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MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation.

Novoselova, TV; Hussain, M; King, PJ; Guasti, L; Metherell, LA; Charalambous, M; Clark, AJL; Chan, LF (2018) MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation. FASEB J, 32 (11). pp. 6186-6196. ISSN 1530-6860 https://doi.org/10.1096/fj.201701274RR
SGUL Authors: Clark, Adrian John L

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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.-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.

Item Type: Article
Additional Information: © The Author(s) 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.
Keywords: ACTH, accessory protein, cell fate, familial glucocorticoid deficiency, melanocortin, ACTH, accessory protein, cell fate, familial glucocorticoid deficiency, melanocortin, Biochemistry & Molecular Biology, 0601 Biochemistry And Cell Biology, 0606 Physiology, 1116 Medical Physiology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: FASEB J
ISSN: 1530-6860
Language: eng
Dates:
DateEvent
1 November 2018Published
7 June 2018Published Online
14 May 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
G080279Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/J006394/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
BB/L00267/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
MR/K020455/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/L002345/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 29879378
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109992
Publisher's version: https://doi.org/10.1096/fj.201701274RR

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