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Dissertation
The regulation of the axonal cytoskeleton by extracellular and intrinsic factors
Doctor of Philosophy (Ph.D.), Drexel University
03 Apr 2009
DOI:
https://doi.org/10.17918/00007964
Abstract
Axon extension and branching involves the coordinated regulation of the neuronal cytoskeleton, consisting of microtubules and actin. Growing evidence suggests that extracellular signaling cues contribute to regulating the roles of cytoskeletal proteins. The overall goal of the work presented in this thesis is to explore the effects of two extracellular signaling cues, laminin (LN) and nerve growth factor (NGF), on the neuronal cytoskeleton during axon extension and branching. Myosin II is a mechanoenzyme that generates contractile forces on actin filaments and is thought to regulate multiple aspects of axon extension. However, little is known on how extracellular guidance cues influence the role of myosin II during axon extension. In Chapter II, I report that in the presence of NGF, inhibition of myosin II differentially affects the rate of axon extension on LN and polylysine (PL) in embryonic sensory neurons. The differential effects of myosin II inhibition on axon extension rate are attributable to myosin II having the primary function of mediating substratum attachment on LN, while conversely on PL, the primary function of myosin II is to inhibit microtubule engorgement. In Chapter III, I investigated the requirement of myosin II activity during axon extension on LN in the absence of NGF. In the absence of NGF, inhibition of myosin II results in a loss of microtubules and the termination of axon extension and protrusive activity. Treatment with NGF restores microtubule polymerization, protrusive activity and axon advance even though myosin II is inhibited. The data indicates that NGF provides signals that bypass the strict requirement of myosin II for axon extension in the absence of myosin II activity. In Chapter IV, the mechanism by which NGF induces filopodia formation was addressed. I report that NGF-induced filopodia formation is a result of an increase in the frequency of axonal F-actin patch formation mediated by the PI3K-Akt pathway. In summary the work presented in this thesis contributes to our knowledge of understanding the effects of molecular signals on the neuronal cytoskeleton. This dissertation advances our understanding of the roles of myosin II activity in axon extension and filopodial formation.
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Details
- Title
- The regulation of the axonal cytoskeleton by extracellular and intrinsic factors
- Creators
- Andrea Ruth Ketschek
- Contributors
- Gianluca Gallo (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 158 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; College of Medicine; Drexel University
- Other Identifier
- 991021888741204721