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1.
FEBS Open Bio ; 9(9): 1623-1631, 2019 09.
Article in English | MEDLINE | ID: mdl-31368651

ABSTRACT

In environments with limited food and high population density, Caenorhabditis elegans larvae may enter the dauer stage, in which metabolism is shifted to fat accumulation to allow larvae to survive for months without food. Mutations in the insulin-like receptor gene daf-2 force C. elegans to constitutively form dauer larva at higher temperature. It has been reported that autophagy is required for fat accumulation in daf-2 dauer larva. However, the mechanism underlying this process remains unknown. Here, we report that autophagy gene atg-18 acts in a cell nonautonomous manner in neurons and intestinal cells to mediate the influence of daf-2 signaling on fat metabolism. Moreover, ATG-18 in chemosensory neurons plays a vital role in this metabolic process. Finally, we report that neuronal ATG-18 functions through neurotransmitters to control fat storage in daf-2 dauers, which suggests an essential role of autophagy in the neuroendocrine regulation of fat metabolism by insulin-like signaling.


Subject(s)
Autophagy-Related Proteins/metabolism , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , Fats/metabolism , Larva/metabolism , Membrane Proteins/metabolism , Neurosecretory Systems/metabolism , Animals , Autophagy-Related Proteins/genetics , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Larva/genetics , Membrane Proteins/genetics
2.
Invert Neurosci ; 18(2): 8, 2018 05 30.
Article in English | MEDLINE | ID: mdl-29845318

ABSTRACT

Increased neuronal excitability causes seizures with debilitating symptoms. Effective and noninvasive treatments are limited for easing symptoms, partially due to the complexity of the disorder and lack of knowledge of specific molecular faults. An unexplored, novel target for seizure therapeutics is the cGMP/protein kinase G (PKG) pathway, which targets downstream K+ channels, a mechanism similar to Retigabine, a recently FDA-approved antiepileptic drug. Our results demonstrate that increased PKG activity decreased seizure duration in C. elegans utilizing a recently developed electroconvulsive seizure assay. While the fly is a well-established seizure model, C. elegans are an ideal yet unexploited model which easily uptakes drugs and can be utilized for high-throughput screens. In this study, we show that treating the worms with either a potassium channel opener, Retigabine or published pharmaceuticals that increase PKG activity, significantly reduces seizure recovery times. Our results suggest that PKG signaling modulates downstream K+ channel conductance to control seizure recovery time in C. elegans. Hence, we provide powerful evidence, suggesting that pharmacological manipulation of the PKG signaling cascade may control seizure duration across phyla.


Subject(s)
Electroshock/adverse effects , Seizures/etiology , Seizures/metabolism , Animals , Anticonvulsants/therapeutic use , Caenorhabditis elegans , Caenorhabditis elegans Proteins , Carbamates/therapeutic use , Cyclic GMP/analogs & derivatives , Cyclic GMP-Dependent Protein Kinases/genetics , Cyclic GMP-Dependent Protein Kinases/metabolism , Disease Models, Animal , Phenylenediamines/therapeutic use , Recovery of Function/drug effects , Recovery of Function/genetics , Seizures/drug therapy , Signal Transduction/drug effects , Signal Transduction/physiology
3.
PLoS Genet ; 13(5): e1006764, 2017 May.
Article in English | MEDLINE | ID: mdl-28557996

ABSTRACT

Dietary restriction (DR) and reduced insulin growth factor (IGF) signaling extend lifespan in Caenorhabditis elegans and other eukaryotic organisms. Autophagy, an evolutionarily conserved lysosomal degradation pathway, has emerged as a central pathway regulated by various longevity signals including DR and IGF signaling in promoting longevity in a variety of eukaryotic organisms. However, the mechanism remains unclear. Here we show that the autophagy protein ATG-18 acts cell non-autonomously in neuronal and intestinal tissues to maintain C. elegans wildtype lifespan and to respond to DR and IGF-mediated longevity signaling. Moreover, ATG-18 activity in chemosensory neurons that are involved in food detection sufficiently mediates the effect of these longevity pathways. Additionally, ATG-18-mediated cell non-autonomous signaling depends on the release of neurotransmitters and neuropeptides. Interestingly, our data suggest that neuronal and intestinal ATG-18 acts in parallel and converges on unidentified neurons that secrete neuropeptides to regulate C. elegans lifespan through the transcription factor DAF-16/FOXO in response to reduced IGF signaling.


