MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation

Novoselova, Tatiana ORCID: https://orcid.org/0000-0002-2394-4667, Hussain, Mashal, King, Peter J., Guasti, Leonardo, Metherell, Louise A., Charalambous, Marika, Clark, Adrian and Chan, Li F. (2018) MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation. The FASEB Journal, 32 (11) . pp. 6186-9196. ISSN 0892-6638 [Article] (doi:10.1096/fj.201701274RR)

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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 Mrap-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 mineralocorticoid 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 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

Item Type: Article
Research Areas: A. > School of Science and Technology > Natural Sciences
Item ID: 28126
Notes on copyright: © FASEB
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Depositing User: Tatiana Novoselova
Date Deposited: 08 Nov 2019 11:48
Last Modified: 20 Aug 2020 22:03
URI: https://eprints.mdx.ac.uk/id/eprint/28126

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