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.
Highlights
Yes-associated protein 1 (YAP1) gene fusions have been observed in a subset of paediatric ependymomas
The core kinase cascade consists of the Hippo kinase in Drosophila and its homologue Mammalian Sterile 20-like 1 (MST1) and MST2 in mammals, together with hippo’s downstream effector Warts in Drosophila, which is homologous to the Large tumour suppressor homologue 1 (LATS1) and LATS2 kinases in mammals[9]
YAP1 was highly expressed in the ventricular zone (VZ) at postnatal day 0 (P0) (Fig. 1a, Supplementary Fig. 1a), becoming localised in the ependymal layer at P20 (Supplementary Fig. 1a)[41]
Summary
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. The role of hippo signalling in mammalian tumorigenesis has been demonstrated in vivo, for example, by conditional deletion of MST1/2 or LATS1/2 in liver, which deregulates progenitor cell proliferation and leads to tumorigenesis in mice[15,16,17]. We use conditional mouse models of active YAP1 expression and LATS1/2 deletion and show that suppression of YAP1 activity in NEX/NeuroD6 expressing neuronal precursor cells is essential for limiting proliferation and enabling neuronal differentiation in the brain, whereas activation of YAP1 is sufficient to produce tumours that display features similar to human ependymoma
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