Subject(s)
Autophagy-Related Proteins/metabolism , Caenorhabditis elegans/metabolism , Longevity , Neuropeptides/metabolism , Animals , Autophagy-Related Proteins/genetics , Caenorhabditis elegans/genetics , Caenorhabditis elegans/growth & development , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Caloric Restriction , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Insulin-Like Growth Factor I/metabolism , Intestinal Mucosa/metabolism , Neuroendocrine Cells/metabolism , Neurotransmitter Agents/metabolism , Sensory Receptor Cells/metabolism
4.
PLoS One ; 11(9): e0163786, 2016.
Article in English | MEDLINE | ID: mdl-27668426

ABSTRACT

The microscopic nematode Caenorhabditis elegans has emerged as a valuable model for understanding the molecular and cellular basis of neurological disorders. The worm offers important physiological similarities to mammalian models such as conserved neuron morphology, ion channels, and neurotransmitters. While a wide-array of behavioral assays are available in C. elegans, an assay for electroshock/electroconvulsion remains absent. Here, we have developed a quantitative behavioral method to assess the locomotor response following electric shock in C. elegans. Electric shock impairs normal locomotion, and induces paralysis and muscle twitching; after a brief recovery period, shocked animals resume normal locomotion. We tested electric shock responses in loss-of-function mutants for unc-25, which encodes the GABA biosynthetic enzyme GAD, and unc-49, which encodes the GABAA receptor. unc-25 and unc-49 mutants have decreased inhibitory GABAergic transmission to muscles, and take significantly more time to recover normal locomotion following electric shock compared to wild-type. Importantly, increased sensitivity of unc-25 and unc-49 mutants to electric shock is rescued by treatment with antiepileptic drugs, such as retigabine. Additionally, we show that pentylenetetrazol (PTZ), a GABAA receptor antagonist and proconvulsant in mammalian and C. elegans seizure models, increases susceptibility of worms to electric shock.

5.
Autophagy ; 11(1): 9-27, 2015.
Article in English | MEDLINE | ID: mdl-25569839

ABSTRACT

The cellular recycling process of autophagy has been extensively characterized with standard assays in yeast and mammalian cell lines. In multicellular organisms, numerous external and internal factors differentially affect autophagy activity in specific cell types throughout the stages of organismal ontogeny, adding complexity to the analysis of autophagy in these metazoans. Here we summarize currently available assays for monitoring the autophagic process in the nematode C. elegans. A combination of measuring levels of the lipidated Atg8 ortholog LGG-1, degradation of well-characterized autophagic substrates such as germline P granule components and the SQSTM1/p62 ortholog SQST-1, expression of autophagic genes and electron microscopy analysis of autophagic structures are presently the most informative, yet steady-state, approaches available to assess autophagy levels in C. elegans. We also review how altered autophagy activity affects a variety of biological processes in C. elegans such as L1 survival under starvation conditions, dauer formation, aging, and cell death, as well as neuronal cell specification. Taken together, C. elegans is emerging as a powerful model organism to monitor autophagy while evaluating important physiological roles for autophagy in key developmental events as well as during adulthood.


Subject(s)
Autophagy , Caenorhabditis elegans/cytology , Guidelines as Topic , Animals , Biological Assay , Caenorhabditis elegans/embryology , Embryonic Development , Models, Biological
6.
PLoS Genet ; 10(10): e1004699, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25330189

