Essential Role of B-Raf in Oligodendrocyte Maturation and Myelination During Postnatal Central Nervous System Development

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2008 Mar 12

PMID 18332218

Citations 45

Authors

Gergana Galabova-Kovacs

Federica Catalanotti

Dana Matzen

Gloria X Reyes

Jurgen Zezula

Ruth Herbst

Alcino Silva

Ingrid Walter

Manuela Baccarini

Affiliations

Soon will be listed here.

Abstract

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.

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