Neural modulation of systemic stress response requires the insulin like-peptide INS-3

VEUTHEY TANIA V; GIUNTI SEBASTIAN; DE ROSA MARIA JOSE; ALKEMA MARK; RAYES, DIEGO

Chascomus

Congreso; V Taller de Biología Celular y del Desarrollo; 2022

From invertebrates to mammals, the perpetuation of the flight response inhibits defensivecytoprotective mechanisms, leading to reduced resistance to overcome environmental stressor. Wehave recently shown that, in C. elegans, the flight response induces the neuronal release of Tyramine(TA, the invertebrate analog of adrenaline), which stimulates the adrenergic-like receptor TYRA-3 in theintestine. This leads to DAF-2/Insulin/IGF-1 pathway activation and inhibition of cytoprotectivemechanisms not only in the intestine but also in other tissues. The signals that bridge intestinal TYRA-3stimulation with DAF-2 insulin receptor activation in distal tissues still remain unknown. We focused onintestinal Insulin-Like Peptides strong agonists of DAF-2. By RNAi we found that silencing ins-3 improvesstress resistance. Since ins-3 is also expressed in neurons, we performed tissue-specific rescues of ins-3in neurons and intestine to assess the tissue where ins-3 is relevant for controlling stress resistance.Only intestinal ins-3 restores the resistance to wild-type levels. Then, we found that exogenous TA doesnot impair stress resistance on ins-3-silenced animals, in contrast to wild-type worms. Moreover,double-null mutants of ins-3 and TA were as resistant to environmental stress as single mutants. Thissuggests that TA and INS-3 act in the same pathway. We then confirmed intestinal INS-3 secretion uponTA exposure by quantifying INS-3::GFP fluorescence in coelomocytes. Moreover, we found that thestress resistance of ins-3 null mutants is mediated, at least partially, by DAF-16/FOXO. Taken together,our results suggest that intestinal activation of TYRA-3 by the escape neurohormone TA leads tointestinal INS-3 release which acts as an endocrine, autocrine, and/or paracrine signal to activate DAF-2in different tissues.