Abstract
NF2-related schwannomatosis, previously known as neurofibromatosis type 2, is a genetic disorder characterized by nerve tumors due to NF2 gene mutations. Mice with Nf2 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 NF2 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 Nf2 and Wwc1/2 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.