A ZNRF3-dependent Wnt/β-catenin signaling gradient is required for adrenal homeostasis
| Autor: | Celso E. Gomez-Sanchez, Pierre Val, Bon-Kyoung Koo, Stéphanie Rodriguez, Kaitlin J. Basham, David T. Breault, Roeland Nusse, Catriona Y. Logan, Hans Clevers, Gary D. Hammer, Adina F. Turcu, Antonio M. Lerario, Madeline R. Rysztak |
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| Přispěvatelé: | Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Scuola Internazionale Superiore di Studi Avanzati / International School for Advanced Studies (SISSA / ISAS), University of Mississippi Medical Center (UMMC), Hubrecht Institute for Developmental Biology and Stem Cell Research, University of Michigan [Ann Arbor], University of Michigan System, Harvard Stem Cell Institute [Cambridge, USA] (HSCI), Harvard University [Cambridge], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Harvard University |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Frizzled Gene Knockout Techniques Mice 0302 clinical medicine Ubiquitin Models Cortex (anatomy) Homeostasis Transcriptional Activation/genetics Wnt Signaling Pathway [SDV.BDD]Life Sciences [q-bio]/Development Biology beta Catenin ComputingMilieux_MISCELLANEOUS 0303 health sciences Adrenal cortex Wnt signaling pathway beta Catenin/metabolism Transmembrane protein Cell biology medicine.anatomical_structure 030220 oncology & carcinogenesis Models Animal Female Wnt Signaling Pathway/physiology Research Paper Adrenal Cortex Diseases Transcriptional Activation Ubiquitin-Protein Ligases proliferation [SDV.CAN]Life Sciences [q-bio]/Cancer Biology Cell Proliferation/genetics 03 medical and health sciences organ maintenance Genetics medicine Ring finger Animals mouse models Ubiquitin-Protein Ligases/genetics Cell Proliferation 030304 developmental biology Animal Homeostasis/genetics Wnt signaling Adrenal Cortex/cytology Adrenal Cortex Diseases/physiopathology adrenal zonation Adrenal Cortex biology.protein Developmental Biology |
| Zdroj: | Genes and Development Genes and Development, Cold Spring Harbor Laboratory Press, 2019, 33 (3-4), pp.209-220. ⟨10.1101/gad.317412.118⟩ Genes & Development, 33(3-4), 209-220. Cold Spring Harbor Laboratory Press Genes and Development, 2019, 33 (3-4), pp.209-220. ⟨10.1101/gad.317412.118⟩ |
| ISSN: | 0890-9369 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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