MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation. Issue 11 (7th June 2018)

• Record Type: Journal Article
• Authors: Novoselova, Tatiana V.; Hussain, Mashal; King, Peter J.; Guasti, Leonardo; Metherell, Louise A.; Charalambous, Marika; Clark, Adrian J. L.; Chan, Li F.
• Is Part Of: FASEB journal. Volume 32:Issue 11(2018)
• Page Start: 6186
• Page End: 6196
• Publication Date: 2018-06-07
• Subjects: ACTH -- accessory protein -- melanocortin -- cell fate -- familial glucocorticoid deficiency; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.201701274RR
• Languages: English
• ISSNs: 0892-6638

Abstract

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 and is essential for adrenocorticotropin hormone (ACTH) receptor expression and function. Human loss‐of‐function mutations in MRAP cause familial glucocorticoid (GC) deficiency (FGD) type 2 (FGD2), whereby the adrenal gland fails to respond to ACTH and to produce cortisol. In this study, we generated Mrnp ‐null mice to study the function of MRAP in vivo. We found that the vast majority of Mrap −/− mice died at birth but could be rescued by administration of corticosterone to pregnant dams. Surviving Mrap −/− mice developed isolated GC deficiency with normal min‐ eralocorticoid and catecholamine production, recapitulating FGD2. The adrenal glands of adult Mrap −/− mice were small, with grossly impaired adrenal capsular morphology and cortex zonation. Progenitor cell differentiation was significantly impaired, with dysregulation of WNT4/β‐catenin and sonic hedgehog pathways. These data dem onstrate 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.—Novoselova, T. V., Hussain, M., King, P. J., Guasti, L., Metherell, L. A., Charalambous, M., Clark, A. J. L., Chan, L. F. MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation. FASEB J. 32, 6186–6196 (2018). www.fasebj.org