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The Journal of Neuroscience, November 28, 2007, 27(48):13117-13129; doi:10.1523/JNEUROSCI.3322-07.2007

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Development/Plasticity/Repair
Cdc42 Regulates Cofilin during the Establishment of Neuronal Polarity

Boyan K. Garvalov,^1 * Kevin C. Flynn,^3 * Dorothee Neukirchen,¹ Liane Meyn,¹ Nicole Teusch,⁴ Xunwei Wu,² Cord Brakebusch,² James R. Bamburg,³ and Frank Bradke¹

¹Axonal Growth and Regeneration Group, Max Planck Institute of Neurobiology and ²Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany, ³Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523-1870, and ⁴Department of Molecular Biology and Biochemistry, Abbott GmbH and Company KG, 67061 Ludwigshafen, Germany

Correspondence should be addressed to Dr. Frank Bradke, Axonal Growth and Regeneration Group, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany. Email: fbradke{at}neuro.mpg.de

The establishment of polarity is an essential process in early neuronal development. Although a number of molecules controlling neuronal polarity have been identified, genetic evidence about their physiological roles in this process is mostly lacking. We analyzed the consequences of loss of Cdc42, a central regulator of polarity in multiple systems, on the polarization of mammalian neurons. Genetic ablation of Cdc42 in the brain led to multiple abnormalities, including striking defects in the formation of axonal tracts. Neurons from the Cdc42 null animals sprouted neurites but had a strongly suppressed ability to form axons both in vivo and in culture. This was accompanied by disrupted cytoskeletal organization, enlargement of the growth cones, and inhibition of filopodial dynamics. Axon formation in the knock-out neurons was rescued by manipulation of the actin cytoskeleton, indicating that the effects of Cdc42 ablation are exerted through modulation of actin dynamics. In addition, the knock-outs showed a specific increase in the phosphorylation (inactivation) of the Cdc42 effector cofilin. Furthermore, the active, nonphosphorylated form of cofilin was enriched in the axonal growth cones of wild-type, but not of mutant, neurons. Importantly, cofilin knockdown resulted in polarity defects quantitatively analogous to the ones seen after Cdc42 ablation. We conclude that Cdc42 is a key regulator of axon specification, and that cofilin is a physiological downstream effector of Cdc42 in this process.

Key words: Cdc42; cofilin; conditional knock-out mouse; hippocampal neurons; neuronal polarity; axon formation; filopodia

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Received July 22, 2007; revised Oct. 6, 2007; accepted Oct. 13, 2007.

Correspondence should be addressed to Dr. Frank Bradke, Axonal Growth and Regeneration Group, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany. Email: fbradke{at}neuro.mpg.de

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