Premium
MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation
Author(s) -
Novoselova Tatiana V.,
Hussain Mashal,
King Peter J.,
Guasti Leonardo,
Metherell Louise A.,
Charalambous Marika,
Clark Adrian J. L.,
Chan Li F.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201701274rr
Subject(s) - adrenal gland , adrenal cortex , medicine , endocrinology , biology , receptor , progenitor cell , progenitor , corticosterone , microbiology and biotechnology , hormone , stem cell
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