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 and is essential for adrenocorticotropin hormone (ACTH) receptor expression and...

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Published in:The FASEB journal 2018-11, Vol.32 (11), p.6186-6196
Main Authors: Novoselova, Tatiana V., Hussain, Mashal, King, Peter J., Guasti, Leonardo, Metherell, Louise A., Charalambous, Marika, Clark, Adrian J. L., Chan, Li F.
Format: Article
Language:English
Subjects:
accessory protein
ACTH
cell fate
familial glucocorticoid deficiency
melanocortin
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Summary: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
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.201701274RR