The Physiological Role of Glucocorticoid and Mineralocorticoid Receptor Activation in Zebrafish

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Glucocorticoids are key mediators of the vertebrate stress response. In teleosts, the primary glucocorticoid, cortisol, is a ligand for two corticosteroid receptors (CRs), the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The affinity of cortisol for these receptors is markedly different, with MR having an almost 10-fold higher affinity for the ligand compared to GR. This led to the hypothesis 30 years ago in mammals, that MR is responsible for basal cortisol function, while GR is active only when cortisol levels are high. In zebrafish (Danio rerio), the role of cortisol-GR signalling during stress is well characterized and is primarily involved in energy substrate mobilization to cope with stress. However, despite the persistence of MR in vertebrate evolution, there is no known physiological role for MR in ray-finned fishes. Ubiquitous knockout of MR (MRKO) and GR (GRKO) in mammals results in death, in utero or postnatally, due to dehydration or delayed lung maturation, respectively. This makes zebrafish an attractive model to study the physiological impacts of GR and MR activation at the systems level. Here we tested the hypothesis that both MR and GR activation are necessary for mediating the effects of cortisol in zebrafish. During embryogenesis (0-5 days post-fertilization [dpf]), the presence of both GR and MR are necessary for the activation of the hypothalamus-pituitary-interrenal axis, and stress-related behaviour. When treated with cortisol, postnatally (5-15 dpf) larvae at 15 dpf are significantly smaller compared to the wildype, and this response was abolished in both the GRKO and MRKO zebrafish larvae. MR activation is necessary for lipid accumulation, while GR activation is required for lipolysis. Both MR and GR activation are also required for growth hormone/insulin-like growth factor 1 axis by GR and MR. However, only GR activation results in an increase in transcript abundance of proteolytic genes. We then tested the hypothesis that under basal cortisol conditions, a loss of GR would have a substantial impact on muscle growth. Indeed, adult GRKO fish had larger body mass, more total muscle protein, increased phosphorylation of eIF4B (protein translation), and a decrease in genes involved in protein catabolism. Taken together this thesis highlights the dichotomy of GR and MR receptor activation; MR acting to promote anabolic processes, while GR is a potent initiator of catabolism during stress. Overall, this thesis establishes a physiological role for MR in ray-finned fishes and indicates that the mode of action may involve either MR activation alone and/or an interaction with GR in modulating metabolism during stress.
zebrafish, stress, cortisol, glucocorticoid receptor, mineralocorticoid receptor
Faught, L. E. (2019). The Physiological Role of Glucocorticoid and Mineralocorticoid Receptor Activation in Zebrafish (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from