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The Journal of Neuroscience, March 2, 2005, 25(9):2338-2347; doi:10.1523/JNEUROSCI.4889-04.2005

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Development/Plasticity/Repair
Ca²⁺-Dependent Regulation of Rho GTPases Triggers Turning of Nerve Growth Cones

Ming Jin,^1,2 * Chen-bing Guan,^1,2 * Yun-ai Jiang,^1,2 * Gang Chen,^1,2 Chun-tao Zhao,^1,2 Kai Cui,^1,2 Yuan-quan Song,¹ Chien-ping Wu,¹ Mu-ming Poo,^1,3 and Xiao-bing Yuan¹

¹Institute of Neuroscience, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, and ²Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China, and ³Division of Neurobiology, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200

Cytoplasmic Ca²⁺ elevation and changes in Rho GTPase activity are both known to mediate axon guidance by extracellular factors, but the causal relationship between these two events has been unclear. Here we show that direct elevation of cytoplasmic Ca²⁺ by extracellular application of a low concentration of ryanodine, which activated Ca²⁺ release from intracellular stores, upregulated Cdc42/Rac, but downregulated RhoA, in cultured cerebellar granule cells and human embryonic kidney 293T cells. Chemoattractive turning of the growth cone triggered by a gradient of ryanodine was blocked by overexpression of mutant forms of Cdc42 but not of RhoA in Xenopus spinal cord neurons. Furthermore, Ca²⁺-induced GTPase activity correlated with activation of protein kinase C and required a basal activity of Ca²⁺/calmodulin-dependent protein kinase II. Thus, Rho GTPases may mediate axon guidance by linking upstream Ca²⁺ signals triggered by guidance factors to downstream cytoskeletal rearrangements.

Key words: axon guidance; growth cone; Rho GTPases; calcium; PKC; CaMKII

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Received Aug 26, 2004; revised January 11, 2005; accepted January 16, 2005.

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