RESUMO
The microbiota is a key determinant of the physiology and immunity of animal hosts. The factors governing the transmissibility of viruses between susceptible hosts are incompletely understood. Bacteria serve as food for Caenorhabditis elegans and represent an integral part of the natural environment of C. elegans. We determined the effects of bacteria isolated with C. elegans from its natural environment on the transmission of Orsay virus in C. elegans using quantitative virus transmission and host susceptibility assays. We observed that Ochrobactrum species promoted Orsay virus transmission, whereas Pseudomonas lurida MYb11 attenuated virus transmission relative to the standard laboratory bacterial food Escherichia coli OP50. We found that pathogenic Pseudomonas aeruginosa strains PA01 and PA14 further attenuated virus transmission. We determined that the amount of Orsay virus required to infect 50% of a C. elegans population on P. lurida MYb11 compared with Ochrobactrum vermis MYb71 was dramatically increased, over three orders of magnitude. Host susceptibility was attenuated even further in the presence of P. aeruginosa PA14. Genetic analysis of the determinants of P. aeruginosa required for attenuation of C. elegans susceptibility to Orsay virus infection revealed a role for regulators of quorum sensing. Our data suggest that distinct constituents of the C. elegans microbiota and potential pathogens can have widely divergent effects on Orsay virus transmission, such that associated bacteria can effectively determine host susceptibility versus resistance to viral infection. Our study provides quantitative evidence for a critical role for tripartite host-virus-bacteria interactions in determining the transmissibility of viruses among susceptible hosts.
Assuntos
Caenorhabditis elegans , Pseudomonas aeruginosa , Animais , Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/virologia , Pseudomonas aeruginosa/fisiologia , Pseudomonas aeruginosa/genética , Interações Hospedeiro-PatógenoRESUMO
The molecular mechanisms underlying diversity in animal behavior are not well understood. A major experimental challenge is determining the contribution of genetic variants that affect neuronal gene expression to differences in behavioral traits. In Caenorhabditis elegans, the neuroendocrine transforming growth factor-ß ligand, DAF-7, regulates diverse behavioral responses to bacterial food and pathogens. The dynamic neuron-specific expression of daf-7 is modulated by environmental and endogenous bacteria-derived cues. Here, we investigated natural variation in the expression of daf-7 from the ASJ pair of chemosensory neurons. We identified common genetic variants in gap-2, encoding a Ras guanosine triphosphatase (GTPase)-activating protein homologous to mammalian synaptic Ras GTPase-activating protein, which modify daf-7 expression cell nonautonomously and promote exploratory foraging behavior in a partially DAF-7-dependent manner. Our data connect natural variation in neuron-specific gene expression to differences in behavior and suggest that genetic variation in neuroendocrine signaling pathways mediating host-microbe interactions may give rise to diversity in animal behavior.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Variação Genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Regulação da Expressão Gênica , Sistemas Neurossecretores/metabolismo , Comportamento Alimentar , Comportamento Animal/fisiologia , Neurônios/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador betaRESUMO
Animal internal state is modulated by nutrient intake, resulting in behavioral responses to changing food conditions. The neural mechanisms by which internal states are generated and maintained are not well understood. Here, we show that in the nematode Caenorhabditis elegans, distinct cues from bacterial food - interoceptive signals from the ingestion of bacteria and gustatory molecules sensed from nearby bacteria - act antagonistically on the expression of the neuroendocrine TGF-beta ligand DAF-7 from the ASJ pair of sensory neurons to modulate foraging behavior. A positive-feedback loop dependent on the expression of daf-7 from the ASJ neurons acts to promote transitions between roaming and dwelling foraging states and influence the persistence of roaming states. SCD-2, the C. elegans ortholog of mammalian anaplastic lymphoma kinase (ALK), which has been implicated in the central control of metabolism of mammals, functions in the AIA interneurons to regulate foraging behavior and cell-non-autonomously control the expression of DAF-7 from the ASJ neurons. Our data establish how a dynamic neuroendocrine daf-7 expression feedback loop regulated by SCD-2 functions to couple sensing and ingestion of bacterial food to foraging behavior. We further suggest that this neuroendocrine feedback loop underlies previously characterized exploratory behaviors in C. elegans. Our data suggest that the expression of daf-7 from the ASJ neurons contributes to and is correlated with an internal state of 'unmet need' that regulates exploratory foraging behavior in response to bacterial cues in diverse physiological contexts.
