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Previous Article | Next Article
The Journal of Neuroscience, January 1, 2000, 20(1):315-325
Regulation of Calcineurin by Growth Cone Calcium Waves Controls Neurite Extension
Nathan J. Lautermilch and Nicholas C. Spitzer Department of Biology and Center for Molecular Genetics, University of California, San Diego, La Jolla, California 92093-0357
Growth cones generate spontaneous transient elevations of intracellular Ca2+ that regulate the rate of neurite outgrowth. Here we report that these Ca2+ waves inhibit neurite extension via the Ca2+-dependent phosphatase calcineurin (CN) in Xenopus spinal neurons. Pharmacological blockers of CN (cyclosporin A and deltamethrin) and peptide inhibitors of CN [the Xenopus CN (xCN) autoinhibitory domain and African swine fever virus protein A238L] block the Ca2+-dependent reduction of neurite outgrowth in cultured neurons. Time-lapse microscopy of growing neurites demonstrates directly that the reduction in the rate of outgrowth by Ca2+ transients is blocked by cyclosporin A. In contrast, expression of a constitutively active form of xCN in the absence of waves results in shorter neurite lengths similar to those seen in the presence of waves. The developmental expression pattern of xCN transcripts in vivo coincides temporally with axonal pathfinding by spinal neurons, supporting a role of CN in regulating Ca2+-dependent neurite extension in the spinal cord. Ca2+ wave frequency and Ca2+-dependent expression of GABA are not affected by inhibition or activation of CN. However, phosphorylation of the cytoskeletal element GAP-43, which promotes actin polymerization, is reduced by Ca2+ waves and enhanced by suppression of CN activity. CN ultimately acts on the growth cone actin cytoskeleton, because disrupting actin microfilaments with cytochalasin D or stabilizing them with jasplakinolide negates the effects of suppressing or activating CN. Destabilization or stabilization of microtubules with colcemide or taxol results in Ca2+-independent inhibition of neurite outgrowth. The results identify components of the cascade by which Ca2+ waves act to regulate neurite extension.
Key words: axonal outgrowth; calcium transients; actin; microtubules; GAP-43; PP1; PP2A; PP2B
Copyright © 2000 Society for Neuroscience 0270-6474/0/201315-11$05.00/0
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