Blomfield, Isabelle Maria;
(2019)
Investigating the molecular regulation of adult neural stem cell quiescence.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Quiescence is essential for long-term maintenance of adult stem cells and tissue homeostasis. The adult mammalian brain was recently discovered to harbour populations of neural stem cells in at least two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricles, and the subgranular zone (SGZ) of the hippocampus. Adult hippocampal neural stem cells (AHNSCs) are a mostly quiescent population, whose activation is tightly controlled by a complex range of signals derived from their niche. How exactly these signals are interpreted by AHNSCs to regulate quiescence is not fully understood. The proneural bHLH transcription factor Ascl1 is crucial for AHNSC activation, and degradation of Ascl1 protein by the E3 ubiquitin ligase Huwe1 is an important mechanism to allow active neural stem cells to return to quiescence. Here I present the discovery that Ascl1 is unexpectedly expressed and transcribed in quiescent NSCs in vivo, and is suppressed at the protein level to maintain quiescence of NSCs. In order to investigate the molecular mechanisms regulating AHNSC quiescence, and to circumvent the complexities of the neurogenic niche, we have developed an in vitro model of AHNSC quiescence. We have found that the in vitro model robustly reproduces the quiescent stem cell state of NSCs in vivo. We undertook a candidate approach to identify regulators of Ascl1 protein and NSC quiescence and identified the inhibitor of differentiation (Id) protein, Id4, as a novel quiescence factor. Functional studies in vitro in combination with genetic approaches in vivo confirmed that Id4 is expressed in quiescent hippocampal NSCs, maintains NSC quiescence, and mediates the inhibition of Ascl1 protein in quiescent NSCs, by sequestration of its E-protein binding partners. Finally, we investigated the niche signals regulating Id4 expression, and discovered that it is regulated in a complex manner likely by more than one signalling pathway.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating the molecular regulation of adult neural stem cell quiescence |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10067164 |
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