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p53 restricts injury-induced plasticity in cortical astrocytes

Simpson Ragdale, Holly; (2020) p53 restricts injury-induced plasticity in cortical astrocytes. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Following injury, cortical astrocytes acquire neurogenic potential when explanted in vitro, but remain restricted to their own lineage in vivo. This lineage barrier can be fully transgressed in tumourigenesis, however the mechanisms that restrict normal astrocyte plasticity or how they are subverted by oncogenic insults are poorly defined. In this thesis, I have demonstrated that loss of the tumour suppressor gene p53 is sufficient to relax astrocyte identity. I found that in vitro, loss of p53 fully dedifferentiates astrocytes to neural stem-like cells in the presence of mitogens. Using single cell RNA sequencing I described the biological changes that underlie this process, revealing that dedifferentiating astrocytes undergo actin remodelling, followed by enhanced ribosomal biogenesis before reaching a highly proliferative, stem-like state. ChIP-sequencing of wildtype astrocytes indicated that p53 does not supress dedifferentiation by directly repressing a neurogenic program or maintaining glial fate. Instead, pathway analysis and loss-of-function experiments revealed that p53 null astrocytes increase expression of EGFR and its downstream signalling sensitising them to EGF and leading to ERK-dependent dedifferentiation. In vivo, p53 loss was induced in cortical astrocytes by stereotaxic injection, and led to some astrocytes retracting their processes and downregulating lineage markers, indicative of a change in cellular identity. Interestingly, these non-astrocytic cells were located very close to the injection wound site, suggesting that, as in vitro, extrinsic injury signals cooperate with p53 loss to drive this phenotype. Consistent with this, increasing EGF levels at the injury site through local infusion, resulted in complete dedifferentiation of p53-deficient astrocytes to a proliferative, stem-like state. Thus, injury signals cooperate with tumour-initiating mutations to increase astrocyte plasticity. This work suggests a possible mechanism of tumour initiation in the adult brain, with important implications for the aetiology and treatment of brain cancer.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: p53 restricts injury-induced plasticity in cortical astrocytes
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 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 > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/10089861
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