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Published online March 10, 2008
doi:10.1083/jcb.200709069
The Journal of Cell Biology, Vol. 180, No. 5, 947-955
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Galabova-Kovacs et al.
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Article

 Essential role of B-Raf in oligodendrocyte maturation and myelination during postnatal central nervous system development

Gergana Galabova-Kovacs1, Federica Catalanotti1, Dana Matzen1, Gloria X. Reyes1, Jürgen Zezula2, Ruth Herbst3, Alcino Silva4, Ingrid Walter5, and Manuela Baccarini1

1 Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria
2 Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, and 3 Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria
4 National Institute of Mental Health, Bethesda, MD 20892
5 Department of Histology and Embryology, University of Veterinary Medicine, 1210 Vienna, Austria

Correspondence to M. Baccarini: manuela.baccarini{at}univie.ac.at

Mutations in the extracellular signal-regulated kinase (ERK) pathway, particularly in the mitogen-activated protein kinase/ERK kinase (MEK) activator B-Raf, are associated with human tumorigenesis and genetic disorders. Hence, B-Raf is a prime target for molecule-based therapies, and understanding its essential biological functions is crucial for their success. B-Raf is expressed preferentially in cells of neuronal origin. Here, we show that in mice, conditional ablation of B-Raf in neuronal precursors leads to severe dysmyelination, defective oligodendrocyte differentiation, and reduced ERK activation in brain. Both B-Raf ablation and chemical inhibition of MEK impair oligodendrocyte differentiation in vitro. In glial cell cultures, we find B-Raf in a complex with MEK, Raf-1, and kinase suppressor of Ras. In B-Raf–deficient cells, more Raf-1 is recruited to MEK, yet MEK/ERK phosphorylation is impaired. These data define B-Raf as the rate-limiting MEK/ERK activator in oligodendrocyte differentiation and myelination and have implications for the design and use of Raf inhibitors.

F. Catalanotti and D. Matzen contributed equally to this paper.

Abbreviations used in this paper: CNS, central nervous system; ERK, extracellular signal-regulated kinase; KO, knockout; KSR, kinase suppressor of Ras; MBP, myelin basic protein; MEK, MAPK/ERK kinase; P, postnatal day; PDGFR{alpha}, PDGF receptor {alpha}; WT, wild type.


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