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Title: p53 is a hub for the integration of multiple vascular quiescence signals in the subventricular zone stem cell niche
Author: Davies, Timothy
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Neurogenesis is the process by which new neurons are produced from neural stem cells (NSCs) in the brain. In the adult mammal, the subventricular zone (SVZ) and subgranular zone constitute the two neurogenic areas that continue to produce neurons over the life of the animal. SVZ NSCs (type b cells) reside in a niche which provides them with a host of signals that co-ordinate their behaviour. Type b cells are maintained in a quiescent, non-dividing state, in part through contact dependent signals supplied by vascular endothelial cells. I performed a mass spectroscopy screen to identify factors expressed by endothelial cells that enforce NSC quiescence, and showed that ephrin B2 and BMP4 are the main endothelial quiescence signals in vitro. To ascertain how these signals are transduced, I performed RNA sequencing of NSCs grown in co-culture with endothelial cells. This showed p53 as a key transducer of endothelial quiescence signals. Both ephrin B2 and BMP4 were found to be dependent on p53 for their quiescence activity. Interestingly, enquiry into signalling downstream of p53 showed that proliferative arrest is independent of its canonical effector p21. In contrast, p53 was found to regulate levels of EGFR, and BMP4 caused a reduction in EGFR which is abrogated upon loss of p53. Thus, p53 may control NSC quiescence at least in part through controlling levels of EGFR in response to endothelial BMP4. Despite indications that p53 is important for transducing endothelial quiescence signals in vitro, acute loss of p53 in type b cells in vivo had no effect on the number of proliferating type b cells. Finally, I describe work performed establishing super-resolution imaging techniques to enquire into morphological changes following type b cell activation. Thus, this thesis makes a contribution to our understanding of the regulation of neural stem cell quiescence by the SVZ vascular niche.
Supervisor: Parrinello, Simona Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral