MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation

Abstract

Melanocortin 2 receptor accessory protein (MRAP) is a single transmembrane domain accessory protein and a critical component of the hypothamo-pituitary-adrenal axis.MRAP is highly expressed in the adrenal gland andis essential for adrenocorticotropinhormone (ACTH) receptor expressionandfunction.Humanloss-of-function mutations in MRAP cause familial glucocorticoid (GC) deficiency (FGD) type 2 (FGD2),whereby the adrenal gland fails to respond toACTHand to produce cortisol. In this study,we generatedMrap-nullmice to study the function of MRAPin vivo. We found that the vastmajority of Mrap-/- mice died at birth but couldbe rescued by administration of corticosterone to pregnant dams. Surviving Mrap-/- mice developed isolated GC deficiency with normal mineralocorticoid and catecholamine production, recapitulating FGD2. The adrenal glands of adult Mrap-/-micewere small, with grossly impaired adrenal capsularmorphology and cortex zonation. Progenitor cell differentiation was significantly impaired, with dysregulation of WNT4/b-catenin and sonic hedgehog pathways. These data demonstrate the roles of MRAP in both steroidogenesis and the regulation of adrenal cortex zonation. This is the first mouse model of isolated GC deficiency and reveals the role of MRAP in adrenal progenitor cell regulation and cortex zonation.