WWC Proteins-mediated Compensatory Mechanism Restricts Schwannomatosis Driven by Loss of Function

Overview

Journal Sci Adv

Date 2025 Jan 22

PMID 39841844

Authors

Xueying Wang

Rui Zhu

Pengcheng Yu

Sixian Qi

Zhenxing Zhong

Ruxin Jin

Yu Wang

Yuan Gu

Dan Ye

Kang Chen

Yilai Shu

Yi Wang

Fa-Xing Yu

Affiliations

Soon will be listed here.

Abstract

NF2-related schwannomatosis, previously known as neurofibromatosis type 2, is a genetic disorder characterized by nerve tumors due to gene mutations. Mice with deletion develop schwannomas slowly with low penetrance, hence inconvenient for preclinical studies. Here, we show that NF2, by recruiting E3 ubiquitin ligases β-TrCP1/2, promotes WWC1-3 ubiquitination and degradation. In mutated cells, WWC1-3 accumulation is a compensatory mechanism to prevent YAP/TAZ hyperactivation and rapid tumorigenesis. Accordingly, we generate a synthetic mouse model with complete penetrance and short latency by concurrently deleting and in Schwann cells. This model closely resembles NF2-related schwannomatosis in patients, as confirmed by histological and single-cell transcriptome analysis. Moreover, a cell line from mouse schwannomas and a syngeneic tumor model in immune-competent mice are established. Furthermore, a screen using established models has identified candidate drugs that effectively suppress schwannoma progression. Hence, this work has developed rapid and transplantable models that will facilitate both basic and translational research on NF2-related schwannomatosis.

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