Eder, Noreen; (2020) YAP1 drives ependymoma-like tumour formation in mice and post mitotic functions of LATS2 in the brain. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In a subset of paediatric ependymomas YAP1 (Yes-associated protein 1) gene fusions have been identified recently. In this study we show that YAP1 is expressed in the ventricular zone of the developing mouse brain. Depletion of two negative regulators of YAP1, Large tumour suppressor 1 and 2 (LATS1/2) kinases, in these cells using conditional NEX/NeuroD6-Cre knockout mice leads to the development of brain tumours. Nuclear YAP1 drives tumourigenesis by maintaining a nestin positive neural stem cell-like progenitor pool. These tumours display molecular, histological and ultrastructural similarities to human ependymoma. Additional depletion of YAP1 and its paralog TAZ (Transcriptional coactivator with PDZ-binding motif) in the Lats1/2 knockout NEX-Cre lineage rescues the phenotype, showing the dependence on YAP/TAZ. Furthermore, expression of active nuclear YAP1 (nlsYAP5SA) in the NEX-Cre linage is sufficient for high tumour burden in mice at the expense of proper hippocampal development. Transcriptomic and proteomic analysis of those murine tumours exhibit further similarities to YAP1-fusion supratentorial ependymoma. Moreover, we demonstrate an upregulation of the transcriptional cofactor HOPX in our mouse models. Finally, we show that HOPX is present in human YAP1-fusion ependymoma and absent in the RELA-fusion ependymoma in patient samples. In conclusion, our results demonstrate that uninhibited YAP/TAZ activity in neuronal precursor cells can lead to ependymoma-like tumours in mice.

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