It has become accepted that the axonal compartment can autonomously synthesize proteins. This local translation provides the axon with a renewable source of proteins to respond to extracellular stimuli. Studies from the Pi's group have shown that axonal protein synthesis is triggered by neural injury and that particularly robust protein synthesis occurs in regenerating axons. This localized protein synthesis represents a mechanism that can likely be harnessed to facilitate the regeneration of axons in the adult nervous system. Despite the obvious functional significance and newly increased interests in axonal protein synthesis, we little understanding of how this process is regulated. Our preliminary studies indicate that adult axons have the potential to synthesize a complex population of more than 200 different proteins; there is clearly some specificity to choose which proteins are generated when and where. The objective of this proposal is to determine how this axonal protein synthesis is regulated. We hypothesize that axonal stimulation alters localized protein synthesis through both directing the transport of particular mRNAs into the axonal compartment and locally controlling the activity of the axonal translational machinery.
In Aim 1, we will determine how axonal guidance cues and growth promoting stimuli modify specificity of axonal protein synthesis. The contributions of axonal transport vs. localized synthesis will be determined for each axonally synthesized protein identified. The physiological consequences of localized synthesis of these proteins in axonal growth will be addressed.
In Aim 2 we will ask how the axon controls synthesis of organelle and membrane proteins and the functional relevance of these pathways to nerve regeneration. Nerve regeneration is abysmally slow and rarely successful. It has recently been recognized that injured nerve processes are capable of generating their own proteins. Our studies indicate that this may be used to enhance recovery after injury of the nervous system. The objective of this grant application is to determine how local protein synthesis in nerve processes is regulated by extracellular stimuli. ? ? ?
| Overman, Justine J; Clarkson, Andrew N; Wanner, Ina B et al. (2012) A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke. Proc Natl Acad Sci U S A 109:E2230-9 |
| Barrientos, Sebastian A; Martinez, Nicolas W; Yoo, Soonmoon et al. (2011) Axonal degeneration is mediated by the mitochondrial permeability transition pore. J Neurosci 31:966-78 |
| Donnelly, Christopher J; Willis, Dianna E; Xu, Mei et al. (2011) Limited availability of ZBP1 restricts axonal mRNA localization and nerve regeneration capacity. EMBO J 30:4665-77 |
| Willis, Dianna E; Twiss, Jeffery L (2011) Profiling axonal mRNA transport. Methods Mol Biol 714:335-52 |
| Li, Songlin; Overman, Justine J; Katsman, Diana et al. (2010) An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke. Nat Neurosci 13:1496-504 |
| Donnelly, Christopher J; Fainzilber, Mike; Twiss, Jeffery L (2010) Subcellular communication through RNA transport and localized protein synthesis. Traffic 11:1498-505 |
| Vuppalanchi, Deepika; Coleman, Jennifer; Yoo, Soonmoon et al. (2010) Conserved 3'-untranslated region sequences direct subcellular localization of chaperone protein mRNAs in neurons. J Biol Chem 285:18025-38 |
| Willis, Dianna E; Twiss, Jeffery L (2010) Regulation of protein levels in subcellular domains through mRNA transport and localized translation. Mol Cell Proteomics 9:952-62 |
| Rosenzweig, Ephron S; Courtine, Gregoire; Jindrich, Devin L et al. (2010) Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nat Neurosci 13:1505-10 |
| Yoo, Soonmoon; van Niekerk, Erna A; Merianda, Tanuja T et al. (2010) Dynamics of axonal mRNA transport and implications for peripheral nerve regeneration. Exp Neurol 223:19-27 |
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