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Nature reviews | Endocrinology Original article Pignatti, E. et al. Beta-catenin causes adrenal hyperplasia by blocking zonal trans differentiation. Cell Reports. 31, 107524 (2020) somatic β-catenin gain-of-function (βcat-GOF) mutations are known to drive adrenal hyperplasia and are common in adrenal cortical carcinoma. a new study published in Cell Reports shows that adrenal hyperplasia induced by βcat-GOF results from a block in adrenal zonal transdifferentiation. “the wnt–β-catenin signalling pathway, which is a key regulator of cellular proliferation, has mostly been studied in rapidly cycling cell systems,” explains corresponding author David Breault. However, the cells of the adrenal cortex have a fairly low proliferation rate, making this tissue an ideal system to study the effects of the wnt–β-catenin signalling pathway, independently of cellular proliferation. “a few years ago, our laboratory developed a mouse model that allows targeted expression of Cre recombinase specifically within the zona Glomerulosa,” describes Breault. “this tool provides us with the opportunity to directly study the effect of activating the wnt–β-catenin pathway within the slowly cycling cells of the zona glomerulosa.” in this mouse model, β-catenin was stabilized specifically in cells of the zona glomerulosa, leading to constitutive activation of the wnt–β-catenin pathway (βcat-GOF adrenals). Notably, mice with βcat-GOF adrenals showed expansion of the zona glomerulosa into the underlying region where the zona fasciculata normally resides. Furthermore, histomorphometric analysis of wild-type adrenals (βcat-wt) and βcat-GOF adrenals showed that this expansion was due to hyperplasia and not hypertrophy. experiments using mt/mG double-fluorescent Cre-reporter mice showed that βcat-GOF adrenals have a functional block in the transdifferentiation of zona glomerulosa to zona fasciculata. the identity of zona fasciculata cells is known to be negatively regulated by phosphodiesterases, via a block in caMP/PKa signalling. in the adrenal gland, PDe2a in the zona glomerulosa induces phosphodiesterase activity. Of note, the researchers saw upregulated expression of Pde2a in βcat-GOF adrenals compared with controls. Further experiments showed inhibited caMP/PKa signalling in the β-catenin-positive zona glomerulosa regions, suggesting a potential mechanism for the transdifferentiation block. Chronic activation of the renin–angiotensin–aldosterone system (raas) is known to be associated with increased zona glomerulosa proliferation. a mouse model with ~5-fold increased raas activation was combined with the βcat-GOF adrenal model. this new model showed substantial adrenal hyperplasia leading to adrenomegaly. “we plan to study the effect of chronic activation of the raas on the zona glomerulosa in patients carrying somatic and/or germ-line mutations in β-catenin,” concludes Breault. “Finally, we plan to explore the interaction of βcat-GOF with other known regulators of adrenal function such as the p53–rb pathway.”