Malignant brain tumors are diseases with poor prognosis and/or severe long-term side effects of treatment. This thesis aimed to discover novel regulators in brain tumor development, based on studying neural stem cell and progenitor cell (NSPC) differentiation and using animal models to introduce new insights to mechanisms of human brain tumors. The enzyme heparanase (HPSE) that degrades heparan sulfate (HS) is active in cell signaling and ECM remodeling. In paper I, we found an enhanced differentiation to oligodendrocytes in ES cell-derived NSPCs overexpressing HPSE. Further analysis suggested that this enhanced formation of oligodendrocytes was associated with alterations in receptor tyrosine kinase signaling, and that HPSE might also exert anti-apoptotic functions. Subsequently, in paper II we studied the involvement of HPSE in glioma development. We observed that high HPSE levels associated with poor survival in glioma patients. In experimental models, we found that HPSE promoted glioma growth, and that an inhibitor of HPSE reduced glioma progression both in vitro and in vivo. We hypothesize that regulators in NSPC differentiation could have a potential role in brain tumor development. In paper III, we explored the function of NRBP2, a pseudokinase that is up-regulated during NSPC differentiation. We found low expression of NRBP2 in brain tumors, in comparison to normal brain. In medulloblastoma, in particular, low NRBP2 expression is linked to poor prognosis. Overexpression of NRBP2 in medulloblastoma cells led to impaired cell growth and migration, concomitant with an increased cell death. In paper IV, we searched for novel glioma susceptibility genes by sequencing dog breeds from the same ancestor but with different glioma incidence. In this way we identified three new glioma-associated genes. Two of these are significantly regulated in human glioma and one of those might have a role in glioblastoma stem cell differentiation.

Neural stem cell self-renewal and differentiation are tightly regulated events during CNS development, leading to cell division into new neural stem cells or the formation of neurons and glial cells. This thesis focuses on the cellular responses induced by known and novel factors in neural stem and progenitor cells (NSPCs). Platelet-derived growth factor (PDGF) signaling has previously been implicated in NSPC regulation as well as in tumor formation. In order to evaluate the differentiation process and find new regulators of NSPCs a micro-array screen was performed, evaluating transcription during normal differentiation and the effect of PDGF-AA in this process. The transcriptional profile of PDGF-AA treated NSPCs was shown to be an intermediate between the profiles of neural stem cells and their progeny. The NSPC transcriptome was also found to have similarities with that of experimental glioma. A previously non-characterized transcript, the nuclear receptor binding protein 2 (NRBP2), was identified and found to be expressed in the developing and adult mouse brain and in medulloblastoma. NRBP2 down-regulation rendered neural progenitors sensitive to induced cell death. Different PDGF ligands interact with different combinations of PDGF receptors. Therefore NSPCs were stimulated with either PDGF-AA or -BB to further evaluate cellular responses with regard to the two specific isoforms. A divergent effect between the two isoforms in long-term proliferation and cell survival was found, with PDGF-BB being the most efficient stimulator. Stem cell factor (SCF) has previously been identified as a regulator in the hematopoietic system and we showed that SCF induces a migratory response in NSPCs. In addition, SCF positively affected cell survival but had no effect on NSPC differentiation. Insights into the regulatory mechanisms involved in neural stem cell signaling are needed to develop diagnostic tools and novel treatments.