Date of Award

Spring 2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Judith Grinspan

Abstract

Abstract

The Role of Wnt Signaling in Oligodendrocyte Development

Keith Feigenson

Judith Grinspan, Ph.D.

The developmental regulation of the central nervous system is established through a complex network of signaling factors that control the timing of cell generation, specification, migration, and differentiation. Oligodendrocytes, the myelinating cells of the central nervous system, originate during embryonic stages in ventricular zones and are responsive to many of these inductive and inhibitory signals as they migrate, mature, and interact with axons. The specific timing and regulation of these actions are critical to axonal conductance. Many signals that promote oligodendrocyte specification and differentiation are active ventrally, and more recent studies have examined the less well known actions of several inhibitory dorsal signaling factors, among these the Bone morphogenic proteins (BMPs) and Wnt signaling factors.

I investigated the role of the canonical Wnt signaling pathway in oligodendrocyte development, both in vivo and in vitro. In primary oligodendrocyte precursor culture systems, canonical Wnt activity inhibits the differentiation of precursors, maintaining them in the precursor stage without causing a change in proliferation, cell death, or cell fate determination. Following these studies, I generated mice with a gain of function Wnt signaling mutation targeted to cells of oligodendroglial lineage. These mice had significant delays in myelin forming cell development early in development, but seemed to recover upon reaching adulthood. Together, these findings indicate that Wnt activity is sufficient to delay oligodendrocyte maturation in vivo and in vivo.

I also investigated the interaction between the Wnt and BMP signaling pathways during oligodendrocyte development. Using pharmacological and genetic paradigms, I found that when the canonical BMP signaling pathway is abrogated, neither BMP nor Wnt manipulation has any effect on oligodendrocyte differentiation in culture. In contrast, blocking the canonical Wnt signaling pathway does not limit the activities of BMP, suggesting that the effect of Wnt signaling on oligodendrocyte development is dependent on BMP signaling, but not vice versa. These two facets of my thesis offer insight into the signaling mechanisms regulating the timing of oligodendrocyte development, and could have implications for the treatment of demyelinating disorders and central nervous system injury.

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