GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules
- 1Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
- 2Neuroregeneration Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
- 3Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
- 4Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
- 5The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
Abstract
Suppression of glycogen synthase kinase 3 (GSK3) activity in neurons yields pleiotropic outcomes, causing both axon growth promotion and inhibition. Previous studies have suggested that specific GSK3 substrates, such as adenomatous polyposis coli (APC) and collapsin response mediator protein 2 (CRMP2), support axon growth by regulating the stability of axonal microtubules (MTs), but the substrate(s) and mechanisms conveying axon growth inhibition remain elusive. Here we show that CLIP (cytoplasmic linker protein)-associated protein (CLASP), originally identified as a MT plus end-binding protein, displays both plus end-binding and lattice-binding activities in nerve growth cones, and reveal that the two MT-binding activities regulate axon growth in an opposing manner: The lattice-binding activity mediates axon growth inhibition induced by suppression of GSK3 activity via preventing MT protrusion into the growth cone periphery, whereas the plus end-binding property supports axon extension via stabilizing the growing ends of axonal MTs. We propose a model in which CLASP transduces GSK3 activity levels to differentially control axon growth by coordinating the stability and configuration of growth cone MTs.
Keywords
- GSK3
- developmental and regenerative axon growth
- growth cone microtubules
- microtubule plus end-tracking proteins
Footnotes
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↵6 Corresponding author.
E-mail fzhou4{at}jhmi.edu.
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.17015911.
- Received May 11, 2011.
- Accepted August 11, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press