Coupled axonal protein synthesis and lipidation in axon growth and homeostasis

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Axons continuously respond to external signals in their environment as they grow and navigate toward their target tissues during development, and for maintenance and repair in adult life. mRNA localization and local protein synthesis is a conserved mechanism that allows for rapid and axon-autonomous responses to external trophic and guidance cues. Despite growing appreciation for the functions of axonal protein synthesis, a major gap in our knowledge is in understanding how the nascent proteins are further processed and localized in axons to generate fully functional proteins. Our preliminary results suggest that a neurotrophic factor (Nerve Growth Factor) acutely regulates local protein synthesis and lipidation (prenylation) of newly-made proteins in axons. It has been assumed that protein prenylation is a constitutive mechanism that occurs throughout the cytoplasm and is permissive for cellular functions. In striking contrast, we find that, in neurons, prenylation is under exquisite spatio-temporal control by extrinsic signals. The goal of this application is to define whether coupled axonal protein synthesis and prenylation serves as a regulatory mechanism to localize and enrich proteins in axonal compartments to ensure dynamic and spatial responses to extrinsic growth-promoting cues. We will use a combination of imaging, biochemical, and functional analyses in compartmentalized neuronal cultures, as well as in vivo analyses in mice to accomplish this goal. These studies will advance the knowledge of spatial modes of signaling in neurons that underlie axon development, maintenance, and regeneration.