TATN-1 Mutations Reveal a Novel Role for Tyrosine as a Metabolic Signal That Influences Developmental Decisions and Longevity in Caenorhabditis elegans

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.