Regulation of hypoxic death in C-elegans by the insulin/IGF receptor homolog DAF-2

Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science (Impact Factor: 31.48). 07/2002; 296(5577):2388-91. DOI: 10.1126/science.1072302
Source: PubMed

ABSTRACT To identify genetic determinants of hypoxic cell death, we screened for hypoxia-resistant (Hyp) mutants in Caenorhabditis elegans and found that specific reduction-of-function (rf) mutants of daf-2, an insulin/insulinlike growth factor (IGF) receptor (INR) homolog gene, were profoundly Hyp. The hypoxia resistance was acutely inducible just before hypoxic exposure and was mediated through an AKT-1/PDK-1/forkhead transcription factor pathway overlapping with but distinct from signaling pathways regulating life-span and stress resistance. Selective neuronal and muscle expression of daf-2(+) restored hypoxic death, and daf-2(rf) prevented hypoxia-induced muscle and neuronal cell death, which demonstrates a potential for INR modulation in prophylaxis against hypoxic injury of neurons and myocytes.

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    • "Owing to its broad oxygen tolerance and lack of a circulatory system, C. elegans has been a particularly useful model system to study the genetic responses to hypoxia and the effects of hypoxia on longevity. Adult worms can survive prolonged anoxia and, interestingly, lifespanextending mutations in the worm insulin-like receptor daf2 also lead to increased survival in high temperature hypoxia or extended anoxia (Mendenhall, LaRue, & Padilla, 2006; Scott, Avidan, & Crowder, 2002; Van Voorhies & Ward, 2000). A simple interpretation of this result is that reduced insulin-like signaling preconditions animals for decreased oxygen consumption and increased reliance on glycolysis. "
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    ABSTRACT: Oxygen is a double-edged sword. Despite the near universal requirement for oxygen for survival and reproduction in animals, oxygen and oxidative metabolism are responsible for the production of reactive oxygen species (ROS), which has, until recently, been considered a cellular toxin and a major cause of aging. Alterations in environmental oxygen can alter rates of aging and ROS production in many organisms. Animals coordinate the cellular response to low oxygen with a conserved hypoxic response mediated by the hypoxia inducible transcription factor, hypoxia-inducible factor (HIF). In addition to hypoxia, HIF has been shown to have roles in aging, cancer, cardiovascular disease, and stem cell maintenance in organisms from worms to humans. Furthermore, HIF has been shown to interact with mechanistic target of rapamycin (mTOR), Sirtuins, and to influence other pathways and interventions known to affect the aging. This chapter focuses on the effects of altered oxygen concentrations on the aging, its similarities to dietary restriction, how mutations in the HIF pathway affect lifespan and health span, and how the HIF pathway interacts with other conserved longevity pathways.
    Annual review of gerontology & geriatrics 02/2014; 34(1). DOI:10.1891/0198-8794.34.59
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    • "3.3. daf-2 alleles have opposite selenium responsive phenotypes under high temperature stress There are over 40 daf-2 alleles that have been isolated and these have been described to express a range of phenotypes in response to environmental and oxidative stressors (Ackerman and Gems, 2012; Honda and Honda, 2002; Scott et al., 2002; Gems et al., 1998). Most recently, Vaccaro et al. (2012) showed that the e1370 allele enhanced neurodegeneration in a worm TDP43/TDP-1 ALS model while another allele e1368 suppressed the neurodegeneration . "
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    ABSTRACT: Exposures to high levels of environmental selenium have been associated with motor neuron disease in both animals and humans and high levels of selenite have been identified in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). We have shown previously that exposures to high levels of sodium selenite in the environment of C. elegans adult animals can induce neurodegeneration and cell loss resulting in motor deficits and death and that this is at least partially caused by a reduction in cholinergic signaling across the neuromuscular junction. Here we provide evidence that reduction in insulin/insulin-like (IIS) signaling alters response to high dose levels of environmental selenium which in turn can regulate the IIS pathway. Most specifically we show that nuclear localization and thus activation of the DAF-16/forkhead box transcription factor occurs in response to selenium exposure although this was not observed in motor neurons of the ventral cord. Yet, tissue specific expression and generalized overexpression of DAF-16 can partially rescue the neurodegenerative and behavioral deficits observed with high dose selenium exposures in not only the cholinergic, but also the GABAergic motor neurons. In addition, two modifiers of IIS signaling, PTEN (phosphatase and tensin homolog, deleted on chromosome 10) and PINK1 (PTEN-induced putative kinase 1) are required for the cellular antioxidant reduced glutathione to mitigate the selenium-induced movement deficits. Studies have suggested that environmental exposures can lead to ALS or other neurological diseases and this model of selenium-induced neurodegeneration developed in a genetically tractable organism provides a tool for examining the combined roles of genetics and environment in the neuro-pathologic disease process.
    NeuroToxicology 01/2014; 41(100). DOI:10.1016/j.neuro.2013.12.012 · 3.05 Impact Factor
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    • "This conserved function is manifested in regulation of dauer formation, stress resistance, and lifespan in C. elegans. Mutations affecting the sole insulinlike receptor DAF-2/InsR (Figure 2) form dauers constitutively (Riddle et al. 1981; Hu 2007), are stress resistant (Honda and Honda 1999; Scott et al. 2002; Lamitina and Strange 2005), and extend adult lifespan (Kenyon et al. 1993; Kimura et al. 1997). Strong loss-of-function alleles also display constitutive L1 arrest (Gems et al. 1998). "
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    ABSTRACT: It is widely appreciated that larvae of the nematode Caenorhabditis elegans arrest development by forming dauer larvae in response to multiple unfavorable environmental conditions. C. elegans larvae can also reversibly arrest development earlier, during the first larval stage (L1), in response to starvation. "L1 arrest" (also known as "L1 diapause") occurs without morphological modification but is accompanied by increased stress resistance. Caloric restriction and periodic fasting can extend adult lifespan, and developmental models are critical to understanding how the animal is buffered from fluctuations in nutrient availability, impacting lifespan. L1 arrest provides an opportunity to study nutritional control of development. Given its relevance to aging, diabetes, obesity and cancer, interest in L1 arrest is increasing, and signaling pathways and gene regulatory mechanisms controlling arrest and recovery have been characterized. Insulin-like signaling is a critical regulator, and it is modified by and acts through microRNAs. DAF-18/PTEN, AMP-activated kinase and fatty acid biosynthesis are also involved. The nervous system, epidermis, and intestine contribute systemically to regulation of arrest, but cell-autonomous signaling likely contributes to regulation in the germline. A relatively small number of genes affecting starvation survival during L1 arrest are known, and many of them also affect adult lifespan, reflecting a common genetic basis ripe for exploration. mRNA expression is well characterized during arrest, recovery, and normal L1 development, providing a metazoan model for nutritional control of gene expression. In particular, post-recruitment regulation of RNA polymerase II is under nutritional control, potentially contributing to a rapid and coordinated response to feeding. The phenomenology of L1 arrest will be reviewed, as well as regulation of developmental arrest and starvation survival by various signaling pathways and gene regulatory mechanisms.
    Genetics 07/2013; 194(3):539-55. DOI:10.1534/genetics.113.150847 · 4.87 Impact Factor
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