ABSTRACT

The Caenorhabditis elegans dauer larva is a facultative state of diapause. Mutations affecting dauer signal transduction and morphogenesis have been reported. Of these, most that result in constitutive formation of dauer larvae are temperature-sensitive (ts). The daf-31 mutant was isolated in genetic screens looking for novel and underrepresented classes of mutants that form dauer and dauer-like larvae non-conditionally. Dauer-like larvae are arrested in development and have some, but not all, of the normal dauer characteristics. We show here that daf-31 mutants form dauer-like larvae under starvation conditions but are sensitive to SDS treatment. Moreover, metabolism is shifted to fat accumulation in daf-31 mutants. We cloned the daf-31 gene and it encodes an ortholog of the arrest-defective-1 protein (ARD1) that is the catalytic subunit of the major N alpha-acetyltransferase (NatA). A daf-31 promoter::GFP reporter gene indicates daf-31 is expressed in multiple tissues including neurons, pharynx, intestine and hypodermal cells. Interestingly, overexpression of daf-31 enhances the longevity phenotype of daf-2 mutants, which is dependent on the forkhead transcription factor (FOXO) DAF-16. We demonstrate that overexpression of daf-31 stimulates the transcriptional activity of DAF-16 without influencing its subcellular localization. These data reveal an essential role of NatA in controlling C. elegans life history and also a novel interaction between ARD1 and FOXO transcription factors, which may contribute to understanding the function of ARD1 in mammals.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/physiology , Forkhead Transcription Factors/metabolism , N-Terminal Acetyltransferases/metabolism , Acetyltransferases/genetics , Acetyltransferases/metabolism , Animals , Animals, Genetically Modified , Caenorhabditis elegans/genetics , Caenorhabditis elegans/growth & development , Caenorhabditis elegans Proteins/genetics , Catalytic Domain , Epistasis, Genetic , Forkhead Transcription Factors/genetics , Gene Expression Regulation , Larva/genetics , Larva/growth & development , Longevity/genetics , Mutation , N-Terminal Acetyltransferase A/chemistry , N-Terminal Acetyltransferase E/chemistry , N-Terminal Acetyltransferases/genetics
7.
J Vis Exp ; (88): e51703, 2014 Jun 26.
Article in English | MEDLINE | ID: mdl-24998902

ABSTRACT

In the last decade, C. elegans has emerged as an invertebrate organism to study interactions between hosts and pathogens, including the host defense against gram-negative bacterium Salmonella typhimurium. Salmonella establishes persistent infection in the intestine of C. elegans and results in early death of infected animals. A number of immunity mechanisms have been identified in C. elegans to defend against Salmonella infections. Autophagy, an evolutionarily conserved lysosomal degradation pathway, has been shown to limit the Salmonella replication in C. elegans and in mammals. Here, a protocol is described to infect C. elegans with Salmonella typhimurium, in which the worms are exposed to Salmonella for a limited time, similar to Salmonella infection in humans. Salmonella infection significantly shortens the lifespan of C. elegans. Using the essential autophagy gene bec-1 as an example, we combined this infection method with C. elegans RNAi feeding approach and showed this protocol can be used to examine the function of C. elegans host genes in defense against Salmonella infection. Since C. elegans whole genome RNAi libraries are available, this protocol makes it possible to comprehensively screen for C. elegans genes that protect against Salmonella and other intestinal pathogens using genome-wide RNAi libraries.


Subject(s)
Caenorhabditis elegans/genetics , Caenorhabditis elegans/microbiology , Salmonella Infections, Animal/genetics , Salmonella Infections, Animal/microbiology , Salmonella typhimurium/physiology , Animals , Disease Models, Animal , Host-Pathogen Interactions/genetics , RNA Interference , RNA, Double-Stranded/genetics
8.
PLoS Genet ; 10(6): e1004409, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24967584

