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PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal
Typhanie Dumontet, … , Pierre Val, Antoine Martinez
Typhanie Dumontet, … , Pierre Val, Antoine Martinez
Published January 25, 2018
Citation Information: JCI Insight. 2018;3(2):e98394. https://doi.org/10.1172/jci.insight.98394.
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Research Article Development Endocrinology

PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal

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Abstract

The adrenal cortex undergoes remodeling during fetal and postnatal life. How zona reticularis emerges in the postnatal gland to support adrenarche, a process whereby higher primates increase prepubertal androgen secretion, is unknown. Using cell-fate mapping and gene deletion studies in mice, we show that activation of PKA has no effect on the fetal cortex, while it accelerates regeneration of the adult cortex, triggers zona fasciculata differentiation that is subsequently converted into a functional reticularis-like zone, and drives hypersecretion syndromes. Remarkably, PKA effects are influenced by sex. Indeed, testicular androgens increase WNT signaling that antagonizes PKA, leading to slower adrenocortical cell turnover and delayed phenotype whereas gonadectomy sensitizes males to hypercorticism and reticularis-like formation. Thus, reticularis results from ultimate centripetal conversion of adult cortex under the combined effects of PKA and cell turnover that dictate organ size. We show that PKA-induced progenitor recruitment is sexually dimorphic and may provide a paradigm for overrepresentation of women in adrenal diseases.

Authors

Typhanie Dumontet, Isabelle Sahut-Barnola, Amandine Septier, Nathanaëlle Montanier, Ingrid Plotton, Florence Roucher-Boulez, Véronique Ducros, Anne-Marie Lefrançois-Martinez, Jean-Christophe Pointud, Mohamad Zubair, Ken-Ichirou Morohashi, David T. Breault, Pierre Val, Antoine Martinez

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Figure 2

Inner hyperplasia formed in AS+/Cre::Prkar1afl/fl mice (DAdKO) has reticularis characteristics.

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Inner hyperplasia formed in AS+/Cre::Prkar1afl/fl mice (DAdKO) has retic...
(A) Confocal analysis of coimmunofluorescent labeling of GFP (green) and 20α-hydroxysteroid dehydrogenase (20αHSD, purple) in 3-month-old nulliparous females. The white AS+/Cre::Prkar1afl/fl mice (DAdKO) arrows denote adult and fetal cortices. (B) qPCR analysis of Akr1c18 and Pik3c2g fetal markers in WT or AS+/Cre::Prkar1afl/fl (DAdKO) female adrenals. (C) Immunostaining and immunofluorescent analyses of HSD3B, CYB5A, and CYP17 from DAdKO 7-month-old females. The black and white double arrows denote inner hyperplasia. The black and white dots represent the border between the cortex and the medulla. (D) qPCR analysis confirms downregulation of Hsd3b1, upregulation of Cyp17a1 and Cyb5a, and, moreover, shows increased expression of Sult1e1 in DAdKO adrenals. (E) Western blot analysis of CYP17 and CYB5A protein accumulation in adrenal extracts from WT and mutant mice. Graphs showed quantification normalized to quantification of GAPDH signal. (F) Cortisol, 21-deoxycortisol, and Δ4 androstenedione levels were measured by mass spectrometry in blood, dehydroepiandrosterone (DHEA) levels were measured by ELISA in adrenal extracts from adult mice (>7 months), and dehydroepiandrosterone sulfate (DHEAS) levels were measured by RIA in blood. zG, zona glomerulosa; zF, zona fasciculata; zX, X-zone; Co, cortex; M, medulla. Lines in dot plots represent the mean ± SEM. Ø, under detection threshold. Statistical analyses were conducted by Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001. The number of samples is indicated above dot plots. Scale bars: 200 μm. Original magnification: ×2 (insets, A); ×4 (insets, C).
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