Year: 2019
Type: preprint
Abstract: Spatiotemporal control of Wnt signaling is essential for the development and homeostasis of many tissues. The transmembrane E3 ubiquitin ligases ZNRF3 (zinc and ring finger 3) and RNF43 (ring finger protein 43) antagonize Wnt signaling by promoting degradation of frizzled receptors. 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-catenin signaling gradient in the adrenal cortex that is disrupted upon loss of ZNRF3. Unlike β-catenin gain-of-function models, which induce high Wnt/β-catenin activation and expansion of the peripheral cortex, ZNRF3 loss triggers activation of moderate-level Wnt/β-catenin signaling that drives proliferative expansion of only the histologically and functionally distinct inner cortex. Genetically reducing β-catenin dosage significantly reverses the ZNRF3-deficient phenotype. Thus, homeostatic maintenance of the adrenal cortex is dependent on varying levels of Wnt/β-catenin activation, which is regulated by ZNRF3.
Source: Genes & Development
Institutions: University of Michigan, Michigan Medicine, Centre National de la Recherche Scientifique, Inserm, Université Clermont Auvergne, Institut Génétique, Reproduction et Développement, U-M Rogel Cancer Center, Howard Hughes Medical Institute, Stanford Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, University of Mississippi Medical Center, Boston Children's Hospital, Harvard University, Harvard Stem Cell Institute, Institute of Molecular Biotechnology, University Medical Center Utrecht, Hubrecht Institute for Developmental Biology and Stem Cell Research
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W2912378470