ABSTRACT

Spinster (Spin) in Drosophila or Spinster homolog 1 (Spns1) in vertebrates is a putative lysosomal H+-carbohydrate transporter, which functions at a late stage of autophagy. The Spin/Spns1 defect induces aberrant autolysosome formation that leads to embryonic senescence and accelerated aging symptoms, but little is known about the mechanisms leading to the pathogenesis in vivo. Beclin 1 and p53 are two pivotal tumor suppressors that are critically involved in the autophagic process and its regulation. Using zebrafish as a genetic model, we show that Beclin 1 suppression ameliorates Spns1 loss-mediated senescence as well as autophagic impairment, whereas unexpectedly p53 deficit exacerbates both of these characteristics. We demonstrate that 'basal p53' activity plays a certain protective role(s) against the Spns1 defect-induced senescence via suppressing autophagy, lysosomal biogenesis, and subsequent autolysosomal formation and maturation, and that p53 loss can counteract the effect of Beclin 1 suppression to rescue the Spns1 defect. By contrast, in response to DNA damage, 'activated p53' showed an apparent enhancement of the Spns1-deficient phenotype, by inducing both autophagy and apoptosis. Moreover, we found that a chemical and genetic blockage of lysosomal acidification and biogenesis mediated by the vacuolar-type H+-ATPase, as well as of subsequent autophagosome-lysosome fusion, prevents the appearance of the hallmarks caused by the Spns1 deficiency, irrespective of the basal p53 state. Thus, these results provide evidence that Spns1 operates during autophagy and senescence differentially with Beclin 1 and p53.


Subject(s)
Apoptosis Regulatory Proteins/antagonists & inhibitors , Lysosomes/metabolism , Membrane Proteins/genetics , Tumor Suppressor Protein p53/genetics , Vacuolar Proton-Translocating ATPases/metabolism , Zebrafish Proteins/antagonists & inhibitors , Zebrafish Proteins/genetics , Aging/genetics , Animals , Apoptosis Regulatory Proteins/genetics , Autophagy/genetics , Beclin-1 , DNA Damage/genetics , DNA Repair/genetics , Enzyme Inhibitors/pharmacology , Gene Knockdown Techniques , Green Fluorescent Proteins/genetics , Lysosomes/genetics , Macrolides/pharmacology , Mitochondria/genetics , Mitochondria/metabolism , Vacuolar Proton-Translocating ATPases/antagonists & inhibitors , Zebrafish
9.
Dev Comp Immunol ; 45(2): 214-8, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24674884

ABSTRACT

Salmonella typhimurium infects both intestinal epithelial cells and macrophages. Autophagy is a lysosomal degradation pathway that is present in all eukaryotes. Autophagy has been reported to limit the Salmonella replication in Caenorhabditis elegans and in mammals. However, it is unknown whether intestinal autophagy activity plays a role in host defense against Salmonella infection in C. elegans. In this study, we inhibited the autophagy gene bec-1 in different C. elegans tissues and examined the survival of these animals following Salmonella infection. Here we show that inhibition of the bec-1 gene in the intestine but not in other tissues confers susceptibility to Salmonella infection, which is consistent with recent studies in mice showing that autophagy is involved in clearance of Salmonella in the intestinal epithelial cells. Therefore, the intestinal autophagy activity is essential for host defense against Salmonella infection from C. elegans to mice, perhaps also in humans.


Subject(s)
Autophagy , Caenorhabditis elegans/immunology , Caenorhabditis elegans/microbiology , Salmonella typhimurium/physiology , Animals , Disease Models, Animal , Humans , Intestines/cytology , Intestines/immunology , Intestines/microbiology , Mice , Salmonella Infections/immunology
10.
Autophagy ; 9(2): 138-49, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-23108454

ABSTRACT

Efficient apoptotic corpse clearance is essential for metazoan development and adult tissue homeostasis. Several autophagy proteins have been previously shown to function in apoptotic cell clearance; however, it remains unknown whether autophagy genes are essential for efficient apoptotic corpse clearance in the developing embryo. Here we show that, in Caenorhabditis elegans embryos, loss-of-function mutations in several autophagy genes that act at distinct steps in the autophagy pathway resulted in increased numbers of cell corpses and delayed cell corpse clearance. Further analysis of embryos with a null mutation in bec- 1, the C. elegans ortholog of yeast VPS30/ATG6/mammalian beclin 1 (BECN1), revealed normal phosphatidylserine exposure on dying cells. Moreover, the corpse clearance defects of bec- 1(ok691) embryos were rescued by BEC-1 expression in engulfing cells, and bec- 1(ok691) enhanced corpse clearance defects in nematodes with simultaneous mutations in the engulfment genes, ced- 1, ced- 6 or ced- 12. Together, these data demonstrate that autophagy proteins play an important role in cell corpse clearance during nematode embryonic development, and likely function in parallel to known pathways involved in corpse removal.


