We find that both sensory neurons and germline activity regulate Daf-16 accumulation in nuclei, but the nuclear localization patterns are different. Together these findings reveal unexpected complexity in the Daf-16-dependent pathways that regulate aging.
Gary Ruvkun - One of the best experts on this subject based on the ideXlab platform.
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gene activities that mediate increased life span of c elegans insulin like signaling mutants
Genes & Development, 2007Co-Authors: Andrew V Samuelson, Christopher E Carr, Gary RuvkunAbstract:Genetic and RNA interference (RNAi) screens for life span regulatory genes have revealed that the daf-2 insulin-like signaling pathway plays a major role in Caenorhabditis elegans longevity. This pathway converges on the Daf-16 transcription factor and may regulate life span by controlling the expression of a large number of genes, including free-radical detoxifying genes, stress resistance genes, and pathogen resistance genes. We conducted a genome-wide RNAi screen to identify genes necessary for the extended life span of daf-2 mutants and identified ∼200 gene inactivations that shorten daf-2 life span. Some of these gene inactivations dramatically shorten daf-2 mutant life span but less dramatically shorten daf-2; Daf-16 mutant or wild-type life span. Molecular and behavioral markers for normal aging and for extended life span in low insulin/IGF1 (insulin-like growth factor 1) signaling were assayed to distinguish accelerated aging from general sickness and to examine age-related phenotypes. Detailed demographic analysis, molecular markers of aging, and insulin signaling mutant test strains were used to filter progeric gene inactivations for specific acceleration of aging. Highly represented in the genes that mediate life span extension in the daf-2 mutant are components of endocytotic trafficking of membrane proteins to lysosomes. These gene inactivations disrupt the increased expression of the Daf-16 downstream gene superoxide dismutase sod-3 in a daf-2 mutant, suggesting trafficking between the insulin-like receptor and Daf-16. The activities of these genes may normally decline during aging.
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gravity force transduced by the mec 4 mec 10 deg enac channel modulates daf 16 foxo activity in caenorhabditis elegans
Genetics, 2007Co-Authors: Chih Jen Kuan, Gary Ruvkun, Catherine M Dempsey, Jim V Zoval, Eyleen J Orourke, Marc J MadouAbstract:The gravity response is an array of behavioral and physiological plasticity elicited by changes in ambient mechanical force and is an evolutionarily ancient adaptive mechanism. We show in Caenorhabditis elegans that the force of hypergravity is translated into biological signaling via a genetic pathway involving three factors: the degenerin/epithelial Na+ channel (DEG/ENaC) class of mechanosensory channels of touch receptor neurons, the neurotransmitter serotonin, and the FoxO transcription factor Daf-16 known to regulate development, energy metabolism, stress responses, and aging. After worms were exposed to hypergravity for 3 hr, their muscular and neuronal functions were preserved, but they exhibited Daf-16∷GFP nuclear accumulation in cells throughout the body and accumulated excess fat. Mutations in MEC-4/MEC-10 DEG/ENaC or its partners MEC-6, MEC-7, and MEC-9 blocked Daf-16∷GFP nuclear accumulation induced by hypergravity but did not affect Daf-16 response to other stresses. We show that exogenous serotonin and the antidepressant fluoxetine can attenuate Daf-16∷GFP nuclear accumulation in WT animals exposed to hypergravity. These results reveal a novel physiological role of the mechanosensory channel, showing that the perception of mechanical stress controls FoxO signaling pathways and that inactivation of DEG/ENaC may decouple mechanical loading and physiological responses.
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daf 16 target genes that control c elegans life span and metabolism
Science, 2003Co-Authors: Siu Sylvia Lee, Andrew C. Tolonen, Scott Kennedy, Gary RuvkunAbstract:Signaling from the DAF-2/insulin receptor to the Daf-16/FOXO transcription factor controls longevity, metabolism, and development in disparate phyla. To identify genes that mediate the conserved biological outputs of daf-2 /insulin-like signaling, we usedcomparative genomics to identify 17 orthologous genes from Caenorhabditis and Drosophila , each of which bears a Daf-16 binding site in the promoter region. One-third of these Daf-16 downstream candidate genes were regulatedby daf-2 /insulin-like signaling in C. elegans , and RNA interference inactivation of the candidates showed that many of these genes mediate distinct aspects of Daf-16 function, including longevity, metabolism, anddevelopment.
