Genetic Inactivation of Synergizes with Loss of to Induce Tumor Formation in the Adult Mouse Forebrain.

Simultaneous genetic inactivation of the key Notch signaling mediator RBP-Jk and p53 leads to the formation of forebrain tumors in mice, suggesting a tumor suppressor role of the Notch pathway in this context. However, the contribution of individual Notch receptors to the tumor-suppressive activity of Notch signaling in the brain remains elusive. Here, we show that simultaneous and deletion, similar to complete ablation of canonical Notch signaling by inactivation, cooperates with deletion to promote tumor growth in the adult forebrain. We also demonstrate that inactivation of and in cells with active Notch signaling is sufficient to induce brain tumor or hyperplasia formation. Analysis of tumor location suggests a multifocal origin and shows that ventral forebrain regions and olfactory bulbs are the most affected sites. Hence, Notch1 cooperates with p53 to repress malignant transformation in the adult mouse forebrain.