During development, oligodendrocytes (OLGs), the myelinating cells of the central nervous system (CNS), undergo a stepwise progression during which OLG progenitors, specified from neural stem/progenitor cells, differentiate into fully mature myelinating OLGs. This progression along the OLG lineage is characterized by well-synchronized changes in morphology and gene expression patterns. The studies presented in this dissertation identified the extracellular factor Autotaxin (ATX) as a novel upstream signal modulating HDAC1/2 activity and gene expression in cells of the OLG lineage. Using the zebrafish as an in vivo model system, as well as rodent primary OLG cultures, this functional property of ATX was found to be mediated by its lysoPLD activity, which has been well-characterized to generate the lipid signaling molecule lysophosphatidic acid (LPA). LPA binds to Gprotein-coupled LPA receptors (LPARs) on the surface of OLGs to initiate downstream signaling events. ATX’s lysoPLD activity was found to modulate HDAC1/2 regulated gene expression during a time window coinciding with the transition from OLG progenitor to early differentiating OLG. When looking further downstream of the ATX-LPA axis, down-regulation of LPA receptor 6 (LPA6) was found to reduce the expression of OLG differentiation genes as well as the overall process network area of OLGs. Thus, LPA6 plays a role in both the gene expression and morphology changes seen in OLG differentiation. These findings prove useful for future therapeutic targets needed for demyelinating diseases of the CNS such as Multiple Sclerosis (MS), in which OLGs fail to differentiate into mature OLGs, needed for remyelination.
Additionally, white matter injury has been frequently reported in HIV+ patients. Previous studies showed that HIV-1 Tat (transactivator of transcription), a viral protein that is produced and secreted by HIV-infected cells, is a toxic factor to OLGs. We show here that Tat treatment reduces the expression of OLG differentiation genes and the overall process network area of OLGs. Additionally, Tat-treated OLGs have reduced ATX lysoPLD activity and there is a physical interaction between Tat and ATX. Together, these data strongly suggest functional implications of Tat blocking ATX’s lysoPLD activities and thus the ATX-LPA signaling axis proves to play a significant role in the development of OLGs.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-5142 |
| Date | 01 January 2016 |
| Creators | Wheeler, Natalie A |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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