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Regulation of C. elegans Daf-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway.
Current Biology, 2001Co-Authors: Jürgen Hench, Gary RuvkunAbstract:Abstract C. elegans insulin-like signaling regulates metabolism, development, and life span. This signaling pathway negatively regulates the activity of the forkhead transcription factor Daf-16. Daf-16 encodes multiple isoforms that are expressed in distinct tissue types and are probable orthologs of human FKHRL1, FKHR, and AFX. We show that human FKHRL1 can partially replace Daf-16, proving the orthology. In mammalian cells, insulin and insulin-like growth factor signaling activate AKT/PKB kinase to negatively regulate the nuclear localization of Daf-16 homologs (reviewed in [1]). We show that the absence of AKT consensus sites on Daf-16 is sufficient to cause dauer arrest in daf-2(+) animals, proving that Daf-16 is the major output of insulin signaling in C. elegans . FKHR, FKRHL1, and AFX may similarly be the major outputs of mammalian insulin signaling. daf-2 insulin signaling, via AKT kinases, negatively regulates Daf-16 by controlling its nuclear localization. Surprisingly, we find that daf-7 TGF-β signaling also regulates Daf-16 nuclear localization specifically at the time when the animal makes the commitment between diapause and reproductive development. Daf-16 function is supported by the combined action of two distinct promoter/enhancer elements, whereas the coding sequences of two major Daf-16 isoforms are interchangeable. Together, these observations suggest that the combined effects of transcriptional and posttranslational regulation of Daf-16 transduce insulin-like signals in C. elegans and perhaps more generally.
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regulation of c elegans daf 16 and its human ortholog fkhrl1 by the daf 2 insulin like signaling pathway
Current Biology, 2001Co-Authors: Raymond Y N Lee, Jürgen Hench, Gary RuvkunAbstract:C. elegans insulin-like signaling regulates metabolism, development, and life span. This signaling pathway negatively regulates the activity of the forkhead transcription factor Daf-16. Daf-16 encodes multiple isoforms that are expressed in distinct tissue types and are probable orthologs of human FKHRL1, FKHR, and AFX. We show that human FKHRL1 can partially replace Daf-16, proving the orthology. In mammalian cells, insulin and insulin-like growth factor signaling activate AKT/PKB kinase to negatively regulate the nuclear localization of Daf-16 homologs (reviewed in ). We show that the absence of AKT consensus sites on Daf-16 is sufficient to cause dauer arrest in daf-2(+) animals, proving that Daf-16 is the major output of insulin signaling in C. elegans. FKHR, FKRHL1, and AFX may similarly be the major outputs of mammalian insulin signaling. daf-2 insulin signaling, via AKT kinases, negatively regulates Daf-16 by controlling its nuclear localization. Surprisingly, we find that daf-7 TGF-beta signaling also regulates Daf-16 nuclear localization specifically at the time when the animal makes the commitment between diapause and reproductive development. Daf-16 function is supported by the combined action of two distinct promoter/enhancer elements, whereas the coding sequences of two major Daf-16 isoforms are interchangeable. Together, these observations suggest that the combined effects of transcriptional and posttranslational regulation of Daf-16 transduce insulin-like signals in C. elegans and perhaps more generally.
Kathleen J. Dumas - One of the best experts on this subject based on the ideXlab platform.