Assuntos
Caenorhabditis elegans , Sinais (Psicologia) , Animais , Caenorhabditis elegans/genética , Bactérias , Células Receptoras Sensoriais , Expressão Gênica , MamíferosRESUMO
The microbiota is a key determinant of the physiology and immunity of animal hosts. The factors governing the transmissibility of viruses between susceptible hosts are incompletely understood. Bacteria serve as food for Caenorhabditis elegans and represent an integral part of the natural environment of C. elegans. We determined the effects of bacteria isolated with C. elegans from its natural environment on the transmission of Orsay virus in C. elegans using quantitative virus transmission and host susceptibility assays. We observed that Ochrobactrum species promoted Orsay virus transmission, whereas Pseudomonas lurida MYb11 attenuated virus transmission relative to the standard laboratory bacterial food Escherichia coli OP50. We found that pathogenic Pseudomonas aeruginosa strains PA01 and PA14 further attenuated virus transmission. We determined that the amount of Orsay virus required to infect 50% of a C. elegans population on P. lurida MYb11 compared with Ochrobactrum vermis MYb71 was dramatically increased, over three orders of magnitude. Host susceptibility was attenuated even further in presence of P. aeruginosa PA14. Genetic analysis of the determinants of P. aeruginosa required for attenuation of C. elegans susceptibility to Orsay virus infection revealed a role for regulators of quorum sensing. Our data suggest that distinct constituents of the C. elegans microbiota and potential pathogens can have widely divergent effects on Orsay virus transmission, such that associated bacteria can effectively determine host susceptibility versus resistance to viral infection. Our study provides quantitative evidence for a critical role for tripartite host-virus-bacteria interactions in determining the transmissibility of viruses among susceptible hosts.
RESUMO
The impact of exposure to microbial pathogens on animal reproductive capacity and germline physiology is not well understood. The nematode Caenorhabditis elegans is a bacterivore that encounters pathogenic microbes in its natural environment. How pathogenic bacteria affect host reproductive capacity of C. elegans is not well understood. Here, we show that exposure of C. elegans hermaphrodites to the Gram-negative pathogen Pseudomonas aeruginosa causes a marked reduction in brood size with concomitant reduction in the number of nuclei in the germline and gonad size. We define 2 processes that are induced that contribute to the decrease in the number of germ cell nuclei. First, we observe that infection with P. aeruginosa leads to the induction of germ cell apoptosis. Second, we observe that this exposure induces mitotic quiescence in the proliferative zone of the C. elegans gonad. Importantly, these processes appear to be reversible; when animals are removed from the presence of P. aeruginosa, germ cell apoptosis is abated, germ cell nuclei numbers increase, and brood sizes recover. The reversible germline dynamics during exposure to P. aeruginosa may represent an adaptive response to improve survival of progeny and may serve to facilitate resource allocation that promotes survival during pathogen infection.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Pseudomonas aeruginosa/metabolismo , Divisão Celular , Proteínas de Caenorhabditis elegans/genética , Células Germinativas/metabolismo , ApoptoseRESUMO
The molecular mechanisms underlying diversity in animal behavior are not well understood. A major experimental challenge is determining the contribution of genetic variants that affect neuronal gene expression to differences in behavioral traits. The neuroendocrine TGF-beta ligand, DAF-7, regulates diverse behavioral responses of Caenorhabditis elegans to bacterial food and pathogens. The dynamic neuron-specific expression of daf-7 is modulated by environmental and endogenous bacteria-derived cues. Here, we investigated natural variation in the expression of daf-7 from the ASJ pair of chemosensory neurons and identified common variants in gap-2, encoding a GTPase-Activating Protein homologous to mammalian SynGAP proteins, which modify daf-7 expression cell-non-autonomously and promote exploratory foraging behavior in a DAF-7-dependent manner. Our data connect natural variation in neuron-specific gene expression to differences in behavior and suggest that genetic variation in neuroendocrine signaling pathways mediating host-microbe interactions may give rise to diversity in animal behavior.
RESUMO
The impact of exposure to microbial pathogens on animal reproductive capacity and germline physiology is not well understood. The nematode Caenorhabditis elegans is a bacterivore that encounters pathogenic microbes in its natural environment. How pathogenic bacteria affect host reproductive capacity of C. elegans is not well understood. Here, we show that exposure of C. elegans hermaphrodites to the Gram-negative pathogen Pseudomonas aeruginosa causes a marked reduction in brood size with concomitant reduction in the number of nuclei in the germline and gonad size. We define two processes that are induced that contribute to the decrease in the number of germ cell nuclei. First, we observe that infection with P. aeruginosa leads to the induction of programmed germ cell death. Second, we observe that this exposure induces mitotic quiescence in the proliferative zone of the C. elegans gonad. Importantly, these processes appear to be reversible; when animals are removed from the presence of P. aeruginosa, germ cell death is abated, germ cell nuclei numbers increase, and brood sizes recover. The reversible germline dynamics during exposure to P. aeruginosa may represent an adaptive response to improve survival of progeny and may serve to facilitate resource allocation that promotes survival during pathogen infection.
