Kinases and Brain Development Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
Protein Analysis and Proteomics Platform, The Francis Crick Institute, London, NW1 1AT, UK.
Nat Commun. 2020 May 13;11(1):2380. doi: 10.1038/s41467-020-16167-y.
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.
YAP1 基因融合已在一部分小儿室管膜瘤中观察到。在这里，我们表明，使用条件诱导的 NEX/NeuroD6-Cre 在脑室区神经祖细胞中异位表达活性核 YAP1（nlsYAP5SA）足以在小鼠中驱动脑瘤形成。海马中的神经元分化受到抑制。在双条件性敲除小鼠中，NEX-Cre 谱系中 YAP1 的负调节因子 LATS1 和 LATS2 激酶的缺失也会产生类似的肿瘤，这些肿瘤可通过缺失 YAP1 和其旁系同源物 TAZ 得到挽救。YAP1/TAZ 诱导的小鼠肿瘤显示出人类室管膜瘤的分子和超微结构特征。对小鼠肿瘤的 RNA 测序和定量蛋白质组学研究表明，其与 YAP1 融合诱导的幕上室管膜瘤具有相似性。最后，我们发现转录共激活因子 HOPX 在小鼠模型和人类 YAP1 融合诱导的室管膜瘤中上调，支持它们的相似性。我们的结果表明，神经元前体细胞中不受控制的 YAP1/TAZ 活性会导致小鼠发生类似室管膜瘤的肿瘤。
