ArticleGenes & development2019
A ZNRF3-dependent Wnt/β-catenin signaling gradient is required for adrenal homeostasis.
Article in Genes & development, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 106 citations in OpenAlex.
- Glucose restriction reprograms lipid metabolism and enhances immunotherapy through ZNRF3-Wnt-SCD signaling axis.Journal for immunotherapy of cancer · 2026Article
- Loss of ZNRF3/RNF43 unleashes EGFR in cancer.eLife · 2026Article
- The transcription factor HHEX maintains glucocorticoid levels and protects adrenals from androgen-induced lipid depletion.Nature communications · 2026Article
- Abrogation of FGFR signaling blocks β-catenin-induced adrenocortical hyperplasia and aldosterone production.JCI insight · 2025Article
- Adrenocortical stem cells in health and disease.Nature reviews. Endocrinology · 2025Review
- Mechanistic insights into Wnt-β-catenin pathway activation and signal transduction.Nature reviews. Molecular cell biology · 2025Review
- Hippo Signaling Is Essential for the Maintenance of Zona Glomerulosa Cell Fate in the Murine Adrenal Cortex.Endocrinology · 2025Article
- Wnt signalosomes: What we know that we do not know.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Article
- Germline targeted next-generation sequencing in patients with adrenal incidentalomas.Frontiers in endocrinology · 2025Article
- Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling.American journal of human genetics · 2024Article
- E3 ligases RNF43 and ZNRF3 display differential specificity for endocytosis of Frizzled receptors.Life science alliance · 2024Article
- Non-canonical Wnt signaling triggered by WNT2B drives adrenal aldosterone production.bioRxiv : the preprint server for biology · 2024Article
- Single-nucleus and spatial transcriptome reveal adrenal homeostasis in normal and tumoural adrenal glands.Clinical and translational medicine · 2024Article
- Why Is Wnt/β-Catenin Not Yet Targeted in Routine Cancer Care?Pharmaceuticals (Basel, Switzerland) · 2024Review
- Chronic activation of adrenal Gq signaling induces Cyp11b2 expression in the zona fasciculata and hyperaldosteronism.Molecular and cellular endocrinology · 2024Article
- Ferroptosis and circular RNAs: new horizons in cancer therapy.EXCLI journal · 2024Review
- Evaluating the role of aldosterone synthesis on adrenal cell fate.Frontiers in endocrinology · 2024Review
- Current insight into the transient X-zone in the adrenal gland cortex.Vitamins and hormones · 2024Review
- In Situ Spatial Reconstruction of Distinct Normal and Pathological Cell Populations Within the Human Adrenal Gland.Journal of the Endocrine Society · 2023Article
Corrections and comments
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Authors and funding
13 authors at 9 institutions in 4 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.