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Title: Understanding the mechanism underlying the neural-to-glial transition in the developing spinal cord
Author: Watson, Thomas
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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In the developing spinal cord, neurons and glia are generated sequentially. In vivo, this process is under tight spatial and temporal control. SOX9, NFIA, and NFIB form the basis of a transcriptional network which coordinates the activation of the glial lineage. However, molecular detail of the regulatory network controlling the timing of their expression is limited. We have developed an in vitro model system using embryonic stem cells that reproduces the dynamics and regulatory relationships observed in vivo. We leverage the in vitro system to investigate the temporal control of the neural-to-glial transition. Previous work has implicated TGF-β and NOTCH signalling in controlling developmental transitions throughout central nervous system development. We used the in vitro system to investigate the role of these pathways in the neural-toglial transition. Manipulating TGF-β signalling shifted the timing of glial lineage activation whilst activating NOTCH signalling was sufficient to induce the expression of glial genes. We suggest that these pathways might form a mechanism by which neuron differentiation instructs developmental progression. Using single-cell transcriptomics, we reconstructed the developmental trajectory of progenitors transitioning to a glial fate. By plotting the transcriptional changes that accompany the transition we identified novel candidate genes involved. Using CRISPR-Cas9 and lentiviral approaches, we test these candidates and investigate their effect on the transition. Through this approach we reveal ZFP536, a transcription factor required for the correct timing of the neural-to-glial transition. ZFP536 is expressed during the transition and regulates SOX9 expression both in vitro and in vivo. Our work provides new understanding of how the timing of the neural-to-glial transition is controlled in the developing spinal cord.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available