Beta-Catenin Causes Adrenal Hyperplasia by Blocking Zonal Transdifferentiation.

ABSTRACT: Activating mutations in the canonical Wnt/?-catenin pathway are key drivers of hyperplasia, the gateway for tumor development. In a wide range of tissues, this occurs primarily through enhanced effects on cellular proliferation. Whether additional mechanisms contribute to ?-catenin-driven hyperplasia remains unknown. The adrenal cortex is an ideal system in which to explore this question, as it undergoes hyperplasia following somatic ?-catenin gain-of-function (?cat-GOF) mutations. Targeting ?cat-GOF to zona Glomerulosa (zG) cells leads to a progressive hyperplastic expansion in the absence of increased proliferation. Instead, we find that hyperplasia results from a functional block in the ability of zG cells to transdifferentiate into zona Fasciculata (zF) cells. Mechanistically, zG cells demonstrate an upregulation of Pde2a, an inhibitor of zF-specific cAMP/PKA signaling. Hyperplasia is further exacerbated by trophic factor stimulation leading to organomegaly. Together, these data indicate that ?-catenin drives adrenal hyperplasia through both proliferation-dependent and -independent mechanisms.

SUBMITTER: Pignatti E 

PROVIDER: S-EPMC7281829 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature