A ZNRF3-dependent Wnt/β-catenin signaling gradient is required for adrenal homeostasis

Spatiotemporal control of Wnt signaling is essential for the development and homeostasis of many tissues. The transmembrane E3 ubiquitin ligasesZNRF3 (zinc and ring finger3) and RNF43 ( ring fingerprotein 43) antagonize Wnt signaling by promoting degradation of frizzledreceptors. ZNRF3 and RNF43 are frequently inactivated in human cancer, but the molecular and therapeutic implications remain unclear. Here, we demonstrate that adrenocortical-specific loss of ZNRF3, but not RNF43, results in adrenal hyperplasia that depends on Porcupine-mediated Wnt ligand secretion. Furthermore, we discovered a Wnt/β- cateninsignaling gradient in the adrenal cortexthat is disrupted upon loss of ZNRF3. Unlike β- cateningain-of-function models, which induce high Wnt/β- cateninactivation and expansion of the peripheral cortex, ZNRF3 loss triggers activation of moderate-level Wnt/β- cateninsignaling that drives proliferative expansion of only the histologically and functionally distinct inner cortex. Genetically reducing β- catenindosage significantly reverses the ZNRF3-deficient phenotype. Thus, homeostatic maintenance of the adrenal cortexis dependent on varying levels of Wnt/β- cateninactivation, which is regulated by ZNRF3.