Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Michigan 48109, USA.
Génétique Reproduction et Développement (GReD), UMR 6293, Centre National de la Recherche Scientifique (CNRS), U1103, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Clermont Auvergne, 63001 Clermont-Ferrand Cedex, France.
Genes Dev. 2019 Feb 1;33(3-4):209-220. doi: 10.1101/gad.317412.118. Epub 2019 Jan 28.
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.
Wnt 信号的时空控制对于许多组织的发育和稳态至关重要。跨膜 E3 泛素连接酶 ZNRF3(锌指和环指 3)和 RNF43(环指蛋白 43)通过促进卷曲受体的降解来拮抗 Wnt 信号。ZNRF3 和 RNF43 在人类癌症中经常失活,但分子和治疗意义仍不清楚。在这里,我们证明了肾上腺特异性的 ZNRF3 缺失,但不是 RNF43,导致依赖于 Porcupine 介导的 Wnt 配体分泌的肾上腺增生。此外,我们在肾上腺皮质中发现了一个 Wnt/β-catenin 信号梯度,该梯度在 ZNRF3 缺失时被破坏。与β-连环蛋白功能获得模型不同,后者诱导高 Wnt/β-catenin 激活和外周皮质扩张,ZNRF3 缺失触发适度水平的 Wnt/β-catenin 信号激活,仅驱动组织学和功能上不同的内皮质的增殖扩张。遗传降低β-连环蛋白剂量可显著逆转 ZNRF3 缺陷表型。因此,肾上腺皮质的稳态维持依赖于 Wnt/β-catenin 激活的不同水平,这由 ZNRF3 调节。
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