RESUMO
Animal internal state is modulated by nutrient intake, resulting in behavioral responses to changing food conditions. The neural mechanisms by which internal states are generated and maintained are not well understood. Here, we show that in the nematode Caenorhabditis elegans, distinct cues from bacterial food - interoceptive signals from the ingestion of bacteria and gustatory molecules sensed from nearby bacteria - act antagonistically on the expression of the neuroendocrine TGF-beta ligand DAF-7 from the ASJ pair of sensory neurons to modulate foraging behavior. A positive-feedback loop dependent on the expression of daf-7 from the ASJ neurons acts to promote transitions between roaming and dwelling foraging states and influence the persistence of roaming states. SCD-2, the C. elegans ortholog of mammalian Anaplastic Lymphoma Kinase (ALK), which has been implicated in the central control of metabolism of mammals, functions in the AIA interneurons to regulate foraging behavior and cell-non-autonomously control the expression of DAF-7 from the ASJ neurons. Our data establish how a dynamic neuroendocrine daf-7 expression feedback loop regulated by SCD-2 functions to couple sensing and ingestion of bacterial food to foraging behavior. We further suggest that this neuroendocrine feedback loop underlies previously characterized exploratory behaviors in C. elegans. Our data suggest that the expression of daf-7 from the ASJ neurons contributes to and is correlated with an internal state of "unmet need" that regulates exploratory foraging behavior in response to bacterial cues in diverse physiological contexts.
RESUMO
In response to stressful growth conditions of high population density, food scarcity, and elevated temperature, young larvae of nematode Caenorhabditis elegans can enter a developmentally arrested stage called dauer that is characterized by dramatic anatomic and metabolic remodeling. Genetic analysis of dauer formation of C. elegans has served as an experimental paradigm for the identification and characterization of conserved neuroendocrine signaling pathways. Here, we report the identification and characterization of a conserved c-Jun N-terminal Kinase-like mitogen-activated protein kinase (MAPK) pathway that is required for dauer formation in response to environmental stressors. We observed that loss-of-function mutations in the MLK-1-MEK-1-KGB-1 MAPK pathway suppress dauer entry. A loss-of-function mutation in the VHP-1 MAPK phosphatase, a negative regulator of KGB-1 signaling, results in constitutive dauer formation, which is dependent on the presence of dauer pheromone but independent of diminished food levels or elevated temperatures. Our data suggest that the KGB-1 pathway acts in the sensory neurons, in parallel to established insulin and TGF-ß signaling pathways, to transduce the dauer-inducing environmental cues of diminished food levels and elevated temperature.
Assuntos
Caenorhabditis elegans , AnimaisRESUMO
Dynamic gene expression in neurons shapes fundamental processes in the nervous systems of animals. However, how neuronal activation by different stimuli can lead to distinct transcriptional responses is not well understood. We have been studying how microbial metabolites modulate gene expression in chemosensory neurons of Caenorhabditis elegans. Considering the diverse environmental stimuli that can activate chemosensory neurons of C. elegans, we sought to understand how specific transcriptional responses can be generated in these neurons in response to distinct cues. We have focused on the mechanism of rapid (<6 min) and selective transcriptional induction of daf-7, a gene encoding a TGF-ß ligand, in the ASJ chemosensory neurons in response to the pathogenic bacterium Pseudomonas aeruginosa. DAF-7 is required for the protective behavioral avoidance of P. aeruginosa by C. elegans. Here, we define the involvement of two distinct cyclic GMP (cGMP)-dependent pathways that are required for daf-7 expression in the ASJ neuron pair in response to P. aeruginosa. We show that a calcium-independent pathway dependent on the cGMP-dependent protein kinase G (PKG) EGL-4, and a canonical calcium-dependent signaling pathway dependent on the activity of a cyclic nucleotide-gated channel subunit CNG-2, function in parallel to activate rapid, selective transcription of daf-7 in response to P. aeruginosa metabolites. Our data suggest that fast, selective early transcription of neuronal genes require PKG in shaping responses to distinct microbial stimuli in a pair of C. elegans chemosensory neurons.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Células Quimiorreceptoras/metabolismo , GMP Cíclico/metabolismo , Pseudomonas aeruginosa/metabolismo , Fator de Crescimento Transformador beta/genética , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Sinalização do Cálcio , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Ativação Transcricional , Fator de Crescimento Transformador beta/metabolismoRESUMO