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a histone h4 lysine 20 methyltransferase couples environmental cues to sensory neuron control of developmental plasticity
Development, 2017Co-Authors: Colin Delaney, Albert Tzong-yang Chen, Kathleen J. Dumas, Jacqueline GranielAbstract:Animals change developmental fates in response to external cues. In the nematode Caenorhabditis elegans, unfavorable environmental conditions induce a state of diapause known as dauer by inhibiting the conserved DAF-2 insulin-like signaling (ILS) pathway through incompletely understood mechanisms. We have previously established a role for the C. elegans dosage compensation protein DPY-21 in the control of dauer arrest and DAF-2 ILS. Here, we show that the histone H4 lysine 20 methyltransferase SET-4, which also influences dosage compensation, promotes dauer arrest in part by repressing the X-linked ins-9 gene, which encodes a new agonist insulin-like peptide (ILP) expressed specifically in the paired ASI sensory neurons that are required for dauer bypass. ins-9 repression in dauer-constitutive mutants requires DPY-21, SET-4 and the FoxO transcription factor Daf-16, which is the main target of DAF-2 ILS. By contrast, autosomal genes encoding major agonist ILPs that promote reproductive development are not repressed by DPY-21, SET-4 or Daf-16/FoxO. Our results implicate SET-4 as a sensory rheostat that reinforces developmental fates in response to environmental cues by modulating autocrine and paracrine DAF-2 ILS.
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Effects of Caenorhabditis elegans sgk-1 mutations on lifespan, stress resistance, and Daf-16/FoxO regulation
2016Co-Authors: Albert Tzong-yang Chen, Chunfang Guo, Kathleen J. Dumas, Kaveh AshrafiAbstract:The AGC family serine–threonine kinases Akt and Sgk are similar in primary amino acid sequence and in vitro substrate specificity, and both kinases are thought to directly phosphorylate and inhibit FoxO transcription factors. In the nematode Caenorhabd-itis elegans, it is well established that AKT-1 controls dauer arrest and lifespan by regulating the subcellular localization of the FoxO transcription factor Daf-16. SGK-1 is thought to act similarly to AKT-1 in lifespan control by phosphorylating and inhibiting the nuclear translocation of Daf-16/FoxO. Using sgk-1 null and gain-of-function mutants, we now provide multiple lines of evidence indicating that AKT-1 and SGK-1 influence C. elegans lifespan, stress resistance, and Daf-16/FoxO activity in funda-mentally different ways. Whereas AKT-1 shortens lifespan, SGK-1 promotes longevity in a Daf-16-/FoxO-dependent manner. In contrast to AKT-1, which reduces resistance to multiple stresses, SGK-1 promotes resistance to oxidative stress and ultraviolet radiation but inhibits thermotolerance. Analysis of several Daf-16/FoxO target genes that are repressed by AKT-1 reveals that SGK-1 represses a subset of these genes while having little influence on the expression of others. Accordingly, unlike AKT-1, which promotes the cytoplasmic sequestration of Daf-16/FoxO, SGK-1 does not influence Daf-16/FoxO subcellular localization. Thus, in spite of their similar in vitro substrate specificities, Akt and Sgk influence longevity, stress resistance, and FoxO activity through distinct mechanisms in vivo. Our findings highlight the need for a re-evaluation of current paradigms of FoxO regulation by Sgk. Key words: aging; C. elegans; FoxO; insulin-like growth factor signaling; lifespan; Sgk
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comparative metabolomics reveals endogenous ligands of daf 12 a nuclear hormone receptor regulating c elegans development and lifespan
Cell Metabolism, 2014Co-Authors: Parag Mahanti, Joshua Wollam, Kathleen J. Dumas, Neelanjan Bose, Axel Bethke, Joshua C Judkins, Anna M Zimmerman, Sydney L Campbell, Patrick J Hu, Adam AntebiAbstract:Summary Small-molecule ligands of nuclear hormone receptors (NHRs) govern the transcriptional regulation of metazoan development, cell differentiation, and metabolism. However, the physiological ligands of many NHRs remain poorly characterized, primarily due to lack of robust analytical techniques. Using comparative metabolomics, we identified endogenous steroids that act as ligands of the C. elegans NHR, DAF-12, a vitamin D and liver X receptor homolog regulating larval development, fat metabolism, and lifespan. The identified molecules feature unexpected chemical modifications and include only one of two DAF-12 ligands reported earlier, necessitating a revision of previously proposed ligand biosynthetic pathways. We further show that ligand profiles are regulated by a complex enzymatic network, including the Rieske oxygenase DAF-36, the short-chain dehydrogenase DHS-16, and the hydroxysteroid dehydrogenase HSD-1. Our results demonstrate the advantages of comparative metabolomics over traditional candidate-based approaches and provide a blueprint for the identification of ligands for other C. elegans and mammalian NHRs.
