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

Nature Cell Biology volume 11, pages 1024–1030 (2009)Cite this article

Abstract

During development, axon growth rates are precisely regulated to provide temporal control over pathfinding1,2. 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 regulator3. 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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Figure 1: Local protein translation is required for NGF signalling.
Figure 2: Proteins constituting the polarity complex are localized to growth cones of DRG and DSC neurons after axon formation.
Figure 3: Signalling through the PAR complex is required for stimulated axon growth.
Figure 4: Par3 mRNA is localized to axons and growth cones, and locally translated in response to NGF.
Figure 5: Local translation of PAR3 is required for NGF signalling.

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Acknowledgements

We thank T. Pawson (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Canada) for the PAR6 antibody, S. Schlesinger and A. Jeromin for Sindbis plasmids, J. Harris (University of California Irvine, USA), for preparing masters for casting microfluidic chambers and members of the Jaffrey laboratory for helpful discussions. This research was supported by the National Institute of Neurological Diseases and Stroke, a Klingenstein Fellowship in the Neurosciences, Irma T. Hirschl and Monique Weill-Caulier Trusts Career Scientist Award, the New York State Spinal Cord Injury Research Board (S.R.J.), a predoctoral fellowship from Boehringer Ingelheim Fonds (A.D.), a fellowship from the Paralysis Project of America and a Pathway to Independence Award (K99) from the National Institute of Mental Health (U.H.).

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Authors and Affiliations

  1. Department of Pharmacology, Weill Medical College, Cornell University, 10065, NY, USA

    Ulrich Hengst, Alessia Deglincerti & Samie R. Jaffrey

  2. Department of Biomedical Engineering, University of California, Irvine, 92697, CA, USA

    Hyung Joon Kim

  3. School of Mechanical & Aerospace Engineering, Seoul National University, 151-742, Seoul, Korea

    Noo Li Jeon

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  1. Ulrich Hengst
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Contributions

U.H. and S.R.J. designed the experiments and wrote the manuscript. U.H. and A.D. performed the experiments and collected and analysed data. U.H. prepared the figures. H.J.K . and N.L.J. designed microfluidic chambers and provided assistance with their manufacture and use.

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Correspondence to Samie R. Jaffrey.

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Hengst, U., Deglincerti, A., Kim, H. et al. Axonal elongation triggered by stimulus-induced local translation of a polarity complex protein. Nat Cell Biol 11, 1024–1030 (2009). https://doi.org/10.1038/ncb1916

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