Transcriptional Activation of Elephant Shark Mineralocorticoid Receptor by Corticosteroids, Progesterone and Spironolactone

Abstract

Abstract.A distinct mineralocorticoid receptor (MR) first appears in cartilaginous fishes (Chondrichthyes), the oldest group of extant jawed vertebrates. To investigate steroid specificity of cartilaginous fish MR, we studied transcriptional activation of full-length elephant shark (Callorhinchus milii) MR by aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone and 19-norprogesterone. All investigated corticosteroids and progestins showed half-maximal responses (EC50s) below 1 nM for elephant shark MR, and hence are potential physiological mineralocorticoids. Progesterone and 19-norprogesterone are antagonists for human, Xenopus and alligator MRs, but agonists for ray-finned fish and chicken MRs, indicating that MR activation by progestins is an ancestral response, conserved in ray-finned fish, lost in Xenopus, alligator and human, and distinct from chicken MR activation, which arose independently. RNA-seq analysis finds strong MR expression in elephant shark ovary and testis, in which progesterone-activated MR may . CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/265348 doi: bioRxiv preprint first posted online Feb. 13, 2018; 2 have novel functions.Running title: Steroid specificity of elephant shark mineralocorticoid receptor

Regulation by Progestins, Corticosteroids and RU486 of Activation of Elephant Shark and Human Progesterone Receptors: An Evolutionary Perspective

“…An ortholog of human PR along with the corticoid receptor (CR), the ancestor of the MR and GR, first appears in the more ancient cyclostomes (jawless fish), which has descendants in modern lamprey and hagfish (3,27,42). It is in cartilaginous fish that distinct orthologs of human MR and GR first appear (43)(44)(45) along with the beginning of the evolution of differences in the responses of the PR, MR and GR for progestins and corticosteroids that appear in terrestrial vertebrates and ray-finned fish (16,17,24,40,41,(43)(44)(45)(46)(47)(48)(49)(50)(51)).…”