Microbes are ubiquitous in the natural environment of Caenorhabditis elegans. Bacteria serve as a food source for C. elegans but may also cause infection in the nematode host. The sensory nervous system of C. elegans detects diverse microbial molecules, ranging from metabolites produced by broad classes of bacteria to molecules synthesized by specific strains of bacteria. Innate recognition through chemosensation of bacterial metabolites or mechanosensation of bacteria can induce immediate behavioral responses. The ingestion of nutritive or pathogenic bacteria can modulate internal states that underlie long-lasting behavioral changes. Ingestion of nutritive bacteria leads to learned attraction and exploitation of the bacterial food source. Infection, which is accompanied by activation of innate immunity, stress responses, and host damage, leads to the development of aversive behavior. The integration of a multitude of microbial sensory cues in the environment is shaped by experience and context. Genetic, chemical, and neuronal studies of C. elegans behavior in the presence of bacteria have defined neural circuits and neuromodulatory systems that shape innate and learned behavioral responses to microbial cues. These studies have revealed the profound influence that host-microbe interactions have in governing the behavior of this simple animal host.
Assuntos
Caenorhabditis elegans/fisiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Bactérias/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/microbiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiologia , Dióxido de Carbono/metabolismo , Sinais (Psicologia) , Escherichia coli , Comportamento Alimentar/fisiologia , Vias Neurais/fisiologia , Oxigênio/metabolismo , Pseudomonas aeruginosa/patogenicidade , Serotonina/fisiologiaRESUMO
Population density can modulate the developmental trajectory of Caenorhabditis elegans larvae by promoting entry into dauer diapause, which is characterized by metabolic and anatomical remodeling and stress resistance [1, 2]. Genetic analysis of dauer formation has identified the involvement of evolutionarily conserved endocrine signaling pathways, including the DAF-2/insulin-like receptor signaling pathway [3-7]. Chemical and metabolomic analysis of dauer-inducing pheromone has identified a family of small molecules, ascarosides, which act potently to communicate increased population density and promote dauer formation [1, 8-10]. Here, we show that adult animals respond to ascarosides produced under conditions of increased population density by increasing the duration of reproduction. We observe that the ascarosides that promote dauer entry of larvae also act on adult animals to attenuate expression of the insulin peptide INS-6 from the ASI chemosensory neurons, resulting in diminished neuroendocrine insulin signaling that extends the duration of reproduction. Genetic analysis of ins-6 and corresponding insulin-signaling pathway mutants showed that the effect of increased population density on reproductive span was mimicked by ins-6 loss of function that exerted effects on duration of reproduction through the canonical DAF-2-DAF-16 pathway. We further observed that the effect of population density on reproductive span acted through DAF-16-dependent and DAF-16-independent pathways upstream of DAF-12, paralleling in adults what has been observed for the dauer developmental decision of larvae. Our data suggest that, under conditions of increased population density, C. elegans animals prolong the duration of reproductive egg laying, which may enable the subsequent development of progeny under more favorable conditions.
Assuntos
Caenorhabditis elegans/fisiologia , Animais , Proteínas de Caenorhabditis elegans/metabolismo , Insulina/metabolismo , Densidade Demográfica , Reprodução , Atrativos Sexuais/metabolismo , Transdução de SinaisRESUMO
The nematode Caenorhabditis elegans has emerged as a genetically tractable animal host in which to study evolutionarily conserved mechanisms of innate immune signaling. We previously showed that the PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway regulates innate immunity of C. elegans through phosphorylation of the CREB/ATF bZIP transcription factor, ATF-7. Here, we have undertaken a genomic analysis of the transcriptional response of C. elegans to infection by Pseudomonas aeruginosa, combining genome-wide expression analysis by RNA-seq with ATF-7 chromatin immunoprecipitation followed by sequencing (ChIP-Seq). We observe that PMK-1-ATF-7 activity regulates a majority of all genes induced by pathogen infection, and observe ATF-7 occupancy in regulatory regions of pathogen-induced genes in a PMK-1-dependent manner. Moreover, functional analysis of a subset of these ATF-7-regulated pathogen-induced target genes supports a direct role for this transcriptional response in host defense. The genome-wide regulation through PMK-1- ATF-7 signaling reveals a striking level of control over the innate immune response to infection through a single transcriptional regulator.
