Hormonal signals produced by DAF-9/cytochrome P450 regulate<i>C. elegans</i>dauer diapause in response to environmental cues

Gerisch, Birgit; Antebi, Adam

doi:10.1242/dev.01068

Cited by 173 publications

(180 citation statements)

References 54 publications

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“…The ncr-1; ncr-2 double mutants have reduced viability, gonadal migration defects, and constitutively form dauer larvae, a dormant life stage specialized for survival under harsh conditions (Sym et al 2000;Li et al 2004). The phenotypes of ncr-1; ncr-2 double mutants are similar to a class of ligand-binding domain mutants of daf-12, which encodes a nuclear steroid hormone receptor (Antebi et al 1998;Antebi et al 2000;Jia et al 2002;Gerisch and Antebi 2004;Li et al 2004). Li et al (2004) recently demonstrated that feeding cholesterol to animals mutant for ncr-1 and ncr-2 is sufficient to suppress the dauer phenotype associated with the loss of both genes.…”

Section: Discussionmentioning

confidence: 99%

Mutations of a Drosophila NPC1 Gene Confer Sterol and Ecdysone Metabolic Defects

2006

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The molecular mechanisms by which dietary cholesterol is trafficked within cells are poorly understood. Previous work indicates that the NPC1 family of proteins plays an important role in this process, although the precise functions performed by this protein family remain elusive. We have taken a genetic approach to further explore the NPC1 family in the fruit fly Drosophila melanogaster. The Drosophila genome encodes two NPC1 homologs, designated NPC1a and NPC1b, that exhibit 42% and 35% identity to the human NPC1 protein, respectively. Here we describe the results of mutational analysis of the NPC1a gene. The NPC1a gene is ubiquitously expressed, and a null allele of NPC1a confers early larval lethality. The recessive lethal phenotype of NPC1a mutants can be partially rescued on a diet of high cholesterol or one that includes the insect steroid hormone 20-hydroxyecdysone. We also find that expression of NPC1a in the ring gland is sufficient to rescue the lethality associated with the loss of NPC1a and that cholesterol levels in NPC1a mutant larvae are unchanged relative to controls. Our results suggest that NPC1a promotes efficient intracellular trafficking of sterols in many Drosophila tissues including the ring gland where sterols must be delivered to sites of ecdysone synthesis. S TEROLS are critical in eukaryotic biology as structural components of all membranes and as precursors for the synthesis of the large eukaryotic family of steroid hormones (Mouritsen and Zuckermann 2004;Payne and Hales 2004;Becher and McIlhinney 2005). While sterols are essential due to the important biological functions they serve, an overabundance of the primary mammalian sterol, cholesterol, is toxic and contributes to a variety of prevalent diseases including heart disease and stroke (Choy et al. 2004;Saini et al. 2004). Accumulating evidence also suggests that alterations in cholesterol homeostasis may contribute to neurodegenerative disorders such as Alzheimer's disease, although the mechanisms by which alterations in cholesterol metabolism affect neuronal integrity remain unclear (Burns and Duff 2002;Reiss et al. 2004;Wellington 2004).The importance of sterols in eukaryotic biology and disease pathogenesis has stimulated intensive investigation of cholesterol homeostasis in vertebrates. This body of work has clarified many features of cholesterol metabolism, including its de novo synthesis from acetate in the endoplasmic reticulum (ER) (Bloch 1965;Lynen 1966), its packaging into and transport within lipoprotein particles (Oncley 1954;Fredrickson 1957), and the receptor-mediated uptake of these particles by cells (Brown and Goldstein 1986). While these advances have fostered the development of treatment strategies that affect the etiology of hypercholesterolemia, this disorder remains a major source of morbidity, and our knowledge of cholesterol metabolism and the health consequences associated with altered cholesterol homeostasis is far from complete. In particular, the molecular mechanisms by which cholesterol is ab...

