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Start Over Author "Kilday JP" Journal nature communications
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2. YAP1/TAZ drives ependymoma-like tumour formation in mice.

Author

Eder N, Roncaroli F, Domart MC, Horswell S, Andreiuolo F, Flynn HR, Lopes AT, Claxton S, Kilday JP, Collinson L, Mao JH, Pietsch T, Thompson B, Snijders AP, and Ultanir SK

Subjects
Adaptor Proteins, Signal Transducing genetics, Adult, Animals, Brain metabolism, Brain pathology, Brain ultrastructure, Brain Neoplasms genetics, Brain Neoplasms pathology, Cell Cycle Proteins genetics, Child, Ependymoma genetics, Ependymoma pathology, Gene Expression Regulation, Neoplastic, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Mice, Knockout, Mice, Transgenic, Microscopy, Electron, Scanning, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Trans-Activators genetics, Transcription Factors genetics, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, YAP-Signaling Proteins, Adaptor Proteins, Signal Transducing metabolism, Brain Neoplasms metabolism, Cell Cycle Proteins metabolism, Ependymoma metabolism, Trans-Activators metabolism, Transcription Factors metabolism
Abstract

YAP1 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.

Published
2020
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