Tchorz, Jan Stephan. Notch2 signaling in development and cancer. 2012, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_9931
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.
|Committee Members:||Rüegg, Markus A.|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Division of Physiology > Molecular Neurobiology Synaptic Plasticity (Bettler)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||77 S.|
|Last Modified:||30 Jun 2016 10:49|
|Deposited On:||24 Jul 2012 12:02|
Repository Staff Only: item control page