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Section: Discussionmentioning

confidence: 99%

Mutations of a Drosophila NPC1 Gene Confer Sterol and Ecdysone Metabolic Defects

2006

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“…Identified pathways regulating this decision include insulin/ IGF-1, TGF-b and cyclic GMP signalling. These signal transduction pathways converge on DAF-9, a cytochrome P450 steroid hydroxylase which is postulated to produce a cholestrol-derived hormone (Gerish and Antebi, 2004;Matyash et al, 2004). The target of this putative hormone is the nuclear hormone receptor DAF-12.…”

Section: Introductionmentioning

confidence: 99%

“…Expressing daf-9 constitutively in the hypodermis rescues the dauer arrest phenotypes of mutants defective in insulin/IGF-1 or TGF-b signalling, providing evidence that daf-9 integrates the outputs from these signalling pathways. However, some residual defects are observed in the rescued worms, suggesting that the dauer signalling pathways may also have some daf-9 independent outputs (Gerish and Antebi, 2004).…”

Section: Introductionmentioning

confidence: 99%

Alternate metabolism during the dauer stage of the nematode Caenorhabditis elegans

Burnell

Houthoofd

O’Hanlon

et al. 2005

Experimental Gerontology

143

149

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When environmental conditions are unsuitable to support nematode reproduction, Caenorhabditis elegans arrests development before the onset of sexual maturity and specialised 'dauer' larvae, adapted for dispersal, and extended diapause are formed. Dauer larvae do not feed and their metabolism is dependent on internal food reserves. Adult worms which express defects in the insulin/insulin-like growth factor receptor DAF-2 also display enhanced longevity. Whole genome mRNA expression profiling has demonstrated that C. elegans dauer larvae and daf-2 adults have similar transcription profiles for a cohort of longevity genes. Important components of this enhanced longevity system are the a-crystallin family of small heat shock proteins, anti-ROS defence systems, increased activity of cellular detoxification processes and possibly also increased chromatin stability and decreased protein turnover. Anaerobic fermentation pathways are upregulated in dauer larvae, while long-lived daf-2 adults appear to have normal oxidative metabolism. Anabolic pathways are down regulated in dauer larvae (and possibly in daf-2 adults as well), and energy consumption appears to be diverted to enhanced cellular maintenance and detoxification processes in both systems. q

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“…These pathways converge on the nuclear hormone receptor DAF-12, which acts downstream of most Daf genes and which is expressed in many tissues that undergo remodeling during dauer formation (30). The TGF␤ and insulin pathways are thought to control DAF-12 in part by regulating enzymes (31)(32)(33)(34) involved in the biosynthesis of the DAF-12 steroid ligands (35,36). In addition to controlling the developmental and metabolic changes important for dauer formation, the TGF␤ and insulin pathways influence metabolism, stress resistance, and aging throughout the life cycle (27,(37)(38)(39).…”

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confidence: 99%

A potent dauer pheromone component in Caenorhabditis elegans that acts synergistically with other components

Butcher

Ragains

Kim

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

146

172

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In the model organism Caenorhabditis elegans, the dauer pheromone is the primary cue for entry into the developmentally arrested, dauer larval stage. The dauer is specialized for survival under harsh environmental conditions and is considered ''nonaging'' because larvae that exit dauer have a normal life span. C. elegans constitutively secretes the dauer pheromone into its environment, enabling it to sense its population density. Several components of the dauer pheromone have been identified as derivatives of the dideoxy sugar ascarylose, but additional unidentified components of the dauer pheromone contribute to its activity. Here, we show that an ascaroside with a 3-hydroxypropionate side chain is a highly potent component of the dauer pheromone that acts synergistically with previously identified components. Furthermore, we show that the active dauer pheromone components that are produced by C. elegans vary depending on cultivation conditions. Identifying the active components of the dauer pheromone, the conditions under which they are produced, and their mechanisms of action will greatly extend our understanding of how chemosensory cues from the environment can influence such fundamental processes as development, metabolism, and aging in nematodes and in higher organisms.ascaroside ͉ natural product structure elucidation

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Hormonal signals produced by DAF-9/cytochrome P450 regulateC. elegansdauer diapause in response to environmental cues

Cited by 173 publications

References 54 publications

Mutations of a Drosophila NPC1 Gene Confer Sterol and Ecdysone Metabolic Defects

Mutations of a Drosophila NPC1 Gene Confer Sterol and Ecdysone Metabolic Defects

Alternate metabolism during the dauer stage of the nematode Caenorhabditis elegans

A potent dauer pheromone component in Caenorhabditis elegans that acts synergistically with other components

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