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Characterising the role of canonical Wnt signalling in adult hippocampal stem cells

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Title: Characterising the role of canonical Wnt signalling in adult hippocampal stem cells
Authors: Austin, Sophie Hannah Luxon
Item Type: Thesis or dissertation
Abstract: Adult neurogenesis is the continuous process of generating new neurons from neural precursors in the adult mammalian brain. Adult hippocampal neurogenesis plays a role in modulating mood and memory and its dysregulation during ageing and disease highlights important clinical and therapeutic implications in understanding how it is regulated. Adult hippocampal neurogenesis begins with a multipotent population of adult hippocampal stem cells (AHSCs) that are largely quiescent to ensure the long-term maintenance of the AHSC pool. AHSCs’ activation is tightly regulated by signals from the surrounding niche to ensure correct initiation of adult hippocampal neurogenesis. Canonical Wnt signalling is present within the hippocampal neurogenic niche, however its’ role during adult hippocampal neurogenesis still remains unclear. Within the current literature Wnt has been postulated to play contradictory roles in promoting neural precursor self-renewal whilst also instructing neuronal commitment and differentiation. It is also unclear if and how Wnt signalling directly affects both quiescent and active AHSCs and whether it plays a role in regulating the switch between these two AHSC states. As such, the aim of this project is to characterise the role of canonical Wnt signalling in quiescent and active AHSCs. Using BATGAL Wnt reporter mice and an in vitro model of active and quiescent adult hippocampal stem and progenitor cells (AHSPCs), I found that AHSCs in both states respond to canonical Wnt in a heterogeneous manner. This suggests that AHSCs’ response to Wnt signalling is independent of their activation state in vivo and in vitro. I found that inhibiting AHSCs’ response to canonical Wnt signalling, by deleting beta-catenin, did not affect AHSC maintenance and function in vitro or in vivo. This indicates that intact canonical Wnt signalling is not required to maintain AHSC homeostasis, which contrasts published reports showing that loss of intact canonical Wnt signalling impairs AHSC maintenance and proliferation. I also found that stimulating canonical Wnt signalling in active AHSPCs initiates neuronal differentiation, whereas the same level of Wnt stimulation in quiescent AHSPCs promotes proliferation. This indicates that AHSPCs respond in a state-specific manner to the same level of canonical Wnt simulation. In addition, a higher level of Wnt stimulation promotes neuronal differentiation of quiescent AHSPCs, indicating that quiescent AHSPCs respond to stimulated canonical Wnt signalling in a dose-dependent manner. This state-specific and dose-dependent response to stimulated canonical Wnt signalling could reconcile the contradictions in the current literature as to the role of canonical Wnt signalling in AHSCs. It could also provide a possible mechanism describing how active and quiescent AHSCs coordinate their response to a niche-derived signal to meet the neurogenic demands of the hippocampus. Finally, I used an in vivo model to stimulate canonical Wnt signalling in AHSCs by stabilising beta-catenin. However, I found that stabilising beta-catenin in AHSCs in vivo promotes their displacement from their correct niche location and impairs adult hippocampal neurogenesis. This displacement could be due to beta-catenin’s role in cell-cell adhesion and highlights the importance of maintaining cell adhesion properties to ensure correct adult hippocampal neurogenesis.
Content Version: Open Access
Issue Date: Mar-2020
Date Awarded: Aug-2020
URI: http://hdl.handle.net/10044/1/82126
DOI: https://doi.org/10.25560/82126
Copyright Statement: Creative Commons Attribution NonCommercial Licence
Supervisor: Guillemot, François
Rodriguez, Tristan
Sponsor/Funder: Francis Crick Institute
Department: Institute of Clinical Sciences
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Department of Clinical Sciences PhD Theses



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