Assuntos
Fatores Ativadores da Transcrição/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/imunologia , Caenorhabditis elegans/microbiologia , Pseudomonas aeruginosa/imunologia , Animais , Caenorhabditis elegans/genética , Imunoprecipitação da Cromatina , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Imunidade Inata , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Análise de Sequência de RNARESUMO
Animals have evolved critical mechanisms to maintain cellular and organismal proteostasis during development, disease, and exposure to environmental stressors. The Unfolded Protein Response (UPR) is a conserved pathway that senses and responds to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen. We have previously demonstrated that the IRE-1-XBP-1 branch of the UPR is required to maintain Caenorhabditis elegans ER homeostasis during larval development in the presence of pathogenic Pseudomonas aeruginosa In this study, we identify loss-of-function mutations in four conserved transcriptional regulators that suppress the larval lethality of xbp-1 mutant animals caused by immune activation in response to infection by pathogenic bacteria: FKH-9, a forkhead family transcription factor; ARID-1, an ARID/Bright domain-containing transcription factor; HCF-1, a transcriptional regulator that associates with histone modifying enzymes; and SIN-3, a subunit of a histone deacetylase complex. Further characterization of FKH-9 suggests that loss of FKH-9 enhances resistance to the ER toxin tunicamycin and results in enhanced ER-associated degradation (ERAD). Increased ERAD activity of fkh-9 loss-of-function mutants is accompanied by a diminished capacity to degrade cytosolic proteasomal substrates and a corresponding increased sensitivity to the proteasomal inhibitor bortezomib. Our data underscore how the balance between ER and cytosolic proteostasis can be influenced by compensatory activation of ERAD during the physiological ER stress of infection and immune activation.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Retículo Endoplasmático/genética , Fatores de Transcrição Forkhead/genética , Homeostase/genética , Resposta a Proteínas não Dobradas/genética , Animais , Bortezomib/administração & dosagem , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Transporte/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Fator C1 de Célula Hospedeira/genética , Sistema Imunitário/crescimento & desenvolvimento , Larva/genética , Larva/crescimento & desenvolvimento , Mutação , Proteínas Serina-Treonina Quinases/genética , Tunicamicina/toxicidadeRESUMO
Siderophores are small molecules produced by bacteria that bind ferric iron in the surrounding environment with extraordinary affinity. A new study provides evidence that a simple animal host, Caenorhabditis elegans, co-opts siderophores to promote its own iron acquisition and growth.
Assuntos
Enterobactina , Sideróforos , Trifosfato de Adenosina , Animais , Bactérias , FerroRESUMO
Sexually dimorphic behaviors are a feature common to species across the animal kingdom, however how such behaviors are generated from mostly sex-shared nervous systems is not well understood. Building on our previous work which described the sexually dimorphic expression of a neuroendocrine ligand, DAF-7, and its role in behavioral decision-making in C. elegans (Hilbert and Kim, 2017), we show here that sex-specific expression of daf-7 is regulated by another neuroendocrine ligand, Pigment Dispersing Factor (PDF-1), which has previously been implicated in regulating male-specific behavior (Barrios et al., 2012). Our analysis revealed that PDF-1 signaling acts sex- and cell-specifically in the ASJ neurons to regulate the expression of daf-7, and we show that differences in PDFR-1 receptor activity account for the sex-specific effects of this pathway. Our data suggest that modulation of the sex-shared nervous system by a cascade of neuroendocrine signals can shape sexually dimorphic behaviors.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Regulação da Expressão Gênica , Neuropeptídeos/metabolismo , Células Receptoras Sensoriais/metabolismo , Caracteres Sexuais , Transdução de Sinais , Animais , Comportamento Animal , Feminino , Masculino , Sistemas Neurossecretores/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição GênicaRESUMO
The nematode Caenorhabditis elegans relies on its innate immune defenses to counter infection. In this review, we focus on its response to infection by bacterial and fungal pathogens. We describe the different families of effector proteins that contribute to host defense, as well as the signal transduction pathways that regulate their expression. We discuss what is known of the activation of innate immunity in C. elegans, via pathogen recognition or sensing the damage provoked by infection. Damage causes a stress response; we review the role of stress signaling in host defense to infection. We examine examples of inter-tissue communication in innate immunity and end with a survey of post-transcriptional regulation of innate immune responses.
