YAP1/TAZ drives ependymoma-like tumour formation in mice

Author:

Eder Noreen,Roncaroli FedericoORCID,Domart Marie-CharlotteORCID,Horswell StuartORCID,Andreiuolo FelipeORCID,Flynn Helen R.ORCID,Lopes Andre T.ORCID,Claxton Suzanne,Kilday John-Paul,Collinson LucyORCID,Mao Jun-Hao,Pietsch Torsten,Thompson BarryORCID,Snijders Ambrosius P.ORCID,Ultanir Sila K.ORCID

Abstract

AbstractYAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that, ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1’s negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of mouse tumours demonstrate similarities to YAP1-fusion induced supratentorial ependymoma. Finally, we find that transcriptional cofactor HOPX is upregulated in mouse models and in human YAP1-fusion induced ependymoma, supporting their similarity. Our results show that uncontrolled YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumours in mice.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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