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Mechanisms of axon pathfinding and survival


The development of functional neuronal circuits occurs via a series of complex events including axon pathfinding and synapse formation followed by selective pruning and refining of these circuits by means of programmed cell death and axon degeneration. The precise molecular machinery that dictates these exquisite development events is not well understood. My thesis study examines the role of Wnt signaling throughout nervous system development. Wnts have recently been identified as axon guidance molecules but the signaling pathways that mediate growth cone turning have yet to be elucidated. Furthermore, is there a connection between these guidance events and subsequent developmental pruning? To study the role of Wnt signaling through these events, I employed a variety of techniques including analysis of genetically modified mice, ex utero electroporation of rat spinal cord cultures, and pharmacological and genetic manipulation of dissociated neuronal cultures. Throughout this study, we will demonstrate that indeed, Wnt signaling mediates multiple events critical for appropriate nervous system development including appropriate anterior-posterior axon guidance of both spinal cord commissural neurons and monoaminergic neurons in the brainstem. In addition, I explored the potential role for an axon guidance pathway in mediating neuron survival. Here I investigate the role of atypical PKC (aPKC) signaling in the survival of developing cortical neurons. Inhibition of aPKC resulted in rapid axon fragmentation. We posit that not only does Wnt proteins serve as guidance cues in the developing nervous system, but that these attractive cues might also serve as trophic signals to developing axons

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