Subject(s)
Apoptosis/genetics , Autophagy/genetics , Caenorhabditis elegans/embryology , Caenorhabditis elegans/genetics , Embryo, Nonmammalian/cytology , Embryonic Development/genetics , Animals , Caenorhabditis elegans/cytology , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Cell Count , Embryo, Nonmammalian/embryology , Embryo, Nonmammalian/metabolism , Genes, Helminth/genetics , Mutation/genetics , Phagocytosis/genetics , Phosphatidylserines/metabolism , Promoter Regions, Genetic/genetics
11.
Adv Exp Med Biol ; 694: 47-60, 2010.
Article in English | MEDLINE | ID: mdl-20886756

ABSTRACT

Aging is a process in which individuals undergo an exponential decline in vitality, leading to death. In the last two decades, the study of the molecular regulation of aging in model organisms, particularly in C. elegans, has greatly expanded our knowledge of aging. Multiple longevity pathways, such as insulin-like growth factor signaling, TOR signaling, dietary restriction and mitochondrial activity, control aging in C. elegans. Recent genetic studies indicate that autophagy, an evolutionary conserved lysosomal degradation pathway, interacts with various longevity signals in the regulation of C. elegans life span. Here, we review the current progress in understanding the role of autophagy in the regulation of C. elegans life span.


Subject(s)
Autophagy , Caenorhabditis elegans/physiology , Longevity/physiology , Animals , Insulin/metabolism , Signal Transduction
12.
Proc Natl Acad Sci U S A ; 106(34): 14564-9, 2009 Aug 25.
Article in English | MEDLINE | ID: mdl-19667176

ABSTRACT

A conserved insulin-like pathway modulates both aging and pathogen resistance in Caenorhabditis elegans. However, the specific innate effector functions that mediate this pathogen resistance are largely unknown. Autophagy, a lysosomal degradation pathway, plays a role in controlling intracellular bacterial pathogen infections in cultured cells, but less is known about its role at the organismal level. We examined the effects of autophagy gene inactivation on Salmonella enterica Serovar Typhimurium (Salmonella typhimurium) infection in 2 model organisms, Caenorhabditis elegans and Dictyostelium discoideum. In both organisms, genetic inactivation of the autophagy pathway increases bacterial intracellular replication, decreases animal lifespan, and results in apoptotic-independent death. In C. elegans, genetic knockdown of autophagy genes abrogates pathogen resistance conferred by a loss-of-function mutation, daf-2(e1370), in the insulin-like tyrosine kinase receptor or by over-expression of the DAF-16 FOXO transcription factor. Thus, autophagy genes play an essential role in host defense in vivo against an intracellular bacterial pathogen and mediate pathogen resistance in long-lived mutant nematodes.


Subject(s)
Autophagy/physiology , Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/microbiology , Receptor, Insulin/physiology , Salmonella typhimurium/physiology , Animals , Animals, Genetically Modified , Autophagy/genetics , Caenorhabditis elegans/genetics , Caenorhabditis elegans/ultrastructure , Caenorhabditis elegans Proteins/genetics , Dictyostelium/genetics , Dictyostelium/microbiology , Epithelial Cells/microbiology , Epithelial Cells/ultrastructure , Forkhead Transcription Factors , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Host-Pathogen Interactions , Immunity, Innate/genetics , Intestinal Mucosa/cytology , Intestinal Mucosa/microbiology , Intestinal Mucosa/ultrastructure , Longevity/genetics , Microscopy, Electron, Transmission , Microscopy, Fluorescence , Mutation , Phagosomes/ultrastructure , RNA Interference , Receptor, Insulin/genetics , Salmonella typhimurium/genetics , Survival Analysis , Transcription Factors/genetics , Transcription Factors/physiology , Vesicular Transport Proteins
13.
Autophagy ; 3(6): 597-9, 2007.
Article in English | MEDLINE | ID: mdl-17912023