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unexpected role for dosage compensation in the control of dauer arrest insulin like signaling and foxo transcription factor activity in caenorhabditis elegans
Genetics, 2013Co-Authors: Kathleen J. Dumas, Colin Delaney, Stephane Flibotte, Donald G Moerman, Gyorgyi CsankovszkiAbstract:During embryogenesis, an essential process known as dosage compensation is initiated to equalize gene expression from sex chromosomes. Although much is known about how dosage compensation is established, the consequences of modulating the stability of dosage compensation postembryonically are not known. Here we define a role for the Caenorhabditis elegans dosage compensation complex (DCC) in the regulation of DAF-2 insulin-like signaling. In a screen for dauer regulatory genes that control the activity of the FoxO transcription factor Daf-16, we isolated three mutant alleles of dpy-21, which encodes a conserved DCC component. Knockdown of multiple DCC components in hermaphrodite and male animals indicates that the dauer suppression phenotype of dpy-21 mutants is due to a defect in dosage compensation per se. In dpy-21 mutants, expression of several X-linked genes that promote dauer bypass is elevated, including four genes encoding components of the DAF-2 insulin-like pathway that antagonize Daf-16/FoxO activity. Accordingly, dpy-21 mutation reduced the expression of Daf-16/FoxO target genes by promoting the exclusion of Daf-16/FoxO from nuclei. Thus, dosage compensation enhances dauer arrest by repressing X-linked genes that promote reproductive development through the inhibition of Daf-16/FoxO nuclear translocation. This work is the first to establish a specific postembryonic function for dosage compensation in any organism. The influence of dosage compensation on dauer arrest, a larval developmental fate governed by the integration of multiple environmental inputs and signaling outputs, suggests that the dosage compensation machinery may respond to external cues by modulating signaling pathways through chromosome-wide regulation of gene expression.
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functional divergence of dafachronic acid pathways in the control of c elegans development and lifespan
Developmental Biology, 2010Co-Authors: Kathleen J. Dumas, Chunfang Guo, Xi Wang, Kirk B Burkhart, Elizabeth J Adams, Hena AlamAbstract:Steroid hormone and insulin/insulin-like growth factor signaling (IIS) pathways control development and lifespan in the nematode Caenorhabditis elegans by regulating the activity of the nuclear receptor DAF-12 and the FoxO transcription factor Daf-16, respectively. The DAF-12 ligands Δ4- and Δ7-dafachronic acid (DA) promote bypass of the dauer diapause and proper gonadal migration during larval development; in adults, DAs influence lifespan. Whether Δ4- and Δ7-DA have unique biological functions is not known. We identified the 3-β-hydroxysteroid dehydrogenase (3βHSD) family member HSD-1, which participates in Δ4-DA biosynthesis, as an inhibitor of Daf-16/FoxO activity. Whereas IIS promotes the cytoplasmic sequestration of Daf-16/FoxO, HSD-1 inhibits nuclear Daf-16/FoxO activity without affecting Daf-16/FoxO subcellular localization. Thus, HSD-1 and IIS inhibit Daf-16/FoxO activity via distinct and complementary mechanisms. In adults, HSD-1 was required for full lifespan extension in IIS mutants, indicating that HSD-1 interactions with IIS are context-dependent. In contrast to the Δ7-DA biosynthetic enzyme DAF-36, HSD-1 is dispensable for proper gonadal migration and lifespan extension induced by germline ablation. These findings provide insights into the molecular interface between DA and IIS pathways and suggest that Δ4- and Δ7-DA pathways have unique as well as overlapping biological functions in the control of development and lifespan.