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.
View: Text | PDF
Research Article Development Endocrinology

PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal

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

×

Figure 3

Endocrine overactivity is associated with upregulation of steroidogenesis pathway and cholesterol synthesis.

Options: View larger image (or click on image) Download as PowerPoint
Endocrine overactivity is associated with upregulation of steroidogenesi...
(A) qPCR analysis of steroidogenic gene expression in adrenals of DAdKO 7-month-old females. eChol/iChol, extra/intracellular cholesterol; Preg., pregnenolone; Prog., progesterone; DOC, deoxycorticosterone; Cort., corticosterone. (B) Immunostaining of CYP11A1 and CYP21 in adrenal sections from DAdKO 7-month-old females. (C) Color-coded heatmap shows expression of the 29 genes that are significantly deregulated (adjusted P = 0.05) relative to the cholesterol synthesis pathway. (D) Gene set enrichment analyses were performed using signatures gene set of cholesterol synthesis pathway by comparing gene expression data from WT and DAdKO female adrenals. Normalized enrichment score (NES) and false discovery rates (FDR) are shown on plots. The enrichment score plot corresponds to the 59 genes listed in Supplemental Table 3. (E) qPCR analysis of genes involved in de novo cholesterol synthesis in adrenals from 7-month-old DAdKO females. (F) Plasma aldosterone levels were measured in WT and DAdKO mice. Plasma from ASCre/Cre::Prkar1afl/fl mice (knockout for Prkar1a and Cyp11b2 [aldosterone synthase]) was used as negative control. Plasma renin activity rate was compared in WT and DAdKO mice. ASCre/Cre mice were used as positive control for renin-angiotensin system upregulation. Lines in dot plots represent the mean ± SEM. zG, zona glomerulosa; zF, zona fasciculata; zX, X-zone; Co, cortex; M, medulla. The black double arrows focus on hyperplasia. If not otherwise mentioned, all 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, B).