Thioredoxins (TRX) are traditionally considered as enzymes catalyzing redox reactions. However, redox-independent functions of thioredoxins have been described in different organisms, although the underlying molecular mechanisms are yet unknown. We report here the characterization of the first generated endogenous redox-inactive thioredoxin in an animal model, the TRX-1 in the nematode Caenorhabditis elegans . We find that TRX-1 dually regulates the formation of an endurance larval stage (dauer) by interacting with the insulin pathway in a redox-independent manner and the cGMP pathway in a redox-dependent manner. Moreover, the requirement of TRX-1 for the extended longevity of worms with compromised insulin signalling or under calorie restriction relies on TRX-1 redox activity. In contrast, the nuclear translocation of the SKN-1 transcription factor and increased LIPS-6 protein levels in the intestine upon trx-1 deficiency are strictly redox-independent. Finally, we identify a novel function of C. elegans TRX-1 in male food-leaving behaviour that is redox-dependent. Taken together, our results position C. elegans as an ideal model to gain mechanistic insight into the redox-independent functions of metazoan thioredoxins, overcoming the limitations imposed by the embryonic lethal phenotypes of thioredoxin mutants in higher organisms.

Sexual phenotypic differences in the nervous system are one of the most prevalent features across the animal kingdom. The molecular mechanisms responsible for sexual dimorphism throughout metazoan nervous systems are extremely diverse, ranging from intrinsic cell autonomous mechanisms to gonad-dependent endocrine control of sexual traits, or even extrinsic environmental cues. In recent years, the DMRT ancient family of transcription factors has emerged as being central in the development of sex-specific differentiation in all animals in which they have been studied. In this review, we provide an overview of the function of Dmrt genes in nervous system sexual regulation from an evolutionary perspective.