32404936.pdf (13.8 MB)

YAP1/TAZ drives ependymoma-like tumour formation in mice

Download (13.8 MB)
journal contribution
posted on 22.05.2020 by Noreen Eder, Federico Roncaroli, Marie-Charlotte Dolmart, Stuart Horswell, Felipe Andreiuolo, Helen Flynn, Andre Teixeira Lopes, Suzanne Claxton, John-Paul Kilday, Lucy Collinson, Jun-Hao Mao, Torsten Pietsch, Barry Thompson, Ambrosius Snijders, Sila K Ultanir
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.

Funding

Crick (Grant ID: 10201, Grant title: Ultanir FC001201) Crick (Grant ID: 10180, Grant title: Thompson FC001180) Crick (Grant ID: 10004, Grant title: Collinson FC001999) Crick (Grant ID: 10011, Grant title: Snijders FC001999)

History

Licence

Exports