MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation.
MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation.
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DOI：
10.1096/fj.201701274rr
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发表时间：
2018-06-07
期刊：
影响因子：
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通讯作者：
Chan LF
中科院分区：
文献类型：
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作者：
Novoselova TV;Hussain M;King PJ;Guasti L;Metherell LA;Charalambous M;Clark AJL;Chan LF
黑素皮质素2受体辅助蛋白(MRAP)是一种跨膜区的辅助蛋白，是下丘脑-垂体-肾上腺轴的重要组成部分。MRAP在肾上腺中高度表达，是促肾上腺皮质激素(ACTH)受体表达和功能所必需的。人类MRAP功能丧失突变导致家族性糖皮质激素缺乏症(FGD)2型(FGD2)，肾上腺对ACTH没有反应，也不能产生皮质醇。在本研究中，我们建立了Mrap缺失的小鼠来研究MRAP在体内的功能。我们发现，绝大多数Mrap−/−小鼠在出生时就死亡了，但可以通过给怀孕的母鼠注射皮质酮来挽救。存活下来的MRAP−/−小鼠出现孤立的GC缺乏症，矿质皮质激素和儿茶酚胺产生正常，重述FGD2。成年MRAP−/−小鼠的肾上腺较小，肾上腺包膜形态和皮质带状结构严重受损。祖细胞分化明显受损，WNT4/β-连环蛋白和声波刺猬通路调节失调。这些数据证明了MRAP在类固醇生成和肾上腺皮质分区调节中的作用。-Novoselova，T.V.，Hussain，M.，King，P.J.，Guasti，L.，Metherell，L.A.，Charalambous，M.，Clark，A.J.，Chan，L.F.MRAP缺陷损害肾上腺前体细胞分化和腺体分区。
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.