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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 4

Cushing’s syndrome due to loss of R1α in the adult cortex develops in a sex-dependent manner.

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Cushing’s syndrome due to loss of R1α in the adult cortex develops in a ...
(A–D) Female data. (A) Image of 7-month-old DAdKO females showing fat distribution compared with WT. (B) Body weight (g) follow-up of WT and DAdKO females (mean ± SEM) from 2.5–7 months of age. (C) EchoMRI analysis of lean and fat mass distribution (%) in 7-month-old females and changes (mg) in gastrocnemius weight (mean ± SEM). (D) Fasted blood glucose concentration (mg/dl) and insulin tolerance test (ITT, % of baseline) in DAdKO females (mean ± SEM); statistical analysis was conducted by 2-way ANOVA followed by Bonferroni’s test. (E–G) Male data. (E) Coimmunofluorescent labeling of GFP (green) and fetal marker 20α-hydroxysteroid dehydrogenase (20αHSD, purple) in AS+/Cre::Prkar1afl/fl::R26RmTmG male mice. The white dots represent the border between the cortex and the medulla. zX, X-zone; Co, cortex; M, medulla. (F) Plasma corticosterone levels in basal conditions and after dexamethasone suppression test (dex) and body weight of DAdKO males. Ø, under detection threshold. (G) qPCR follow-up of Prkar1a expression in adrenals from FAdKO and DAdKO males. Lines in dot plots represent the mean relative quantification of Prkar1a expression (relative to the control counterparts, white bars) ± SEM. If not otherwise mentioned, all statistical analyses were conducted by Student’s t test. *P < 0.05, ***P < 0.001. The number of samples is indicated in curves or above dot plots. Scale bars: 200 μm.
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