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Dissertation Information for Aaron Daniel Pilling

NAME:
- Aaron Daniel Pilling

DEGREE:
- Ph.D.

DISCIPLINE:
- Molecular Biology

SCHOOL:
- Indiana University (USA) (2005)

ADVISORS:
- None

COMMITTEE MEMBERS:
- None

MPACT Status: Incomplete - Not_Inspected

Title: Analysis of the role of kinesin-1 and cytoplasmic dynein in axonal organelle transport in Drosophila melanogaster

Abstract: Neurons are highly elongated and polarized cells. To maintain their length and polarity, neurons employ a diverse set of force-generating motor proteins to drive the transport and localization of specific components. Kinesin-1 and Cytoplasmic Dynein are major motor proteins found in neurons. Both bind to specific cargoes (organelles, proteins, and RNAs) and move them along microtubule filaments. Microtubules are polarized structures with a dynamic fast-growing plus-end and a slow-growing minus-end. In axons, microtubules are oriented uniformly with plus-ends directed distally toward axon terminals. This organization helps neurons maintain functionally important asymmetric cargo distributions because individual microtubule motors move only in one direction. Kinesin-1 transports materials from cell bodies toward axon terminals (anterograde). Cytoplasmic Dynein transports material in the opposite direction from axon terminals toward cell bodies (retrograde). There are important questions about the functions of Kinesin-1 and Dynein in neurons. Which cargos do the motors move? How are they linked to specific cargoes? Finally, how are the activities of Kinesin-1 and Dynein regulated/coordinated to generate cargo asymmetries that are essential for neuronal function? To address these questions, I have developed a system to analyze axonal transport in living Drosophila neurons. Using molecular biology, microscopy, and computational techniques, I have analyzed mechanisms for axonal transport of mitochondria and vesicles. Mitochondria are involved in energy production, signaling, and Ca +2 homeostasis. Vesicles are involved in signaling and recycling. Both organelles are essential for neuronal function. Using classical genetic and other techniques, I have focused on the roles of kinesin-1 and cytoplasmic dynein in mitochondrial and vesicle transport. Cytoplasmic dynein carries mitochondria and vesicles toward neuronal cell bodies. Kinesin-1 carries mitochondria and vesicles toward axon terminals. Because of their directional programming, dynein-driven organelle motion requires the function of kinesin-1. Disruptions in kinesin-1 cause defects in dynein-driven retrograde transport. Dynein components, which are themselves incapable of moving toward microtubule plus-ends, may require kinesin-1 to get into axons and axon terminals. The relationship between Kinesin-1 and Dynein also goes the other way. Disruptions in a dynein regulator, dynactin, influence kinesin-1-based transport. The coupling between kinesin-1 and cytoplasmic dynein may be mediated by the p150 Glued subunit of Dynactin and mitochondrial physiology may regulate the activity of kinesin-1 and cytoplasmic dynein on mitochondria.

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