TATN-1 Mutations Reveal a Novel Role for Tyrosine as a Metabolic Signal That Influences Developmental Decisions and Longevity in Caenorhabditis elegans Annabel A. Ferguson 1 , Sudipa Roy 2,3. , Kaitlyn N. Kormanik 1. , Yongsoon Kim 4. , Kathleen J. Dumas 4 , Vladimir B. Ritov 5 , Dietrich Matern 6 , Patrick J. Hu 4,7 , Alfred L. Fisher 2,3,8 * 1 Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 2 Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America, 3 Center for Healthy Aging, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America, 4 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America, 5 Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 6 Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America, 7 Departments of Internal Medicine and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 8 GRECC, South Texas VA Health Care System, San Antonio, Texas, United States of America Abstract Recent work has identified changes in the metabolism of the aromatic amino acid tyrosine as a risk factor for diabetes and a contributor to the development of liver cancer. While these findings could suggest a role for tyrosine as a direct regulator of the behavior of cells and tissues, evidence for this model is currently lacking. Through the use of RNAi and genetic mutants, we identify tatn-1, which is the worm ortholog of tyrosine aminotransferase and catalyzes the first step of the conserved tyrosine degradation pathway, as a novel regulator of the dauer decision and modulator of the daf-2 insulin/IGF-1-like (IGFR) signaling pathway in Caenorhabditis elegans. Mutations affecting tatn-1 elevate tyrosine levels in the animal, and enhance the effects of mutations in genes that lie within the daf-2/insulin signaling pathway or are otherwise upstream of daf-16/ FOXO on both dauer formation and worm longevity. These effects are mediated by elevated tyrosine levels as supplemental dietary tyrosine mimics the phenotypes produced by a tatn-1 mutation, and the effects still occur when the enzymes needed to convert tyrosine into catecholamine neurotransmitters are missing. The effects on dauer formation and lifespan require the aak-2/AMPK gene, and tatn-1 mutations increase phospho-AAK-2 levels. In contrast, the daf-16/FOXO transcription factor is only partially required for the effects on dauer formation and not required for increased longevity. We also find that the controlled metabolism of tyrosine by tatn-1 may function normally in dauer formation because the expression of the TATN-1 protein is regulated both by daf-2/IGFR signaling and also by the same dietary and environmental cues which influence dauer formation. Our findings point to a novel role for tyrosine as a developmental regulator and modulator of longevity, and support a model where elevated tyrosine levels play a causal role in the development of diabetes and cancer in people. Citation: Ferguson AA, Roy S, Kormanik KN, Kim Y, Dumas KJ, et al. (2013) TATN-1 Mutations Reveal a Novel Role for Tyrosine as a Metabolic Signal That Influences Developmental Decisions and Longevity in Caenorhabditis elegans. PLoS Genet 9(12): e1004020. doi:10.1371/journal.pgen.1004020 Editor: Stuart K. Kim, Stanford University Medical Center, United States of America Received January 15, 2013; Accepted October 28, 2013; Published December 19, 2013 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: VBR was supported by grant R01 AG044768 from the National Institutes of Health. PJH was supported by a Kimmel Scholars Award from the Sidney Kimmel Foundation for Cancer Research and grant R56 DK078183 from the National Institutes of Health. ALF was supported by grants K08 AG24414, R01 ES017761, and R01 AG044768 from the National Institutes of Health. ALF is also supported by the Geriatric Research Education and Clinical Center (GRECC) based in the South Texas VA Healthcare system as well as by funds from the Center for Healthy Aging at UTHSCSA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: fishera2@uthscsa.edu . These authors contributed equally to this work. Introduction The aromatic amino acid tyrosine serves many metabolic roles including being a building block for protein synthesis, a source of energy, and a precursor for the synthesis of melanin and several neurotransmitters including dopamine and other catecholamines. Beyond these currently known functions for tyrosine, recent work has suggested that tyrosine could also play regulatory roles in both metabolism and the control of cell proliferation. Specifically, in people elevated serum tyrosine levels occur with obesity and represent a risk factor for the development of diabetes [1–6]. Additionally, the enzyme tyrosine aminotransferase (TAT), which acts to normally convert tyrosine to energy, has been identified as a tumor suppressor gene which acts to promote apoptosis and prevent the development of hepatocellular carcinoma [7]. How changes in tyrosine metabolism could contribute to these disease processes is currently unknown, but it is possible that levels of this amino acid could play a direct regulatory role for the behavior of specific cells and tissues. While consistent with the available data, direct evidence for this model is currently lacking. The nematode Caenorhabditis elegans normally progresses through four larval stages before developing into a reproductive adult PLOS Genetics | www.plosgenetics.org 1 December 2013 | Volume 9 | Issue 12 | e1004020