Defense Date

2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Neuroscience

First Advisor

Babette Fuss

Abstract

In order for oligodendrocyte progenitor cells (OPCs) to differentiate into fully mature, myelinating oligodendrocytes, they must be specified at the correct times and undergo coordinated changes in both gene expression and morphology. As oligodendrocytes differentiate, they transition from a bipolar morphology into a morphology characterized by a complex network of multiple processes, which will eventually generate membranous structures necessary for myelination of axonal segments. As changes are observed in cellular morphology, oligodendrocytes also undergo changes in their gene expression profile and express genes necessary for both early and later stages of development such as olig1 and myelin basic protein (mbp), respectively. Data from our laboratory demonstrate that autotaxin (ATX), also referred to as phosphodiesterase Iα/autotaxin (PD-Iα/ATX), is involved in all of these processes as a multifunctional protein by regulating lysophospholipid signaling and cell-extracellular matrix interactions. Previously, our laboratory has identified ATX as an oligodendrocyte-secreted factor present in the extracellular environment that via a newly-identified functional domain, named the MORFO domain (modulator of oligodendrocyte remodeling and focal adhesion organization), can regulate adhesion of oligodendrocytes to naturally occurring extracellular matrix (ECM) proteins and ultimately the establishment of the oligodendrocyte’s complex process network. In vitro data presented in this dissertation suggest that lysophosphatidic acid (LPA), via production from ATX’s well characterized lysophospholipase D (lysoPLD) domain, can induce the expression of myelin basic protein (mbp) and the establishment of membranous structures by differentiating oligodendrocytes, both necessary for the initial stages of myelination. Interested in relating these functions to an in vivo model and due to the early embryonic lethality of atx-null mice, we utilized the zebrafish as an in vivo model. The in vivo data presented in this dissertation demonstrate that atx expression in the zebrafish is evolutionarily conserved within vertebrates. Interestingly, in both mouse and the zebrafish, atx was found expressed by cells of the cephalic floor plate in addition to differentiating oligodendrocytes. Functionally the in vivo data presented in this dissertation confirmed ATX’s role in stimulating mbp expression during later stages of oligodendrocyte development. In addition, a novel function for ATX was revealed by the studies undertaken as part of this dissertation that has never been described before. More specifically, based on the timing of atx expression and the phenotype seen upon atx knock-down, the data presented here suggest that ATX, released by the cephalic floor plate, regulates early oligodendrocyte development and/or specification. Taken together, these data identify ATX as a major regulator for early as well as late developmental stages of the oligodendrocyte lineage.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-17-2010

Included in

Neurosciences Commons

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