The nematode C. elegans secretes a pheromone that controls whether the animal molts into the developmentally arrested, extremely long-lived dauer diapause stage, or into a non-arrested normally aging animal. The dauer pheromone signal is detected by sensory neurons which couple by an unknown neurosecretory mechanism to a response pathway in the various target tissues that are remodeled during the dauer stage. The neuronally- regulated developmental and neuroendocrine changes associated with dauer formation are a model for the hypothalmic/pituitary/somatic and autonomic nervous system signaling axes in vertebrates. We have genetically identified a number of genes that regulate the development or function of the dauer sensory to secretory neural pathway. We propose a molecular analysis of three of these genes, daf2, daf-16, and daf-23. Mutations in daf-2 and daf-23 also cause two to three fold increases in longevity of non-dauer animals, and mutations in daf-16 suppress this increase in longevity. Thus daf-2, daf-16 and daf23 not only regulate diapause, they also regulate senescence. We have shown that daf-23 encodes a phosphatidyl inositol-3 kinase, PI-3 kinase, a protein known from vertebrates to associate with receptor and non-receptor tyrosine kinases. We have shown that the mammalian homologue of DAF-23 can fully complement a daf-23 mutant. PI-3 kinase generates a membrane-bound signaling molecule, phosphatidyl inositol-3,4,5-P3, which couples to unknown effector molecules. Thus daf-23 could control dauer formation and senescence by coupling a tyrosine kinase to downstream effectors, either during development of the nervous system or during pheromone signaling. Our genetic analysis suggests that daf-2 and daf-16 encode proteins that transduce the phosphatidyl inositol signal generated by daf-23. We propose to study how the genes in &his pathway couple phosphatidyl inositol biosynthesis to control neuroendocrine function during diapause. Our analysis of the molecular basis of neurosecretory function in C. elegans could reveal the genes that control the development and function of human neurosecretory pathways, with implication for therapies in diabetes, metabolic disorders, and high blood pressure. In addition, since diapause represents a neurosecretory function that is used across invertebrate phylogeny, including in insect pests, new insecticides designed to inhibit P1P3 signaling and thus induce diapause, with its concomitant suspension of feeding and reproduction, would have important implications for agriculture and indirectly, human health and welfare. Our molecular analysis of senescence in C. elegans may also be broadly applicable to human aging. The long lifespan that is caused by a decrease in PI-3 kinase activity suggests that senescence in C. elegans is regulated by the production of phosphatidyl inositol-3,4,5-P3. Drugs which antagonize the production or activity of this lipid might increase longevity.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Neurology C Study Section (NEUC)
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Mccormick, Anna M
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Massachusetts General Hospital
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