Ortiz-Sanchez, Marco Antonio;
(2020)
Role of Sonic Hedgehog signalling in regulating neural stem cell activity in the adult and aged murine hippocampus.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The homeostatic behaviour of neural stem cells (NSCs) in the adult hippocampus is controlled by signals from the niche. In young mice, the activation of dormant NSCs is typically followed by consecutive divisions producing neuronal progenitors followed by astrocyte differentiation, resulting in a rapid depletion of the NSC population. In a subset of active NSCs, however, the proactivation factor ASCL1 is degraded by the ubiquitinligase HUWE1, resulting in the return of these NSCs to a transient state of quiescence. These resting NSCs show a high propensity to reactivate and are essential for the maintenance of neurogenesis. How niche signals control the generation of the different NSC populations in appropriate ratios to ensure the long-term maintenance of neurogenesis is unknown. In my thesis, I have studied the regulation of NSC activity in the adult and mature mouse hippocampus by Sonic hedgehog (Shh) signalling. Firstly, I show that NSCs are able to respond to Shh signalling and that in young mice, this promotes activation of dormant NSCs and suppresses the formation of resting NSCs by inhibiting HUWE1-mediated degradation of ASCL1. In older mice, however, I show that Shh signalling activity diminishes progressively, which slows down the rate of NSC depletion. Finally, I identify oligodendrocyte cells as a cellular source of Shh in the adult hippocampus. My results provide cellular and molecular insights into the preservation of the hippocampal NSC pool in mature mice.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Role of Sonic Hedgehog signalling in regulating neural stem cell activity in the adult and aged murine hippocampus |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10097941 |
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