The proposal focuses upon the role of mRNA translational control during nerve regeneration. It has become increasingly clear that the translation of mRNA into its protein product is a regulated and, often times, specific process. Additionally, localization of mRNAs to particular regions of the cell provides a means to spatially regulate mRNA translation. There are examples for both temporal and spatial regulation of neuronal protein synthesis. Protein synthesis within dendrites has recieved much attention in recent years, but only immature neurons were thought to be capable of intra-axonal protein synthesis. Preliminary data from our laboratory indicate that protein synthesis occurs directly within regenerating axons of adult sensory neurons. Moreover, the rapid axonal regeneration from conditioned sensory neurons occurs by translational regulation of existing neuronal mRNAs. Taken together, these findings suggest that temporal and spatial regulation of protein synthesis occurs during axonal regeneration from adult neurons. In this proposal we will address the role of temporal and spatial regulation of protein synthesis during axonal regeneration. We have two specific aims. In the first aim, we will take two different approaches to determine what mRNAs are translationally regulated in the conditioned sensory neuron cultures. First, we will focus upon the translational regulation of mRNAs for cytoskeletal and growth-associated proteins in the conditioned neurons. We reason that the neuron will need more of these proteins to extend axons. Second, we will use polysomal RNAs from the conditioned and naive DRG neurons to probe cDNA arrays. In this second aim, we will use a tissue culture model developed by Torre and Steward (1992) to specifically clone intra-axonal mRNAs from conditioned sensory neurons. We will identify these intra-axonal mRNAs and prove that they are translated directly within axons.
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