Notch2 signaling in development and cancer

Notch signaling via cell to cell interaction is a key mechanism in regulating proliferation, cell fate decisions and survival of various cell types in both invertebrates and vertebrates. Among the four Notch receptors (Notch1-4) described in mammals, most studies focused on Notch1, while Notch2 functions are poorly understood. In humans, Notch2 mutations are associated with a variety of developmental disorders and tumor formation in several tissues. In the liver, Notch2 deletion was shown to cause Alagille syndrome (AGS), which is characterized by impaired intrahepatic bile duct (IHBD) development. In glioblastoma multiforme (GBM), the most aggressive form of CNS tumors, Notch2 is amplified and high Notch2 levels correlate with poor prognosis. However, the exact role of Notch2 in these human pathologies is not established. In order to investigate the function of Notch2 in AGS and GBM at the level of cells, tissues and organs, I generated transgenic mice that allow for tissue-specific expression of activated Notch2 (Notch2ICD), which mimics ligand-induced activation of Notch2 signaling.
To address the function of Notch2 signaling in AGS and IHBD development, Notch2ICD expression was induced in hepatoblasts. Hepatoblasts are the bipotential progenitors in the liver that give rise to either hepatocytes or biliary epithelial cells (BECs) that undergo tubulogenesis to form IHBDs. I observed that ectopic Notch2ICD expression in hepatoblasts induces biliary epithelial cell (BEC) differentiation, tubulogenesis of IHBDs, and BEC survival. These findings shed light on the role for Notch2 in AGS, since they provide an explanation why AGS patients with Notch2 mutations suffer from impaired IHBD development.
It is believed that GBM originates from glioma stem cells (GSCs) which can derive from developmentally stalled neural stem cells (NSCs). Thus, I addressed whether Notch2 plays a role in regulating NSC proliferation and differentiation, possibly predisposing NSCs to become GSCs and eventually GBMs. Therefore, I generated mice that ectopically express activated Notch2 in NSCs and compared the induced molecular alterations to those in GSCs from GBM cell lines and primary GBM biopsies. I show that key features of GSCs, such as increased proliferation and astrocytic lineage commitment, are induced by ectopic Notch2 signaling in NSCs. Aberrant Notch2 expression may therefore predispose NSCs to become GSCs that give rise to GBMs. Moreover, Notch2 signaling enhanced survival of GBM cells, possibly explaining the increased aggressiveness of GBMs with high Notch2 levels. Therefore, blockade of Notch2 signaling may interfere with GBM cell survival, and the formation and proliferation of GSCs and thus be of therapeutic benefit for the treatment of GBMs, for which no cure is available yet.