PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal

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 sho...

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Published inJCI insight Vol. 3; no. 2
Main Authors Dumontet, Typhanie, Sahut-Barnola, Isabelle, Septier, Amandine, Montanier, Nathanaëlle, Plotton, Ingrid, Roucher-Boulez, Florence, Ducros, Véronique, Lefrançois-Martinez, Anne-Marie, Pointud, Jean-Christophe, Zubair, Mohamad, Morohashi, Ken-Ichirou, Breault, David T, Val, Pierre, Martinez, Antoine
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 25.01.2018
Subjects
Animal genetics
Biochemistry, Molecular Biology
Cancer
Development Biology
Embryology and Organogenesis
Endocrinology and metabolism
Genetics
Genomics
Human health and pathology
Life Sciences
Molecular biology
Development
Genetic diseases
Mouse models
Protein kinases
Endocrinology
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Summary: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.
Bibliography:PMCID: PMC5821213
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.98394