ESPEYB15 8 Adrenals New Paradigms (2 abstracts)
8.18 PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal
Dumontet T , Sahut-Barnola I , Septier A , Montanier N , Plotton I , Roucher-Boulez F , Ducros V , Lefrançois-Martinez AM , Pointud JC , Zubair M , Morohashi KI , Breault DT , Val P & Martinez A
GReD, Université Clermont Auvergne, CNRS, INSERM, Clermont-Ferrand, France
To read the full abstract: JCI Insight. 2018;3(2). pii: 98394
The (human) adrenal cortex undergoes massive changes in structure and function from fetal to postnatal life, with the first consisting of a small outer definitive zone and a larger inner fetal zone, and the latter finally consisting of three distinct layers, namely the zona glomerulosa (ZG), fasciculata (ZF) and reticularis (ZR). However, details about how these layers are formed are largely missing. Recent cell lineage-fate tracing studies in mice revealed that the adult definitive and the fetal adrenal cortex derive from common precursor cells expressing Sf1, and that the definitive cortex is constantly renewed from a stem/progenitor cell pool residing (sub-) capsular. Differentiation of these cells in a centripetal direction form the ZG and ZF. In this process, RSPO/WNT/β-cathenin drive ZG formation, inhibit ZF, and promote tumorigenesis when constitutively active. By contrast, cAMP/PKA drive ZF formation, inhibit ZG and counteract β-cathenin induced tumorigenesis. Loss of PKA signaling results in cortex atrophy due to altered ZF differentiation, while excess PKA activity leads to nodular hyperplasia with glucocorticoid excess in both mice and men as shown in human PRKAR1A mutations and in the Prkar1a (AdKO mouse), in which PKA is constitutively active.
Here, the authors study the AdKO mouse model to show that PKA accelerates and expands ZF renewal and provokes the formation of the X-zone, which corresponds to the human ZR. Interestingly, they found that this effect of PKA to promote the differentiation to ZR-like cells was only specifically seen with definitive progenitor cells, but not with fetal progenitor cells, and that this effect was negatively regulated by androgens. Thus, this study gives first insight into how the formation of ZR might be stimulated and regulated postnatally in the first 6-8 years of age before becoming steroidogenically active in the production of DHEA at adrenarche. It also suggests that this process is sex-specific, regulated by androgens produced in the male gonad. The authors suggest that this may explain why females are more susceptible to disorders of the adrenal cortex, such as Cushing’s syndrome (CS) or adrenocortical cancers (ACC). The question remains whether this may also imply that women with androgen excess syndromes, such as polycystic ovary syndrome (PCOS), are protected from CS or ACC. Or, on the contrary, do they have disrupted androgen regulation on PKA, given the fact that women with hyperandrogenic PCOS often have a medical history of preceding premature adrenarche?
Volume 15
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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