Regulation of Hypoxic Death in C. elegans by the Insulin/IGF Receptor Homolog DAF-2

• Published in: Science (American Association for the Advancement of Science) 2002-06, Vol.296 (5577), p.2388-2391
• Main Authors: Scott, Barbara A., Avidan, Michael S., Crowder, C. Michael
• Format: Article
• Language: English
• Subjects: 3-Phosphoinositide-Dependent Protein Kinases; Adults; Ageing, cell death; Alleles; Animals; Anoxia; Axons - ultrastructure; Biological and medical sciences; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - growth & development; Caenorhabditis elegans - physiology; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - physiology; Cell Death; Cell Nucleus - ultrastructure; Cell physiology; Cell Survival; Cellular biology; Climate; Effects of physical and chemical agents; Forkhead Transcription Factors; Fundamental and applied biological sciences. Psychology; Genes; Genes, Helminth; Genetic mutation; Genetics; Hypoxia; Hypoxia - genetics; Insulin; Insulin-like growth factors; Intestines - cytology; Intestines - metabolism; Longevity; Medical genetics; Molecular and cellular biology; Mortality; Movement; Muscles - cytology; Muscles - metabolism; Muscles - ultrastructure; Mutation; Mutation, Missense; Nematode larvae; Neurons; Neurons - cytology; Neurons - metabolism; Neurons - ultrastructure; Patient outcomes; Phenotype; Phenotypes; Phosphatidylinositol 3-Kinases; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - physiology; Receptor, Insulin - genetics; Receptor, Insulin - physiology; Receptors; Reporter genes; Signal Transduction; Somatomedins; Temperature; Transcription Factors - genetics; Transcription Factors - physiology
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1072302

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.