A, Deli; (2017) The role of promyelocytic leukemia (PML) protein in regulation of adult subventricular zone neurogenesis. Doctoral thesis , UCL (University College London).

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Abstract

The control of cell fate in neural progenitor/stem cells (NPCs/NSCs) is essential for central nervous system (CNS) development. NSCs are also found within the adult brain. In particular, NSCs in the subventricular zone (SVZ) migrate through the rostral migratory stream (RMS) and terminally differentiate in the olfactory bulb (OB). However, our understanding of mechanisms regulating cell migration during SVZ neurogenesis remains limited. Previous work from our lab showed that the promyelocytic leukaemia protein (PML), a growth suppressor inactivated in leukaemia, controls cell fate during corticogenesis, with implications for regulation of brain size. The main aim of the present work was to investigate the role of PML in the context of adult SVZ neurogenesis. Our findings show that PML loss leads to reduction of the more primitive NSC pool accompanied by expansion of transit-amplifying NPCs and neuroblasts. However, PML-deficient neuroblasts display impaired migratory capacity through the RMS, thus resulting in reduced number of terminally differentiated neurons and a smaller OB. These changes can be recapitulated in vitro, demonstrating an intrinsic defect of PML KO NSCs. Mechanistically, our findings suggest that PML controls NSC expansion and migration via Polycomb Repressive Complex-2 (PRC-2) - dependent suppression of a transcriptional programme involving the axon guidance genes Slit2/Robo1 and the key epithelial-to-mesenchymal transition (EMT) gene Twist1. Notably, Twist1 is part of an amplification loop for transcriptional induction of Slit2. I was also involved in work aimed at determining whether the PML/Slit axis is functional in neoplastic settings. In this respect, alterations of adult neurogenesis are believed to lead to glioblastoma multiforme (GBM), and tumour spreading through the brain parenchyma is one of key factors underlying GBM aggressiveness. Our work revealed that a PML/Slit axis controls cell migration also in GBM cells, suggesting that mechanisms underlying cell migration are common to normal and neoplastic cells in the CNS. 6 Overall, these findings have important implications for our understanding of adult neurogenesis and may provide novel insights into the process of oncogenesis in the CNS.

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