Fascin in brain development and function

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Project Summary The actin cytoskeleton and its dynamic regulation play an essential role in neuronal development and function. The proposed study aims to investigate the role of Fascin, a family of actin bundling proteins, in brain development and function. Fascin1 exhibits an intriguing expression profile in mammalian brains: it is highly expressed during development but the expression is substantially decreased in the adult brain During development, elongating axons are guided to their specific targets for synaptic connections. Axon pathfinding depends on the motile growth cone at the tip of developing axons, which senses and responds to a variety of extracellular signals to navigate through a complex and changing environment. The first part of the proposed study aims to test the hypothesis that fascin, a family of actin filament bundling proteins, functions in the formation and dynamic regulation of growth cone filopodia during axon guidance. The part of research will take advantage of our expertise in growth cone research, and employment of a multifaceted approach involving imaging, molecular manipulation, and combined assays in cell cultures and ex vivo brain tissues. While fascin1 expression is substantially reduced in adult brains, fascin1 remains highly expressed in adult hippocampus. We will test the exciting hypothesis that fascin1 plays an important role in the formation, maintenance, and remodeling of mossy fiber- CA3 synaptic connections. Using a combination of an in vivo labeling and manipulation, imaging, and electrophysiology, we aim to evaluate and establish, for the first time, the role of fascin1 and its actin bundling in brain development and synaptic regulation in adult brain. Given that elevated fascin1 levels have been associated with cancer cell metastasis, the proposed work on fascin1 will not only provide significant insights into the molecular mechanisms of brain development and function, but also extend our knowledge concerning the actin mechanisms underlying directed cell movement in many physiological and pathological events.