PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development

Coralie Drelon, Annabel Berthon, Isabelle Sahut-Barnola, Mickaël Mathieu, Typhanie Dumontet, Stéphanie Rodriguez, Marie Batisse-Lignier, Houda Tabbal, Igor Tauveron, Anne-Marie Lefrançois-Martinez, Jean-Christophe Pointud, Celso E. Gomez-Sanchez, Seppo Vainio, Jingdong Shan, Sonia Sacco, Andreas Schedl, Constantine A. Stratakis, Antoine Martinez and Pierre Val ()
Additional contact information
Coralie Drelon: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Annabel Berthon: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Isabelle Sahut-Barnola: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Mickaël Mathieu: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Typhanie Dumontet: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Stéphanie Rodriguez: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Marie Batisse-Lignier: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Houda Tabbal: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Igor Tauveron: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Anne-Marie Lefrançois-Martinez: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Jean-Christophe Pointud: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Celso E. Gomez-Sanchez: G.V. (Sonny) Montgomery VA Medical Center
Seppo Vainio: Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu
Jingdong Shan: Biocenter Oulu, Laboratory of Developmental Biology, InfoTech Oulu, Center for cell Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu
Sonia Sacco: Inserm UMR1091, CNRS UMR 7277, Institute of Biology Valrose
Andreas Schedl: Inserm UMR1091, CNRS UMR 7277, Institute of Biology Valrose
Constantine A. Stratakis: Developmental Endocrine Oncology and Genetics, Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Antoine Martinez: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université
Pierre Val: CNRS, UMR 6293, GReD, Inserm U1103, Clermont Université

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Adrenal cortex physiology relies on functional zonation, essential for production of aldosterone by outer zona glomerulosa (ZG) and glucocorticoids by inner zona fasciculata (ZF). The cortex undergoes constant cell renewal, involving recruitment of subcapsular progenitors to ZG fate and subsequent lineage conversion to ZF identity. Here we show that WNT4 is an important driver of WNT pathway activation and subsequent ZG differentiation and demonstrate that PKA activation prevents ZG differentiation through WNT4 repression and WNT pathway inhibition. This suggests that PKA activation in ZF is a key driver of WNT inhibition and lineage conversion. Furthermore, we provide evidence that constitutive PKA activation inhibits, whereas partial inactivation of PKA catalytic activity stimulates β-catenin-induced tumorigenesis. Together, both lower PKA activity and higher WNT pathway activity lead to poorer prognosis in adrenocortical carcinoma (ACC) patients. These observations suggest that PKA acts as a tumour suppressor in the adrenal cortex, through repression of WNT signalling.

Date: 2016
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DOI: 10.1038/ncomms12751

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