Axonal elongation triggered by stimulus-induced local translation of a polarity complex protein.

Department of Pharmacology, Weill Medical College, Cornell University, NY 10065, USA.
Nature Cell Biology (Impact Factor: 20.06). 09/2009; 11(8):1024-30. DOI: 10.1038/ncb1916
Source: PubMed

ABSTRACT During development, axon growth rates are precisely regulated to provide temporal control over pathfinding. The precise temporal regulation of axonal growth is a key step in the formation of functional synapses and the proper patterning of the nervous system. The rate of axonal elongation is increased by factors such as netrin-1 and nerve growth factor (NGF), which stimulate axon outgrowth using incompletely defined pathways. To clarify the mechanism of netrin-1- and NGF-stimulated axon growth, we explored the role of local protein translation. We found that intra-axonal protein translation is required for stimulated, but not basal, axon outgrowth. To identify the mechanism of translation-dependent outgrowth, we examined the PAR complex, a cytoskeleton regulator. We found that the PAR complex, like local translation, is required for stimulated, but not basal, outgrowth. Par3 mRNA is localized to developing axons, and NGF and netrin-1 trigger its local translation. Selective ablation of Par3 mRNA from axons abolishes the outgrowth-promoting effect of NGF. These results identify a new role for local translation and the PAR complex in axonal outgrowth.

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    ABSTRACT: Localized protein synthesis is a mechanism by which morphologically polarized cells react in a spatially confined and temporally acute manner to changes in their environment. During the development of the nervous system intra-axonal protein synthesis is crucial for the establishment of neuronal connections. In contrast, mature axons have long been considered as translationally inactive but upon nerve injury or under neurodegenerative conditions specific subsets of mRNAs are recruited into axons and locally translated. Intra-axonally synthesized proteins can have pathogenic or restorative and regenerative functions, and thus targeting the axonal translatome might have therapeutic value, for example in the treatment of spinal cord injury or Alzheimer's disease. In the case of Alzheimer's disease the local synthesis of the stress response transcription factor activating transcription factor 4 mediates the long-range retrograde spread of pathology across the brain, and inhibition of local Atf4 translation downstream of the integrated stress response might interfere with this spread. Several molecular tools and approaches have been developed to target specifically the axonal translatome by either overexposing proteins locally in axons or, conversely, knocking down selectively axonally localized mRNAs. Many questions about axonal translation remain to be answered, especially with regard to the mechanisms establishing specificity but, nevertheless, targeting the axonal translatome is a promising novel avenue to pursue in the development for future therapies for various neurological conditions.
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