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Dissertation
Axonal growth, retraction, and growth-cone navigation are regulated by the balance of molecular motor forces within the axon
Doctor of Philosophy (Ph.D.), Drexel University
May 2007
DOI:
https://doi.org/10.17918/00010106
Abstract
During axonal growth, retraction, and growth-cone navigation, the neuronal microtubule array is subjected to molecular motor-based forces that are tighly coordinated with the polarized morphological adaptations of the actin cytomatrix. Within the axon, microtubule-actin interactions drive the advance and retreat of the microtubule array; while within the growth-cone, these same interactions determine the directionality of axonal elongation in response to extracellular signaling cues. These motor-based organizational changes are dependent upon the particular properties of the motor protein, as well as the orientation of the microtubule array. Despite the well documented importance for microtubule-actin interactions, to date there is little evidence regarding the influences of molecular motor forces generated between neuronal microtubules and the actin cytomatrix. My dissertation investigates the balance of motor forces during axonal growth, retraction, and growth-cone navigation. There are three specific aims. Aim 1: Determine the influence of cytoplasmic dynein forces on the transport and organization of axonal microtubules during growth. Aim 2: Characterize the influences of myosin-11 and dynein motor forces on microtubule-actin organization during axonal retraction and growth-cone navigation. Aim 3: Identity how the homotetrameric kinesin-5 motor influences axonal microtubule transport and its relationship to axonal outgrowth and retraction. Methodology for Aim 1 utilized siRNA-based depletion of cytoplasmic dynein, as well as pharmacologic depletion of filamentous actin. These studies revealed that both actin filaments and the dynein motor effect the anterograde transport of short microtubules without influencing retrograde transport. In addition, dynein depletion resulted in a reduction in axonal length and increses in the distance of axonal retraction. Aim 2 combined dynein depletion with pharmacologic inhibition of the myosin-II motor. These studies revealed that dynein motor forces are crucial to proper microtubule invasion of actin-rich growth cone filopodia during growth cone turning, while myosin-II forces act to antagonize dynein's effects on microtubule advance. Aim 3 utilized kinesin-5 siRNA in order to study microtubule transport and neuronal morphology. These investigations revealed that the kinesin-5 motor regulates the bi-directional transport of axonal microtubules and also functions to regulate stepwise axonal growth and retraction.
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Details
- Title
- Axonal growth, retraction, and growth-cone navigation are regulated by the balance of molecular motor forces within the axon
- Creators
- Kenneth A. Myers
- Contributors
- Peter W. Baas (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
- xiv, 194 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; College of Medicine; Drexel University
- Other Identifier
- 991021888959304721