Date of Award

5-11-2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biological Sciences

First Advisor

Porter, Lisa

Keywords

Cell Cycle, Central Nervous System, Reprogramming, Stem Cells

Rights

CC-BY-NC-ND

Abstract

At a cellular level, neurogenesis relies on homeostasis in the brain, allowing neural stem cell (NSC) populations to maintain their pool throughout life, while remaining capable of re-entering the cell cycle during periods of time when there is a demand for cells to be repopulated. The cell cycle lies at the center of these decisions and alterations to the cell cycle prove costly. The cyclin-like protein Spy1 can bind and activate cyclin dependent kinases (CDKs) 1 and 2 in a unique manner to promote cell cycle progression. Spy1 can target p27 for degradation and overcomes checkpoints introduced by DNA damage, thus leading to enhanced cell proliferation. Previous data implicates Spy1 in the brain tumour initiating CD133+ population of aggressive glioblastoma multiforme (GBM). This suggests a role for Spy1 in normal NSCs as well impairments in cognitive functions and potentially development of tumourigenesis. This work describes the development and characterization of a novel transgenic mouse model to study Spy1 in the Nestin-positive NSCs of neurogenic regions of the brain. Using this newly generated NTA-Spy1 mouse we have shown that elevated levels of Spy1 in NSCs increases proliferation, decreases differentiation capacity, increases self-renewal leading to impaired memory recognition. We demonstrate that when cultured in vitro and damaged by ultraviolet (UV) irradiation, NSCs down-regulate and bypass class DNA damage repair pathways. Lastly, we link mechanisms of Spy1 stem cell maintenance as potential regulators of reprogramming to induce pluripotency. We demonstrate increased reprogramming efficiency as a result of the role of Spy1 in epigenetic regulation. Collectively, these results may provide a better understanding of molecular mechanisms that drive abnormal cell growth and division in reprogramming and NSCs.

Available for download on Monday, June 03, 2019

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