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

TY - JOUR

T1 - A ZNRF3-dependent Wnt/β-catenin signaling gradient is required for adrenal homeostasis

AU - Basham, Kaitlin J

AU - Rodriguez, Stéphanie

AU - Turcu, Adina F

AU - Lerario, Antonio M

AU - Logan, Catriona Y

AU - Rysztak, Madeline R

AU - Gomez-Sanchez, Celso E

AU - Breault, David T

AU - Koo, Bon-Kyoung

AU - Clevers, Hans

AU - Nusse, Roeland

AU - Val, Pierre

AU - Hammer, Gary D

N1 - © 2019 Basham et al.; Published by Cold Spring Harbor Laboratory Press.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

KW - Adrenal Cortex/cytology

KW - Adrenal Cortex Diseases/physiopathology

KW - Animals

KW - Cell Proliferation/genetics

KW - Female

KW - Gene Knockout Techniques

KW - Homeostasis/genetics

KW - Male

KW - Mice

KW - Models, Animal

KW - Transcriptional Activation/genetics

KW - Ubiquitin-Protein Ligases/genetics

KW - Wnt Signaling Pathway/physiology

KW - beta Catenin/metabolism

U2 - 10.1101/gad.317412.118

DO - 10.1101/gad.317412.118

M3 - Article

C2 - 30692207

SN - 0890-9369

VL - 33

SP - 209

EP - 220

JO - Genes & Development

JF - Genes & Development

IS - 3-4

ER -