ABSTRACT

Dietary restriction extends life span in diverse species including Caenorhabditis elegans. However, the downstream cellular targets regulated by dietary restriction are largely unknown. Autophagy, an evolutionary conserved lysosomal degradation pathway, is induced under starvation conditions and regulates life span in insulin signaling C. elegans mutants. We now report that two essential autophagy genes (bec-1 and Ce-atg7) are required for the longevity phenotype of the C. elegans dietary restriction mutant (eat-2(ad1113) animals. Thus, we propose that autophagy mediates the effect, not only of insulin signaling, but also of dietary restriction on the regulation of C. elegans life span. Since autophagy and longevity control are highly conserved from C. elegans to mammals, a similar role for autophagy in dietary restriction-mediated life span extension may also exist in mammals.


Subject(s)
Autophagy/physiology , Caenorhabditis elegans/physiology , Caloric Restriction/methods , Food Deprivation/physiology , Longevity/physiology , Animals , Autophagy/genetics , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/physiology , Genes, Helminth/physiology , Longevity/genetics , Plasmids , RNA Interference , Vesicular Transport Proteins
14.
Autophagy ; 3(1): 21-5, 2007.
Article in English | MEDLINE | ID: mdl-17172799

ABSTRACT

Expanded polyglutamine (polyQ) proteins aggregate intracellularly in Huntington's disease and other neurodegenerative disorders. The lysosomal degradation pathway, autophagy, is known to promote clearance of polyQ protein aggregates in cultured cells. Moreover, basal autophagy in neuronal cells in mice prevents neurodegeneration by suppressing the accumulation of abnormal intracellular proteins. However, it is not yet known whether autophagy genes play a role in vivo in protecting against disease caused by mutant aggregate-prone, expanded polyQ proteins. To examine this question, we used two models of polyQ-induced toxicity in C. elegans, including the expression of polyQ40 aggregates in muscle and the expression of a human huntingtin disease fragment containing a polyQ tract of 150 residues (Htn-Q150) in ASH sensory neurons. Here, we show that genetic inactivation of autophagy genes accelerates the accumulation of polyQ40 aggregates in C. elegans muscle cells and exacerbates polyQ40-induced muscle dysfunction. Autophagy gene inactivation also increases the accumulation of Htn-Q150 aggregates in C. elegans ASH sensory neurons and results in enhanced neurodegeneration. These data provide in vivo genetic evidence that autophagy genes suppress the accumulation of polyQ aggregates and protect cells from disease caused by polyQ toxicity.


Subject(s)
Autophagy/genetics , Autophagy/physiology , Caenorhabditis elegans Proteins/genetics , Heredodegenerative Disorders, Nervous System/prevention & control , Peptides/metabolism , Animals , Animals, Genetically Modified , Caenorhabditis elegans , Caenorhabditis elegans Proteins/metabolism , Heredodegenerative Disorders, Nervous System/genetics , Huntingtin Protein , Muscles/metabolism , Muscles/ultrastructure , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , RNA Interference , Ubiquitin-Activating Enzymes/metabolism , Vesicular Transport Proteins
15.
Development ; 131(16): 3897-906, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15253933

ABSTRACT

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.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/growth & development , Insulin/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Proteins/metabolism , Signal Transduction/physiology , Adaptor Proteins, Signal Transducing , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/genetics , Forkhead Transcription Factors , Molecular Sequence Data , Phosphotransferases (Alcohol Group Acceptor)/genetics , Proteins/genetics , Regulatory-Associated Protein of mTOR , Transcription Factors/metabolism
16.
Development ; 129(1): 221-31, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11782415

ABSTRACT

The daf-9 gene functions to integrate transforming growth factor-beta 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.


Subject(s)
Caenorhabditis elegans/genetics , Cytochrome P-450 Enzyme System/genetics , Longevity/genetics , Amino Acid Sequence , Animals , Caenorhabditis elegans/embryology , Embryo, Nonmammalian/physiology , Gene Expression Regulation, Developmental , Molecular Sequence Data , Mutation
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