The mineralocorticoid receptor is essential for stress axis regulation in zebrafish larvae

Abstract

The mineralocorticoid receptor (MR) in mammals mediates the effects of aldosterone in regulating fluid balance and potassium homeostasis. While MR signalling is essential for survival in mammals, there is no evidence that MR has any physiological role in ray-finned fish. Teleosts lack aldosterone and emerging evidence suggest that cortisol mediates ion and fluid regulation by activating glucocorticoid receptor (GR) signalling. Consequently, a physiological role for MR signalling, despite its conserved and ancient origin, is still lacking. We tested the hypothesis that a key physiological role for MR signalling in fish is the regulation of stress axis activation and function. Using either MR or GR knockout zebrafish, our results reveal distinct and complementary role for these receptors in stress axis function. GR−/− mutants were hypercortisolemic and failed to elicit a cortisol stress response, while MR−/− mutants showed a delayed, but sustained cortisol response post-stressor. Both these receptors are involved in stress-related behaviour, as the loss of either receptors abolished the glucocorticoid-mediated larval hyperactivity to a light stimulus. Overall, the results underscore a key physiological role for MR signalling in ray-finned fishes, and we propose that the regulation of the highly conserved stress axis as the original function of this receptor.

Postnatal triglyceride accumulation is regulated by mineralocorticoid receptor activation under basal and stress conditions

“…Previous reports using knockout fish models indicate that MR plays an important role in regulating HPI axis function (Faught & Vijayan, ) and stress‐related behaviour (Sakamoto et al . ; Faught & Vijayan, ).…”

“…Previous reports using knockout fish models indicate that MR plays an important role in regulating HPI axis function (Faught & Vijayan, ) and stress‐related behaviour (Sakamoto et al . ; Faught & Vijayan, ). In combination with mammalian work (Joëls & de Kloet, ), this suggested that the primary role for this receptor may have been in stress sensing and appraisal prior to its mineralocorticoid role in the tetrapod lineage (Baker et al .…”

“…Transcript levels of specific genes were measured by qPCR and consisted of a sample size of 4-6 larvae per group. Total RNA was extracted, and cDNA synthesis was performed using published methods (Faught & Vijayan, 2018). qPCR was performed in duplicate using (Faught & Vijayan, 2018) Sso Advanced SYBR green (BioRad, Canada) on the Applied Biosystems QuantStudio 3 Real-Time PCR System (Applied Biosystems, USA).…”

“…To date, there is little information regarding the physiological role of MR in lower vertebrates or the molecular targets of MR. There is some evidence that MR complements the role of GR in the larval zebrafish stress response and mediates stress-related behaviour (Faught & Vijayan, 2018). There is no evidence that MR plays any role in adipogenesis in lower vertebrates; however, in GRKO fish there was an increase in both total lipid and subcutaneous fat, despite the fish being hypercortisolemic (Facchinello et al 2017;Faught & Vijayan, 2019).…”

“…Therefore, only conditional knockouts can be generated in mice, which may lead to compensatory mechanisms in other tissues (Shimizu et al 2015). To interrogate the physiological role of corticosteroid receptors (CR) in shaping lipid metabolism during postnatal growth at the systems level, we generated zebrafish with ubiquitous knockouts of MR (MRKO) or GR (GRKO) (Faught & Vijayan, 2018). Discriminating the contribution of MR and GR signalling in postnatal lipid regulation is paramount to our understanding of metabolic disorders associated with childhood stress, as well as exogenous GC treatment.…”