mRNA transport and local translation after axotomy

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DESCRIPTION (provided by applicant): Neurons can spatially regulate gene expression by targeting mRNAs to subcellular domains to locally generate new proteins. Although best characterized in the dendritic compartment, recent studies have proven that the axonal compartment is also capable of local protein synthesis. This localized axonal protein synthesis is regulated by extracellular stimuli that alter axonal growth. From proteomics-based studies, we have identified a substantial number of proteins that are synthesized in the regenerating axons of cultured DRG neurons. This new knowledge of the proteins that are locally synthesized in axons allows us to ask how transport of mRNAs and translation of specific mRNAs is regulated in the axons. The central hypothesis of this proposal is that neurons modulate the protein makeup of axonal subdomains in response to environmental cues by specifically altering transport of mRNAs into, and synthesis of new proteins directly in, growing axons. I will test this hypothesis with two specific aims. First, I will address the regulation of axonal mRNA trafficking by extracellular stimuli and test the hypothesis that transport of mRNAs into the regenerating axon is modulated by extracellular signals acting through receptor-mediated signal transduction pathways. Second, I will test the specificity of intra-axonal protein synthesis and the hypothesis that axonal protein synthesis is differentially regulated by environmental stimuli. I will focus these analyses on axonal mRNAs encoding structural proteins (Beta-actin, peripherin and vimentin) and injury-response proteins (HSP70, grp78/BiP and Importin Beta1) that play central roles in axonal growth.