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: 33.61). 07/2002; 296(5577):2388-91. DOI: 10.1126/science.1072302
Source: PubMed


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.

Download full-text


Available from: Barbara A Scott, Dec 17, 2013
  • Source
    • "To study chronic hypoxic stress response under laboratory conditions, C. elegans are placed in hypoxia chamber filled with low oxygen gas (0.1–1%) for a variable number of hours, and then are allowed to recover in ambient oxygen (21%). About half of adult animals die after 12 h of hypoxia followed by a 24-h recovery, and all die if exposed for 24 h of hypoxia [11]. The damage to the organism under this hypoxic condition can be exacerbated if an adaptive response to hypoxia fails. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The nervous system plays critical roles in the stress response. Animals can survive and function under harsh conditions, and resist and recover from injuries because neurons perceive and respond to various stressors through specific regulatory mechanisms. Caenorhabditis elegans has served as an excellent model to discover fundamental mechanisms underlying the neuronal response to stress. The basic physiological processes that C. elegans exhibits under stress conditions are similar to those observed in higher organisms. Many molecular pathways activated by environmental and cellular stresses are also conserved. In this review, we summarize major findings in examining neuronal responses to hypoxia, oxidative stress, osmotic stress, and traumatic injury. These studies from C. elegans have provided novel insights into our understanding of neuronal responses to stress at the molecular, cellular, and circuit levels. Copyright © 2015. Published by Elsevier B.V.
    FEBS letters 05/2015; 589(14). DOI:10.1016/j.febslet.2015.05.005 · 3.17 Impact Factor
  • Source
    • "We initially focused on altering gene expression in neurons, a target tissue for hypoxia rescue in C elegans [32]. Figure 3A shows the results of overexpression of canonical Wnt pathway activators arm and dally. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adaptation to hypoxia, defined as a condition of inadequate oxygen supply, has enabled humans to successfully colonize high altitude regions. The mechanisms attempted by organisms to cope with short-term hypoxia include increased ATP production via anaerobic respiration and stabilization of Hypoxia Inducible Factor 1α (HIF-1α). However, less is known about the means through which populations adapt to chronic hypoxia during the process of development within a life time or over generations. Here we show that signaling via the highly conserved Wnt pathway impacts the ability of Drosophila melanogaster to complete its life cycle under hypoxia. We identify this pathway through analyses of genome sequencing and gene expression of a Drosophila melanogaster population adapted over >180 generations to tolerate a concentration of 3.5-4% O2 in air. We then show that genetic activation of the Wnt canonical pathway leads to increased rates of adult eclosion in low O2. Our results indicate that a previously unsuspected major developmental pathway, Wnt, plays a significant role in hypoxia tolerance.
    PLoS ONE 08/2014; 9(8):e103292. DOI:10.1371/journal.pone.0103292 · 3.23 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
Show more