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Phosphorylation of Olig2 and the control of stem cell fate choice in the developing spinal cord

Sinclair-Wilson, A; (2015) Phosphorylation of Olig2 and the control of stem cell fate choice in the developing spinal cord. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS), ensheathing axons and enabling the rapid conduction of nerve impulses. In CNS development, lineage-restricted OL precursors (OLPs) arise in discrete regions of the ventricular zone under strict spatial and temporal control. In the embryonic spinal cord, for example, the majority of OLPs derive from a subpopulation of neural stem cells (NSCs) residing in the ventral progenitor of motor neurons (pMN) domain. These pMN domain NSCs are characterized by expression of the basic helix-loop-helix (HLH) transcription factor Olig2 and are also responsible for the generation of all spinal motor neurons (MNs). MN generation precedes OLP generation and it has been shown that phosphorylation of serine 147 (S147) in the HLH domain of Olig2 is a key modulator of the MN-OLP fate switch. During MN production, Olig2 is phosphorylated at S147 and forms Olig2:Olig2 homodimers. Dephosphorylation at S147 induces Olig2 homodimer dissociation and formation of heterodimers, and activates the MN-OLP fate switch. In this Thesis, I present the results of my research into the mechanisms that regulate the dephosphorylation of Olig2 and mediate the impact this has on stem cell fate choice. Analysing the genomic binding sites of phosphorylated wild-type Olig2 and a constitutively dephosphorylated mutant form of Olig2 (Olig2-S147A), I have revealed that S147 phosphorylation has a major impact on Olig2 gene target choice. I have also explored the role of angiogenesis in regulation of the fate switch – both in vitro and in vivo using mouse and zebrafish models of development – and I have identified an inhibitory phosphatase component that is down-regulated over the period of the fate switch and is a candidate regulator of Olig2 S147 dephosphorylation. Finally, I have performed computational analysis of Olig2 phosphorylation and designed and constructed genetic tools for studying the regulation and function of an additional Olig2 phospho-acceptor site at S263.

Type: Thesis (Doctoral)
Title: Phosphorylation of Olig2 and the control of stem cell fate choice in the developing spinal cord
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: 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 Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: https://discovery.ucl.ac.uk/id/eprint/1472153
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