The flight response induces the release of an insulin-like peptide from the intestine to inhibit cytoprotective mechanism in C. elegans

VEUTHEY, T.; GIUNTI, S.; DE ROSA M.J.; ALKEMA, M.J.; RAYES, D.H.

Rosario

Congreso; SEcond LAtin American Worm meeting; 2020

The perpetuation of theflight response inhibits defensive cytoprotective mechanisms, leading toreduced resistance to environmental stressors and shorter lifespan. We recentlyshown that, in C. elegans, the flight response induces neuronal releaseof Tyramine (TA), which stimulates the intestinal adrenergic-like receptorTYRA-3. This leads to DAF-2/Insulin/IGF-1 pathway activation and inhibition ofcytoprotective mechanisms in intestine and other tissues. However, the signalsthat bridge intestinal TYRA-3 stimulation with DAF-2 insulin receptoractivation in other tissues remain unknown. C. elegans genome encodes 40 Insulin-likepeptides (ILPs) that bind to DAF-2, 28 of them expressed in the intestine. We testthe resistance to environmental stressors (oxidative and thermal stress)silencing individual intestinal ILPs by RNAi. We found that silencing ins-3 improves stressresistance. In contrast to control, exogenous TA addition does not impairstress resistance in ins-3-silencedanimals. Moreover, double-null mutants of ins-3 and TA are as resistantto environmental stress as single mutants. This suggests that tyramine andINS-3 act in the same pathway. Since ins-3 isalso expressed in neurons, we performed tissue-specific rescues of ins-3 in neuron and intestine to assessthe tissue where ins-3 is relevant for controlling stress resistance.Only intestinal ins-3 restoresthe resistance to wild-type levels. Moreover, stress resistance of ins-3 null-mutants ismediated, at least partially, by DAF-16/FOXO. We propose that intestinalactivation of TYRA-3 by the escape neurohormone TA leads to INS-3 release whichacts as endocrine, autocrine and/or paracrine signal to activate DAF-2 in theintestine and distal tissues. Given the high degree of conservation offundamental mechanisms among species, this study can contribute tounderstanding molecular pathways and cellular communication involved in neuralregulation of stress response in multicellular organisms.