Assuntos
Caenorhabditis elegans/imunologia , Imunidade Inata , Transdução de Sinais , Animais , Bactérias/imunologia , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/microbiologia , Fungos/imunologia , Imunidade Inata/genéticaRESUMO
Cell-nonautonomous effects of signaling in the nervous system of animals can influence diverse aspects of organismal physiology. We previously showed that phosphorylation of Ser49 of the α-subunit of eukaryotic translation initiation factor 2 (eIF2α) in two chemosensory neurons by PEK-1/PERK promotes entry of Caenorhabditis elegans into dauer diapause. Here, we identified and characterized the molecular determinants that confer sensitivity to effects of neuronal eIF2α phosphorylation on development and physiology of C. elegans Isolation and characterization of mutations in eif-2Ba encoding the α-subunit of eIF2B support a conserved role, previously established by studies in yeast, for eIF2Bα in providing a binding site for phosphorylated eIF2α to inhibit the exchange factor eIF2B catalytic activity that is required for translation initiation. We also identified a mutation in eif-2c, encoding the γ-subunit of eIF2, which confers insensitivity to the effects of phosphorylated eIF2α while also altering the requirement for eIF2Bγ. In addition, we show that constitutive expression of eIF2α carrying a phosphomimetic S49D mutation in the ASI pair of sensory neurons confers dramatic effects on growth, metabolism, and reproduction in adult transgenic animals, phenocopying systemic responses to starvation. Furthermore, we show that constitutive expression of eIF2α carrying a phosphomimetic S49D mutation in the ASI neurons enhances dauer entry through bypassing the requirement for nutritionally deficient conditions. Our data suggest that the state of eIF2α phosphorylation in the ASI sensory neuron pair may modulate internal nutrient sensing and signaling pathways, with corresponding organismal effects on development and metabolism.
Assuntos
Caenorhabditis elegans/genética , Fator de Iniciação 2B em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/genética , Biossíntese de Proteínas , Animais , Sítios de Ligação , Caenorhabditis elegans/crescimento & desenvolvimento , Fator de Iniciação 2 em Eucariotos/biossíntese , Fator de Iniciação 2B em Eucariotos/biossíntese , Mutação , Fosforilação , Células Receptoras Sensoriais/metabolismoRESUMO
Animal behavior is directed by the integration of sensory information from internal states and the environment. Neuroendocrine regulation of diverse behaviors of Caenorhabditis elegans is under the control of the DAF-7/TGF-ß ligand that is secreted from sensory neurons. Here, we show that C. elegans males exhibit an altered, male-specific expression pattern of daf-7 in the ASJ sensory neuron pair with the onset of reproductive maturity, which functions to promote male-specific mate-searching behavior. Molecular genetic analysis of the switch-like regulation of daf-7 expression in the ASJ neuron pair reveals a hierarchy of regulation among multiple inputs-sex, age, nutritional status, and microbial environment-which function in the modulation of behavior. Our results suggest that regulation of gene expression in sensory neurons can function in the integration of a wide array of sensory information and facilitate decision-making behaviors in C. elegans.
Assuntos
Comportamento Animal , Caenorhabditis elegans/fisiologia , Tomada de Decisões , Regulação da Expressão Gênica , Células Receptoras Sensoriais/fisiologia , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Feminino , Masculino , Fator de Crescimento Transformador beta/metabolismoRESUMO
Dietary restriction extends lifespan in evolutionarily diverse animals. A role for the sensory nervous system in dietary restriction has been established in Drosophila and Caenorhabditis elegans, but little is known about how neuroendocrine signals influence the effects of dietary restriction on longevity. Here, we show that DAF-7/TGFß, which is secreted from the C. elegans amphid, promotes lifespan extension in response to dietary restriction in C. elegans. DAF-7 produced by the ASI pair of sensory neurons acts on DAF-1/TGFß receptors expressed on interneurons to inhibit the co-SMAD DAF-3. We find that increased activity of DAF-3 in the presence of diminished or deleted DAF-7 activity abrogates lifespan extension conferred by dietary restriction. We also observe that DAF-7 expression is dynamic during the lifespan of C. elegans, with a marked decrease in DAF-7 levels as animals age during adulthood. We show that this age-dependent diminished expression contributes to the reduced sensitivity of aging animals to the effects of dietary restriction. DAF-7 signaling is a pivotal regulator of metabolism and food-dependent behavior, and our studies establish a molecular link between the neuroendocrine physiology of C. elegans and the process by which dietary restriction can extend lifespan.