Remyelination is a spontaneous regenerative process whereby myelin sheaths are restored to demyelinated axons. Key players in this process are oligodendrocyte progenitor cells (OPCs), a widespread population of CNS progenitor cells which persist into adulthood. Remyelination is impaired in patients with chronic demyelinating conditions such as Multiple Sclerosis, and as with other regenerative processes, its efficiency declines with increasing age. Hence, there is a need for the development of therapeutic interventions that will aid in promoting endogenous remyelination when the endogenous regenerative potential is compromised. The nuclear receptor RXR$\gamma$ is an important positive regulator of OPC differentiation and an accelerator of endogenous remyelination in aged rats. RXR$\gamma$ functions as a ligand-induced transcription factor and is able to regulate gene transcription. It does so by heterodimerising with other nuclear receptors and recruiting co-regulators involved in chromatin remodelling. However, we lack understanding on the specific mechanism by which RXR$\gamma$ promotes OPC differentiation. With the work presented in this thesis I demonstrate that RXR$\gamma$ function is regulated at multiple signalling levels. Proximity ligation assays revealed that RXR$\gamma$ remains consistently bound to its partners throughout the oligodendrocyte lineage, and the biological relevance of each heterodimer is determined by the dynamic association of co-regulators. This is in turn influenced by ligand presence and subcellular receptor localisation. To identify the genes controlled by RXR$\gamma$ in OPCs I carried out ChIP sequencing, which revealed genes involved in proliferation and cell cycle control. Further functional assessments aided me in the development of a hypothesis whereby RXR$\gamma$ activation does not directly influence oligodendrocyte formation, but rather promotes cell cycle exit thereby accelerating and facilitating OPC differentiation. Altered nuclear receptor expression and ligand presence in ageing OPCs may consequently impair this process. My thesis provides an alternative hypothesis to how RXR$\gamma$ regulates lineage cell progression, highlighting a new avenue in the development of therapeutic interventions targeting generic stem cell functions for which drugs are already FDA approved, rather than oligodendrocyte-specific pathways.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:767819 |
| Date | January 2019 |
| Creators | Di Canio, Ludovica |
| Contributors | Franklin, Robin J. M. ; Wayne, Gareth |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.repository.cam.ac.uk/handle/1810/289129 |
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