Beta-Catenin Causes Adrenal Hyperplasia by Blocking Zonal Transdifferentiation
Emanuele Pignatti, Sining Leng, Yixing Yuchi, Kleiton Silva Borges, Nick A. Guagliardo, Manasvi S. Shah, Gerard Ruiz‐Babot, Dulanjalee Kariyawasam, Makoto M. Taketo, Ji Miao, Paula Q. Barrett, Diana L. Carlone, David T. Breault
Abstract
Activating mutations in the canonical Wnt/β-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 β-catenin-driven hyperplasia remains unknown. The adrenal cortex is an ideal system in which to explore this question, as it undergoes hyperplasia following somatic β-catenin gain-of-function (βcat-GOF) mutations. Targeting βcat-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 β-catenin drives adrenal hyperplasia through both proliferation-dependent and -independent mechanisms.