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The Journal of Neuroscience, October 4, 2006, 26(40):10110-10119; doi:10.1523/JNEUROSCI.2158-06.2006

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Development/Plasticity/Repair
Cdc42 and Rac1 Signaling Are Both Required for and Act Synergistically in the Correct Formation of Myelin Sheaths in the CNS

Tina Thurnherr,^1 * Yves Benninger,^1 * Xunwei Wu,² Anna Chrostek,³ Sven M. Krause,¹ Klaus-Armin Nave,⁴ Robin J. M. Franklin,⁵ Cord Brakebusch,² Ueli Suter,¹ and João B. Relvas¹

¹Institute for Cell Biology, Department of Biology, Federal Institute of Technology (ETH) Zurich, CH-8093 Zurich, Switzerland, ²Department of Molecular Pathology, University of Copenhagen, 2100 Copenhagen, Denmark, ³Department of Molecular Medicine, Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany, ⁴Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Goettingen, Germany, and ⁵Cambridge Centre for Brain Repair and Neuroregeneration Laboratory, Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, United Kingdom

Correspondence should be addressed to João B. Relvas, Institute for Cell Biology, Department of Biology, Federal Institute of Technology (ETH) Zurich, CH-8093 Zurich, Switzerland. Email: joao.relvas{at}cell.biol.ethz.ch

The formation of myelin sheaths in the CNS is the result of a complex series of events involving oligodendrocyte progenitor cell (OPC) proliferation, directed migration, and the morphological changes associated with axon ensheathment and myelination. To examine the role of Rho GTPases in oligodendrocyte biology, we have used a conditional tissue-specific gene-targeting approach. Ablation of Cdc42 in cells of the oligodendrocyte lineage did not affect OPC proliferation, directed migration, or in vitro differentiation, but it led to the formation of a unique and stage-specific myelination phenotype. This was characterized by the extraordinary enlargement of the inner tongue of the oligodendrocyte process and concomitant formation of a myelin outfolding as a result of abnormal accumulation of cytoplasm in this region. Ablation of Rac1 also resulted in the abnormal accumulation of cytoplasm in the inner tongue of the oligodendrocyte process, and we provide genetic evidence that rac1 synergizes with cdc42 in a gene dosage-dependent way to regulate myelination.

Key words: cdc42; rac1; Rho GTPase; myelin; CNS; oligodendrocyte

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Received May 22, 2006; revised Aug. 16, 2006; accepted Aug. 20, 2006.

Correspondence should be addressed to João B. Relvas, Institute for Cell Biology, Department of Biology, Federal Institute of Technology (ETH) Zurich, CH-8093 Zurich, Switzerland. Email: joao.relvas{at}cell.biol.ethz.ch

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